Principle of Animal Physiology (Christopher D. Moyes, Patricia Schulte) Principle of

Principles of Animal Physiology
Moyes Schulte
2e Principles of Animal Physiology
ISBN 978-1-29202-638-1
Christopher D. Moyes
Patricia M. Schulte
9 781292 026381 Second Edition

Principles of Animal Physiology
Christopher D. Moyes
Patricia M. Schulte
Second Edition
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P E A R S O N C U S T O M L I B R A R Y
Table of Contents
Glossary
Christopher D. Moyes/Patricia M. Schulte 1
1. Introduction to Physiological Principles
2. Chemistry, Biochemistry, and Cell Physiology
3. Cell Signaling and Endocrine Regulation
4. Neuron Structure and Function
5. Cellular Movement and Muscles
6. Sensory Systems
7. Functional Organization of Nervous Systems
8. Circulatory Systems
9. Respiratory Systems
10. Ion and Water Balance
11. Digestion
12. Locomotion
I
13. Thermal Physiology
14. Reproduction
Appendix: The International System of Units
Appendix: Logarithms
Appendix: Linear, Exponential, Power, and Allometric Functions
Index 743
II
action potential A relatively large- adrenal cortex See adrenal gland.
Glossary amplitude, rapid change in the
membrane potential of an excitable
adrenal gland A gland near the
kidney, which in mammals is
cell as a result of the opening and composed of an outermost layer (the
closing of voltage-gated ion channels; adrenal cortex) and an inner layer
A-band (or anisotropic band) The involved in transmitting signals (adrenal medulla).
region of a muscle sarcomere where across long distances in the nervous adrenal medulla See adrenal gland.
the thick filaments occur. system. adrenergic receptors Receptors for
absolute refractory period The period activation energy (Ea) The energetic the catecholamines norepinephrine
during and immediately following an barrier that must be reached before a and epinephrine.
action potential in which an excitable reactant can be transformed into a adrenoreceptors See adrenergic
cell cannot generate another action product. receptors.
potential, no matter how strong the activation gate One of the two gates aerobic Occurring in, or depending on,
stimulus. that open and close voltage-gated the presence of oxygen.
absolute temperature A measure of sodium channels (see also aerobic scope The ratio of the
temperature in kelvins, where 0 K inactivation gate). maximal aerobic metabolic rate to
(absolute zero) is the temperature at active site A region of an enzyme that the basal metabolic rate, typically in
which there is no atomic or binds the substrate and undergoes the range of 3–10.
molecular movement. 1 unit on the conformational changes to catalyze afferent Leading toward a region of
Kelvin scale equals 1° on the Celsius the reaction. interest (see also efferent).
scale. 0 K ⫽ ⫺273°C. active state The phase of a cross- afferent neuron A neuron that
acclimation A persistent but reversible bridge cycle in which myosin is conducts a signal from the periphery
change in a physiological function attached to actin and generating to an integrating center (see also
that occurs as a result of an force. sensory neuron).
alteration in an environmental active transport Protein-mediated affinity A measure of the degree of
parameter, such as temperature or movement of a substance across a attraction between a ligand and a
photoperiod. Acclimation usually membrane with the utilization of molecule that binds the ligand (see
occurs as a result of an experimental some form of energy. Primary active also Km).
manipulation (see also transport uses ATP. Secondary active affinity constant (or Ka) Reciprocal of
acclimatization). transport uses an electrochemical the dissociation constant.
acclimatization A reorganization of gradient (see also facilitated after-hyperpolarization A prolonged
physiological functions that occurs as diffusion, passive transport). hyperpolarization following an action
a result of complex environmental acuity, sensory The ability to resolve potential.
changes, such as season or altitude fine detail of a stimulus. aglomerular kidney A derived form of
(see also acclimation). acute response The rapid phase of kidney, with tubules that lack a
accommodation The process by which response to an external or internal glomerulus, found in many lineages
an eye changes its focal length. change in conditions, usually within of marine fish.
Accommodation allows the eye to seconds to minutes. agonist A substance that binds to a
produce a focused image of objects at adaptation Used in two contexts in receptor and initiates a signaling
different distances. physiology: (1) a change in the event. May include both the natural
acetyl CoA An activated form of genetic structure of a population as a endogenous ligand as well as
acetate that serves as the entry point result of natural selection; (2) a pharmaceutical agents that mimic the
for carbon into the TCA cycle. reversible change in a physiological natural substance.
acetylcholine A neurotransmitter found parameter that provides a beneficial albumen A protein found in eggs that
in most animal species in many types response to an environmental cushions the embryo.
of neurons, including motor neurons change. Evolutionary and albumin A binding globulin (carrier
and the autonomic ganglia of comparative physiologists prefer to protein) that is one of the primary
vertebrates. use only the first definition. proteins of vertebrate plasma; makes
acetylcholinesterase An enzyme that adaptation, sensory See receptor a major contribution to blood osmotic
catalyzes the breakdown of adaptation. pressure.
acetylcholine into choline and adenine A purine nitrogenous base aldosterone Mineralocorticoid
acetate. component of nucleotides, including hormone secreted by the adrenal
acid A chemical that donates a proton nucleic acids. cortex. Its main function is to alter
(see also base). adenosine A nucleoside composed of the levels of Na⫹ and K⫹ in the urine,
acidosis A decrease in pH arising adenine and the sugar deoxyribose, secondarily affecting water transport.
through respiration (respiratory important as a signaling molecule. alkaloids A large group of compounds
acidosis) or metabolism (metabolic adenosine diphosphate (ADP) A derived from plants that have
acidosis). nucleotide composed of the pharmacological effects in animals.
acrosomal reaction The exocytosis of nucleoside adenine with two alkalosis The condition of being
the enzyme-laden acrosomal vesicle phosphate groups, with a single high- alkaline (see also metabolic alkalosis,
of sperm in response to contact with energy phosphodiester bond. respiratory alkalosis).
the ovum. adenosine triphosphate (ATP) A allantoic membrane One of four
acrosome A vesicle in sperm that nucleotide composed of the membranes in an amniote egg.
contains digestive enzymes that nucleoside adenine with three allantoin An intermediate in
enable the sperm to penetrate the phosphate groups, with two high- nucleotide breakdown and uric acid
outer layers of an ovum. energy phosphodiester bonds. synthesis; an important form of
actin G-actin is a monomeric protein adenylate cyclase (adenylyl cyclase) nitrogenous waste for some animals.
that can be polymerized to construct The enzyme that converts ATP to allatostatin A neuropeptide hormone
filamentous actin (F-actin). Actin is cyclic AMP. in arthropods that inhibits the corpus
the basis of both cytoskeletal adhesion plaque A membrane protein allatum from secreting juvenile
microfilaments (composed of the ␣- complex that anchors thin filaments hormone.
actin isoform of G-actin) and skeletal to the membrane. allatotropin A neuropeptide hormone
thin filaments (composed of the ␤- adipose tissue A tissue composed of in arthropods that stimulates the
actin isoform of G-actin) (see also fat cells (adipocytes) that produce corpus allatum to secrete juvenile
myosin). and store lipid. hormone.
actinomyosin The combination of actin ADP See adenosine diphosphate. alleles Different forms of the same
and myosin, joined by a cross-bridge. protein that are encoded by the same
From Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
Copyright © 2008 by Pearson Education, Inc. Published by Pearson Benjamin Cummings. All rights reserved.
1
GLOSSARY
gene but differ slightly in primary amylase An enzyme that breaks down anus The sphincter through which
sequence. starch (amylose, amylopectin). feces exit the gastrointestinal tract.
allometry (or allometric scaling) The anabolic pathways (or anabolism) aorta The major artery exiting the
pattern seen when comparing Metabolic reactions or pathways that heart.
structural or functional parameters in build complex molecules from aortic body A sensory structure
relation to body size. simpler molecules. located in the vertebrate aorta that
allosteric regulator A molecule that anadromous The life history strategy contains baroreceptors and
binds an enzyme at a site distinct of an animal living most of its life in chemoreceptors.
from the substrate binding site to the sea, then returning to apical The end of a structure opposite
regulate activity. freshwater to reproduce (see also the base.
allosteric site A region of an enzyme, catadromous). apical membrane The end of the cell
distinct from the active site, that anaerobic Without oxygen. Pertains to furthest from the basolateral
binds a molecule other than the an environment without oxygen, or a membrane; the membrane oriented
substrate or product, triggering a pathway that occurs in the absence of away from the circulatory system.
structural change that alters the oxygen (see also aerobic). apnea A period without breathing.
catalytic properties of the enzyme. anaplerotic pathway (or anaplerosis) apocrine A type of secretion whereby
allozyme An allelic variant of an A metabolic reaction that replenishes the cell sheds the apical region of
enzyme. intermediates of pathways. plasma membrane as part of a
␣ adrenergic receptor A G-protein- anastomosis A convergence of two or signaling pathway.
linked cell membrane receptor that more branches of a tubular structure; apoenzyme The proteinaceous part of
binds norepinephrine preferentially, e.g., a direct connection between two an enzyme.
with a lower affinity for epinephrine. arteries in the circulatory system. aquaporin A large tetrameric channel
␣-helix A secondary structure of anatomical dead space The portion of that allows the passage of water
protein or DNA in which the a respiratory structure that cannot through the plasma membrane.
molecule twists in a characteristic participate in gas exchange (e.g., the arginine phosphate A major
pattern, with structure stabilized by trachea and bronchi). phosphagen in invertebrates, which
hydrogen bonds between adjacent androgens Steroid hormones performs the same role as creatine
regions. structurally related to testosterone phosphate in vertebrates.
alternative splicing One of the that control masculine features. aromatase See cytochrome P450
processes that can result in different anemia A condition in which the aromatase.
mRNAs being coded by a single gene. number of erythrocytes or Arrhenius plot A curve relating
Different exons of the gene are hemoglobin in the blood is lower temperature to activity, enabling the
spliced out in each mRNA, resulting than normal. calculation of activation energy.
in a number of possible angiogenesis Synthesis of new blood arteriole A small branch of the arterial
combinations. vessels, often in response to local network immediately preceding a
alveoli (singular: alveolus) The site of hypoxia. capillary bed (see venule).
gas exchange in mammalian lungs. angiotensin A peptide hormone that artery A large blood vessel carrying
ambient External or environmental controls blood pressure. Its precursor blood away from the heart.
conditions, such as ambient is angiotensinogen, which is cleaved asexual reproduction Production of
temperature. by renin to form angiotensin I. This offspring without the fertilization of
amine A class of molecules based on decapeptide is cleaved to the final an ovum by a sperm (see also
ammonia, with a side group form, angiotensin II, an octapeptide. automictic parthenogenesis).
substituting for at least one N atom. angiotensin-converting enzyme (ACE) assimilation Conversion of dietary
amino acid Organic molecules with at An enzyme that converts angiotensin nutrients into metabolizable fuels.
least one amino group and at least I to angiotensin II. assimilation efficiency Proportion of
one carboxyl group. The amino acids anion An ion with a negative charge. dietary nutrients successfully
that are used to build proteins are ␣- anoxic See anaerobic. assimilated.
amino acids. antagonist A substance that binds to a astrocytes Vertebrate glial cells that
ammonia A general term that includes receptor but does not stimulate a help to support and regulate the
both NH3 and NH4⫹ (ammonium), signaling event. Antagonists interfere action of neurons in the central
potent neurotoxins. with the binding of the natural nervous system.
ammoniotele An animal with an ligand. asynchronous muscle A muscle in
excretory strategy in which more than antagonistic controls For a given step which a single neuronal stimulation
half of the nitrogen is excreted as or pathway, sets of controls that exert causes multiple cycles of contraction
ammonia (see also ureotele, uricotele). opposing effects. and relaxation.
amniote Vertebrates with an amnion, antagonistic muscle A muscle that ATP See adenosine triphosphate.
namely reptiles, birds, and opposes the movement of another ATP-binding cassette A common
mammals. muscle. structural motif found in diverse
amphibolic pathway A metabolic anterior pituitary gland The anterior proteins that binds ATP.
pathway that both synthesizes lobe of the pituitary gland of ATPase A class of proteins, including
(catabolic) and degrades (anabolic) vertebrates, also called the enzymes and transporters, that
metabolites. adenohypophysis; secretes tropic couples ATP hydrolysis to a
amphipathic A molecule with both hormones. mechanical or chemical process.
hydrophobic and hydrophilic parts. antidiuretic A substance that induces ATPS Standardized reference condition
amplification An exponential increase a reduction in urine volume. for measuring gas volumes: ambient
in activity from one step of a pathway antifreeze protein A protein that temperature, pressure, and saturated
to the next; typically used in the disrupts the growth of ice crystals, with water.
context of signal transduction allowing an organism to survive atresia The programmed cell death
pathways. subzero temperatures. (apoptosis) of follicles other than the
ampullae of Lorenzini Polymodal antigen A substance, usually a protein, dominant follicle that matures during
receptors that detect both electrical that induces the formation of an the ovulatory cycle.
and mechanical stimuli; found on the antibody that can bind the antigen. atrial natriuretic peptide (ANP) A
nose of sharks. antiport (or exchanger) A transport peptide hormone produced in the
amygdala A part of the limbic system protein that exchanges one ion (or heart that exerts effects on ion and
of the vertebrate brain that is molecule) for another ion (or water balance that tend to reduce
involved in emotional responses such molecule) on the opposite side of a blood pressure. It increases urine
as fear and anger. membrane. volume and Na⫹ excretion.
2
GLOSSARY
atrioventricular node (AV node) Part axoneme The microtubule-based taurine; assist in emulsification of
of the conducting pathways of the structure that underlies flagella and lipid within the small intestine.
mammalian heart; delays conduction cilia. binocular vision The ability to
of the electrical signal between the axosomatic synapse A synapse formed compare the images coming from two
atrium and ventricles. between the axon terminal of one eyes to produce three-dimensional
atrium (plural: atria) One of the neuron and the soma (cell body) of perception.
chambers of a heart. Blood moves another neuron. biogenic amine A class of
from the atrium to the ventricle. neurotransmitters derived from
atrophy Loss of tissue mass as a result baroreceptor A receptor that senses amino acids including the
of dying cells; often seen with pressure (by sensing the resulting catecholamines and dopamine.
locomotor muscle in response to stretch on the cell membrane). bioluminescence The production of
prolonged periods of inactivity. basal lamina The extracellular matrix light by living organisms.
August Krogh principle Principle that underlying a sheet of epithelial cells; bipolar neuron A neuron with two
for every biological problem, there is part of the connective tissue formed main processes leading from the cell
an organism on which it can most largely by fibroblasts. body, one of which conveys signals
conveniently be studied. basal metabolic rate (BMR) The toward the cell body, and one of
autocrine A type of cell signaling in metabolic rate of an homeothermic which conveys signals away from the
which a single cell signals another animal at rest, at a thermal neutral cell body.
cell of the same type, including itself. temperature, and post-absorptive blastocoel The cavity formed by the
automictic parthenogenesis (see also resting metabolic rate, inpouching of the blastocyst, which
Production of offspring by a female in standard metabolic rate). eventually forms the alimentary
which the second polar body fuses basal nuclei Interconnected groups of canal.
with the ovum to produce a diploid gray matter within the mammalian blastocyst The hollow sphere of cells
offspring. brain. formed early in embryonic
autonomic division (of the nervous base A molecule that accepts a proton, development.
system) See autonomic nervous or otherwise causes a reduction in bleaching The fading of a
system. proton concentration through effects photopigment following absorption of
autonomic ganglia Ganglia of the on the dissociation of water. energy from photons. In the case of
vertebrate peripheral nervous system. basement membrane See also basal the retinal-opsin complex, absorption
autonomic nervous system Part of the lamina. of energy from light causes retinal to
vertebrate peripheral nervous system basilar membrane The location of the dissociate from opsin. Opsin is not
that controls largely involuntary auditory hair cells in the mammalian pigmented, and thus the
functions such as heart rate. It is cochlea. photopigment loses its color.
divided into three main branches: the basophil A type of white blood cell that blood The circulatory fluid in animals
sympathetic, parasympathetic, and releases histamine; involved in the with closed circulatory systems.
enteric nervous systems. vertebrate immune response. Generally contains proteins, ions,
autotrophy An organism that batch reactor A chemical reactor in organic molecules, and various cell
synthesizes its own nutrients from which nutrients enter and exit types.
inorganic material, using the energy through the same opening; nutrients blood-brain barrier A specialized
of the sun (photoautotroph) or are retained in the reactor and protective barrier made up of glial
inorganic reactions digested; the undigested material is cells that separates the circulatory
(chemoautotrophs). then expelled, and replaced by system and the central nervous
Avogadro’s number The number of another batch of nutrients to be system in vertebrates.
molecules in a mole (6.02252 × 1023). processed. blood vessels Tubes that carry blood
axoaxonic synapse A synapse formed behavioral thermoregulation The use through an animal’s body.
between the axon terminal of one of behavior to control the body blubber Subcutaneous lipid deposits of
neuron and the axon of another temperature of a poikilotherm, or to marine mammals, which provide
neuron (at any point along its length). reduce the costs of thermoregulation thermal insulation.
axodendritic synapse A synapse for a homeotherm. Bohr effect A change in hemoglobin
formed between the axon terminal of ␤-oxidation Pathway of fatty acid oxygen affinity due to a change in
one neuron and the dendrite of catabolism that produces acetyl CoA pH.
another neuron. and reducing equivalents. bolus A volume of material introduced
axon A projection of the cell body of a ␤-sheet Protein folding pattern in into a flow-through system that
neuron that is involved in carrying which stretches of amino acids are moves through the system as a unit,
information, usually in the form of aligned along another amino acid with some dispersion along the way;
action potentials, from the cell body stretch. This secondary structure is often used in the context of a bolus of
to the axon terminal. stabilized by hydrogen bonds. food moving through the
axon hillock The junction between the bilateral symmetry A body form in gastrointestinal tract.
cell body and axon of a neuron. In which the body can be divided by a bombesin A hormone that regulates
many neurons, the axon hillock is the single plane such that the right and release of gastrointestinal hormones
site of action potential initiation, left sides are approximate mirror and control of gastrointestinal
acting as the trigger zone for the images. motility in vertebrates.
neuron. bile A thick, yellow-green fluid bond energy The energy required to
axon terminal The distal end of an composed of salts, pigments, and form a chemical bond.
axon that forms a synapse with an lipids produced by the liver and stored bone In vertebrates, a solid structure
effector cell or neuron. by the gallbladder; when released into composed of mineralized
axon varicosity A type of synapse in the small intestine it neutralizes extracellular matrix of osteocytes;
which the presynaptic cell releases gastric acid and aids in the digestion with cartilage and tendon, it
neurotransmitter at a series of of nutrients, particularly lipids. constitutes the skeleton.
swellings along the axon. bile duct The connection between the book gills The respiratory surfaces of
axonal transport Cytoskeletal- liver and the small intestine. water-breathing chelicerates such as
mediated movement of organelles bile pigments Nondigestible horseshoe crabs.
and vesicles along the length of an breakdown products of porphyrins, book lungs The respiratory surfaces of
axon. including the hemes found in some air-breathing chelicerates such
axonemal dyneins Motor proteins that hemoglobin and cytochromes. as spiders and scorpions.
enable the sliding of microtubules in bile salts Cholic acid conjugated with boundary layer The region of a
cilia and flagella. amino acids, primarily glycine and solution that is in direct contact or
3
GLOSSARY
otherwise influenced by a surface; cable properties The electrical carotid rete A network of blood
often called an unstirred layer. properties of axons. vessels that cools the brain.
Bowman’s capsule A cup-shaped calcium-induced calcium release A carrier protein (or binding protein;
expansion of the vertebrate kidney mode of muscle activation where binding globulin) Blood proteins
tubule; surrounds the glomerulus. calcium crossing the sarcolemma that help to transport hydrophobic
brackish water Water that is through a Ca2⫹ channel causes a Ca2⫹ molecules (such as steroid hormones)
intermediate between freshwater and channel in the sarcoplasmic reticulum in the blood.
seawater; typically found in estuaries, to open. carrier-mediated transport All forms
salt marshes, or isolated ponds. caldesmon A calcium-binding protein of transport across membranes that
bradycardia A heart rate that is important in the regulation of smooth require a protein.
slower than normal. muscle contractility. cartilage In vertebrates, a semisolid
brain A large grouping of ganglia that calmodulin A calcium-sensing protein structure composed of the
act as a sophisticated integrating involved in many signal transduction extracellular matrix of chondrocytes:
center. Typically located toward the pathways. the major component of the skeleton
anterior end of the body in the caloric deficit The condition in which of chondrichthians but important in
cephalic (head) region. energy derived from the diet is less other vertebrates as a cushion
brainstem A portion of the vertebrate than energetic expenditure, resulting between joints.
central nervous system that connects in net loss of energy by the animal. catabolic pathway (or catabolism) A
the cerebrum of the brain to the calorie A unit of heat equal to 4.2 metabolic pathway that degrades
spinal cord; contains the pons and joules; nutritional literature may macromolecules into smaller
medulla, the sites of the respiratory refer to the unit Calorie, which is molecules.
and cardiovascular control centers. equivalent to 1000 calories. The unit catadromous A life history strategy of
branchial Relating to gills. of heat required to raise 1 g of water fish (e.g., eels) in which the adult
bronchi (singular: bronchus) Airways at 1 atm by 1°C. migrates from freshwater to seawater
of vertebrate lungs leading from the calorimetry The measurement of heat to breed (see also anadromous).
trachea to the bronchioles. production as an index of metabolic catalysis The progression of a
bronchioles The smallest branches of rate. chemical reaction that proceeds with
the airways of mammalian lungs; calsequestrin A calcium-binding the help of a catalyst.
lead to the terminal alveoli. protein that allows a muscle to catalyst A molecule that accelerates
brood spot A well-vascularized, concentrate Ca2⫹ within the chemical reactions but is not changed
featherless region on the underside of sarcoplasmic reticulum. in the process.
birds that is important for warming cAMP (cyclic AMP) A second catalytic rate constant (kcat) The
developing eggs. messenger produced by adenylate number of reactions catalyzed by a
brown adipose tissue Also known as cyclase; most important action is the single molecule of enzyme per second.
brown fat, a thermogenic tissue stimulation of protein kinase A. catecholamines The biogenic amines
found in many small mammals, often capacitation A maturation step epinephrine and norepinephrine.
in the back or neck region. Abundant experienced by sperm after they cation An ion with a positive charge.
mitochondria in the brown encounter fluids from the female caudal A location near the posterior of
adipocytes possess thermogenin, a reproductive tract. an animal.
protein that uncouples oxidative capillary The smallest of the blood cecum A blind-ended sac that carries
phosphorylation to enhance heat vessels in a closed circulatory system; out digestive reactions in the
production. the site of exchange of materials with gastrointestinal tract.
brush border Abundant microvilli on the tissues. cell body See soma.
epithelial cells in the gastrointestinal carbaminohemoglobin Hemoglobin cell membrane See plasma membrane.
tract, giving the tissue a microscopic bound to carbon dioxide. cellular membranes A general term
brushlike appearance. carbohydrate A group of organic that refers to the collection of
BTPS Standardized reference molecules that share a membranes within a cell, including
conditions for measuring gas preponderance of hydroxyl groups plasma membrane and organelle
volumes: body temperature, (see also disaccharide, membranes.
atmospheric pressure, and saturated monosaccharide, polysaccharide). cellulose A glucose polymer that
with water. carbonic anhydrase (CA) An enzyme serves a structural role in plants;
buccal cavity Mouth cavity. that catalyzes the conversion of indigestible by most animals without
buffer Chemicals which, when placed carbon dioxide and water to the assistance of symbionts.
in solution, confer on the solution an bicarbonate and protons. central chemoreceptors A group of
ability to resist changes in pH when carboxyhemoglobin Hemoglobin chemoreceptors located in the
acid or base is added. bound to carbon monoxide. medulla of vertebrate brains.
bulbourethral gland A mucus- cardiac muscle A form of striated central lacteal A small, saclike vessel
secreting accessory gland of the male muscle that occurs in the heart. in an intestinal villus; collects lipids
reproductive tract. cardiac output The volume of blood that cross the intestinal epithelium.
bulbus arteriosus The outflow pumped by the heart per unit time; central nervous system The portion of
tract of the heart in bony fishes; the product of heart rate and stroke the nervous system containing the
nonmuscular and elastic (see also volume. primary integrating centers. In
conus arteriosus). cardiomyocyte A muscle cell found in vertebrates it consists of the brain
bulk flow The movement of a fluid as a the heart. and spinal cord. In invertebrates, it
result of a pressure or temperature cardiovascular control center A consists of the brain, the major
gradient. region of the brain within the ganglia, and the connecting
bulk phase (or bulk solution) The medulla oblongata that is involved in commissures.
volume of solution that is beyond the regulating heart rate and blood central pattern generator A group of
influence of the surfaces (see also pressure. neurons located in the central
boundary layer). cardiovascular system An alternate nervous system that produce a
bundle of His One of the conducting term for the circulatory system of rhythmic neural output.
pathways of the mammalian heart. animals such as vertebrates. Consists cephalic Toward the anterior end of an
burst exercise High-intensity of the heart, blood, and blood vessels. animal.
exercise powered by glycolytic carotid body A structure located in the cephalization An evolutionary trend
muscle fibers; can continue for only carotid artery leading to the head of toward the centralization of nervous
short periods, until glycogen stores vertebrates; contains baroreceptors and sensory functions at the anterior
are exhausted. and chemoreceptors. end of the body (in the head).
4
GLOSSARY
cerebellum A part of the vertebrate cholesterol A steroid compound cloaca The distal portion of the
hindbrain that is involved in produced from isoprene units; hindgut in some fishes, amphibians,
maintaining balance and present in cellular membranes and birds, and reptiles; in these species
coordinating voluntary muscle acts as a precursor for steroid both excretory and reproductive
movement. hormones. products are emitted into the cloaca,
cerebral cortex Outer surface of the cholinergic receptor A receptor that and leave the body via a single
vertebrate brain. binds the signaling molecule opening.
cerebral hemispheres Paired acetylcholine. Cholinergic receptors clonal reproduction A form of asexual
structures of the cerebrum (part of can be divided into nicotinic and reproduction whereby an animal
the vertebrate forebrain). The muscarinic receptors. produces a genotypically identical
cerebral hemispheres are the most chondrocytes The cells that produce offspring (a clone).
obvious structures of a mammalian cartilage. closed circulatory system A
brain. chorion The outer protein layer of an circulatory system in which the blood
cerebral ventricle See ventricle. insect egg; the outer membrane of a remains within a series of enclosed
cerebrospinal fluid (CSF) A fluid vertebrate ovum. blood vessels throughout the
contained within the meninges that chorionic gonadotropin (CG) A third circulation.
surrounds the brain and spinal cord gonadotropin of vertebrates, cochlea Spiral structure in the inner
of vertebrates. produced by the placenta but only in ear of mammals; contains the organs
cerebrum The largest part of the primates. of hearing. Less elaborate, but
mammalian forebrain. chromaffin cells Cells that secrete the present in birds as the cochlear duct.
cGMP See cyclic GMP. hormone epinephrine (adrenaline). In Derived from the lagena of other
cGMP phosphodiesterase An enzyme mammals they are located in the vertebrates.
that cleaves cGMP, producing GMP. compact adrenal medulla, but in coelom The internal compartment of
channel A transport protein that other vertebrates they are more coelomate animals that forms
facilitates the movement of specific dispersed. between two layers of mesoderm.
ions or molecules across a cellular chromophore A molecule that is able coenzymes Organic cofactors.
membrane down an electrochemical to absorb light. In photoreception, coenzyme A A coenzyme derived from
gradient. the chromophore absorbs the energy the vitamin pantothenic acid.
chaperone protein See molecular from incoming photons and cofactors Nonprotein components of
chaperone. undergoes a conformational change, enzymes, including metals,
chemical energy The energy which sends a signal to an associated coenzymes, and prosthetic groups.
associated with the reorganization G protein, in the first step of visual coitus Sexual intercourse.
of the chemical structure of a phototransduction. collagen A trimeric protein found in
molecule. chromosome A single, contiguous extracellular matrix. It interacts with
chemical gradient An area across polymer of DNA found within the other collagen molecules to form
which the concentration of a genome. rigid fibers or durable sheets.
chemical differs, often across a chylomicron A large lipoprotein collecting duct The tube that receives
membrane. complex that carries lipid from the the fluid from the distal tubules of the
chemical synapse A junction between digestive tract through the nephron and empties into the minor
a neuron and another cell in which circulation to processing and target calyx of the kidney.
the signal is transmitted across the tissues. colligative properties Four properties
synapse in the form of a cilia (singular: cilium) Microtubule- of a solute that are due solely to the
neurotransmitter. based extensions from a cell that concentration of solutes, and not
chemoautotroph An organism that move in a wavelike pattern. their chemical nature.
uses inorganic chemical energy to ciliary body A part of the vertebrate colloidal osmotic pressure See oncotic
convert organic sources of carbon eye that secretes the aqueous humor. pressure.
and nitrogen into biosynthetic ciliary muscle The muscle that colon A region of the large intestine
building blocks. controls the shape of the lens of the primarily responsible for water
chemokinetic An increase in vertebrate eye; involved in producing resorption.
nondirectional movement in response a focused image. compatible solute A solute that, at
to the detection of a chemical. ciliary photoreceptors One of two high concentration, does not disrupt
chemoreceptor Used to describe either types of animal photoreceptor cells. protein structure or enzyme kinetics.
a cell containing chemoreceptive Vertebrate photoreceptors belong to competitive inhibition A mode of
proteins, or the proteins themselves. this class (see also rhabdomeric enzyme inhibition in which a
Chemicals such as hormones, photoreceptors). molecule competes with the substrate
odorants, and tastants bind circadian rhythm Regular changes in for the active site on the enzyme;
specifically to chemoreceptor gene expression, biochemistry, competitive inhibitors have the effect
proteins, altering their conformation physiology, and behavior that cycle of reducing the apparent substrate
and causing a signal within the with a period of approximately 24 affinity without affecting Vmax.
chemoreceptor cell. hours. Endogenous circadian compliance A measure of the ability of
chemotaxic Movement toward higher rhythms persist even in constant a hollow structure (e.g., blood vessel,
concentrations of a chemical. darkness. lung) to stretch in response to an
chief cell The secretory cells of the circulatory system A group of organs applied pressure.
gastric epithelium that release and tissues involved in moving fluids compound eye A type of eye seen in
pepsin. through the body; consists of one or arthropods; consists of many
chitin A polymer of N-acetyl more pumping structures and a individual photoreceptive structures.
glucosamine used by arthropods to series of tubes or other spaces conduction Transfer of heat from one
construct the exoskeleton. through which fluid can move. object to another object or a fluid.
chloride cell An ion-pumping cell of citric acid cycle See tricarboxylic acid cone A type of vertebrate
fish gill epithelium (also called a cycle. photoreceptor cell (see also rod).
mitochondria-rich cell). clathrin A triskelion-shaped (three- Cones are typically responsible for
chloride shift The exchange of armed) protein that coats some types color vision in bright light.
chloride and bicarbonate across the of vesicles; vesicle formation begins conformer A strategy whereby the
erythrocyte membrane. with a clathrin-coated pit, which physicochemical properties of an
chlorocruorin A type of hemoglobin enlarges to form a clathrin-coated animal (e.g., temperature and
found in some annelids; known as vesicle. osmolarity) parallel those of the
the green hemoglobins. clearance See renal clearance. environment.
5
GLOSSARY
conservation of Km A pattern in which purely by passive means; e.g., heat cytokines Hormones that trigger cell
enzymes from different animals exchange in a rete. division.
share a similar Km when assayed countercurrent multiplier A structure cytoplasm Soluble and particulate
under conditions that approximate in which two fluids flow in opposite interior of a cell, excluding the
those that occur in the animal. directions on either side of an nucleus.
constitutive Usually describes a gene exchange surface, allowing high- cytosine A nucleoside composed of
for a protein that is expressed at efficiency exchange of materials by cytidine and a ribose sugar.
near-constant levels regardless of active means; e.g., ion concentration cytoskeleton Intracellular protein
conditions; can be applied to the in the loop of Henle. network of microtubules,
protein itself, as in “a constitutive covalent bonds Strong chemical bonds microfilaments, and intermediate
enzyme.” involving the sharing of electrons filaments.
continuous-flow stirred-tank reactor between two atoms. cytosol Fluid portion of the cytoplasm,
In gut reactor theory, a type of gut in covalent modification Alteration of a also known as intracellular fluid.
which nutrients flow into the gut macromolecule by the addition (or
where they are mixed with gut removal) of another molecule by Dalton’s law of partial pressures The
contents, and simultaneously the gut forming (or breaking) a covalent total pressure of a gas mixture is the
expels fluids that consist of partially bond; e.g., glycosylation, methylation, sum of the partial pressures of the
degraded nutrients. acetylation, and phosphorylation. constituent gases.
conus arteriosus The outflow tract of cranial nerves A group of vertebrate dead space The portion of the
the heart ventricle in elasmobranchs, nerves that originate in the brain. respiratory system containing gas
lungfish, and amphibians; muscular Vertebrates have 12 or 13 pairs of that does not participate in gas
and valved (see also bulbus cranial nerves depending on the exchange; the sum of the anatomical
arteriosus). species. and physiological dead spaces.
convection Fluid circulation driven by creatine phosphate A high-energy deamination Removal of an amino
temperature gradients; a special case phosphate compound used to store group from a molecule, usually an
of bulk flow. energy and to facilitate its transfer amino acid.
convergence A pattern in a neural from the sites of energy production defecation The expulsion of feces.
pathway in which multiple (mitochondria) to the sites of dehydrogenase A class of enzymes
presynaptic neurons form synapses utilization, such as myofibrils. that involves an exchange of
with a single postsynaptic neuron. cristae The highly convoluted inner electrons between a substrate and
cooperativity A phenomenon membrane of mitochondria. product.
demonstrated by multimeric proteins critical thermal maximum The delayed implantation A reproductive
in which binding of a ligand to one highest environmental temperature strategy in which a fertilized ovum
protein subunit increases the tolerated by an animal. fails to implant in the uterus, thereby
likelihood of binding to other crop milk Produced by some birds, a delaying embryonic growth until
subunits. Seen in vertebrate blood regurgitated slurry of nutrients external conditions are favorable.
hemoglobins. arising from ingested material denature The loss of three-
cornea The clear outer surface of an augmented by secretions. dimensional structure (unfolding) of a
eye. The cornea of an insect cross-bridge The linkage of a myosin complex macromolecule, such as
ommatidium and a vertebrate eye are head to an actin subunit; an protein or nucleic acid.
analogous structures, but they are not essential step in actinomyosin dendrites The branching extensions of
homologous. mechanoenzyme activity. a neuronal cell body that carry
coronary artery Artery that supplies crosscurrent exchanger An exchanger signals toward the cell body.
blood to the heart in vertebrates. in which the flow of the respiratory dendritic A tree-like pattern of
corpus allatum (plural: corpora allata) medium is at an angle to the flow of branching.
A paired neurohemal organ in blood through the exchange surface; dendrodendritic synapse A synapse
arthropods that secretes juvenile seen in bird lungs. formed between the dendrites of two
hormone. crypt of Lieberkühn A pit at the base neurons.
corpus callosum A thick band of axons of intestinal villi. deoxyhemoglobin Hemoglobin that is
that connects the right and left cryptobiosis A dormant state in which not bound to oxygen.
hemispheres of the vertebrate brain. an animal experiences a severe (but deoxyribonucleic acid See DNA.
corpus cardiacum (plural: corpora reversible) metabolic depression depolarization A change in the
cardiaca) A paired neurohemal during adverse conditions. membrane potential of a cell from its
organ in arthropods that secretes cutaneous respiration Gas exchange normally negative resting membrane
adipokinetic hormone. across the skin. potential to a more positive value; a
corpus luteum The remnants of a cuticle The outer layer of the relative increase in the positive
mammalian ovarian follicle that arthropod exoskeleton; composed of charge on the inside of the cell
grows in size and becomes an chitin and proteins. membrane.
endocrine organ that secretes cyclic AMP (cAMP) Cyclic adenosine depolarization-induced calcium release
hormones in support of embryonic monophosphate formed by the action A mode of muscle activation in which
development. of adenylate cyclase; a second calcium crossing the sarcolemma
cortex The surface or outer layer of an messenger that activates protein through a Ca2⫹ channel causes a
organ (e.g., the cortex of the kidney; kinase A. depolarization of the membrane,
the cerebral cortex; cortical bone). cyclic GMP (cGMP) Cyclic guanosine which directly opens a Ca2⫹ channel
cost of transport (COT) The energetic monophosphate formed by the action in the sarcoplasmic reticulum.
cost for an animal to cross a given of guanylate cyclase; a second desmosome A type of cell-cell junction
distance. messenger that activates protein common in epithelial tissues.
cotransporter See symport. kinase G. diabetes mellitus A metabolic
counteracting solutes Pairs of solutes cytochromes Metalloproteins produced condition involving defects in insulin
that act in conjunction to offset the from porphyrins that are central to secretion or signal transduction that
detrimental effects that would arise if many enzymatic reactions, including lead to abnormal regulation of blood
either solute were present alone. the mitochondrial electron transport glucose. There are two main types of
countercurrent exchanger A chain (cytochromes a, a3, b, c) and diabetes mellitus: insulin-dependent
structure in which two fluids flow in cytochrome P450 enzymes. (type 1) and non-insulin-dependent
opposite directions on either side of cytochrome P450 aromatase An (type 2).
an exchange surface, allowing high- enzyme in steroid metabolism that diacylglycerol (DAG, or diglyceride)
efficiency exchange of materials converts androgens to estrogens. A second messenger in the
6
GLOSSARY
phosphatidylinositol signaling distal A location furthest from a point can be discriminated by a sensory
system. of reference. Opposite of proximal. receptor.
diadromous A life history strategy of distal tubule The region of a dynein Motor protein that works in
fish that includes movement from vertebrate kidney tubule just before combination with microtubules,
freshwater to seawater to breed the collecting tubules. usually moving in the minus direction
(catadromous) or vice versa disulfide bridge A covalent bond (see also kinesin).
(anadromous). between two sulfhydryl groups, dynein arms The motor proteins that
diaphragm A sheetlike group of denoted as –S–S–; also known as a extend from microtubules in the
muscles that separates the thoracic disulfide bond. axoneme of cilia and flagella.
and abdominal cavities of mammals. diuresis The process of urine dyspnea The sensation of difficulty
diastole The portion of the cardiac formation. with breathing.
cycle in which the heart is relaxing. diuretic An agent that promotes urine
diastolic pressure The arterial blood formation. eccrine gland A type of exocrine gland
pressure during cardiac diastole. dive response A collection of characterized by a long coiled duct
diffusion The net movement of a physiological responses to forced that delivers secretions from the
molecule throughout the available diving in air-breathing animals. secretory region to the surface.
space from an area of high divergence A pattern in a neural ecdysis The periodic shedding of the
concentration to an area of low pathway in which a single exoskeleton of invertebrates
concentration. presynaptic neuron forms synapses (molting).
diffusion coefficient A parameter that with multiple postsynaptic neurons. eclosion The process whereby an adult
reflects the ability of an ion or diving bradycardia A reduction in insect emerges from its cocoon.
molecule to diffuse. heart rate as a result of submergence ectoderm The outermost of the
digastric stomach A two-compartment in air-breathing animals. primary germ layers in a developing
stomach found in ruminants; each of DNA (deoxyribonucleic acid) A embryo that eventually gives rise to
the two compartments is further polymer of nucleotides that acts as tissue such as the nervous system.
divided into two chambers. the genetic template. ectopic pacemaker A pacemaker in an
digestible energy The proportion of DNA microarray A high-throughput abnormal location.
ingested energy that can be further method of analyzing DNA or RNA. ectotherm An animal with body
processed, leaving only indigestible Donnan equilibrium The chemical temperature determined primarily by
material. equilibrium reached between two external factors, including but not
digestion The breakdown of nutrients solutions separated from each other limited to ambient temperature (see
in the gastrointestinal tract. by a membrane permeable to some also endotherm).
digestive enzymes Hydrolytic enzymes of the ions in the solutions. edema Excess accumulation of fluid in
secreted into the lumen of the dopamine A neurotransmitter a tissue.
gastrointestinal tract by the digestive (biogenic amine) produced in various effective refractory period The time
epithelium and accessory glands. regions of the vertebrate brain. period in which an excitable tissue
dihydropyridine receptor (DHPR) The dormancy A general term for cannot be stimulated due to changes
Ca2⫹ channel found in muscle plasma hypometabolic states accompanied in the membrane potential.
membrane, so named because of its by a reduction in activity (see also efferent Leading away from a
ability to bind members of the estivation, hibernation, and torpor). structure; e.g., efferent neurons carry
dihydropyridine class of drugs. dorsal horn A region of gray matter signals from the central nervous
dimer A combination of two within the spinal cord located on the system to the periphery; efferent
monomers, typically in the context of dorsal side. arterioles carry blood away from the
protein structure. A homodimer has dorsal root The dorsal of the two glomerulus of the kidney.
two identical monomers, and a branches of a vertebrate spinal nerve efferent neuron A neuron that
heterodimer has two dissimilar as it enters the spinal cord. Contains conducts impulses from an
monomers. afferent neurons. integrating center to an effector.
dipnoan A group of sarcopterygian fish dorsal root ganglion Clusters of efflux Movement of a substance
commonly called lungfish, most afferent cell bodies of neurons in the outward, usually in the context of
closely related to the fish ancestor of spinal nerves. Located adjacent to the movement out of a cell or tissue.
amphibians. spinal cord. eicosanoids A type of short-lived
dipole A molecule with both partial doubly labelled water An isotopic chemical signaling molecule.
positive (d⫹) and partial negative (d⫺) variant of water (H2O), where a less elasmobranch fish One of two groups
charges resulting from the common isotope is used for both 1H of cartilaginous fish, including skates,
asymmetrical distribution of (2H or 3H) and 16O (18O). Used to rays, and sharks. The other group of
electrons. measure field metabolic rate. cartilaginous fish is holocephalans
direct calorimetry Measurement of down-regulation A decrease in the (ratfish).
heat production; in the context of amount or activity of a protein or elastance A measure of how readily a
animal physiology, a measure of process; e.g., a decrease in receptor structure returns to its original shape
metabolic rate. number or activity on a target cell after having been stretched.
disaccharide A sugar composed of two (see also up-regulation). elastic recoil Movement as a result of
monosaccharides. drag A force that resists the forward the release of elastic storage energy.
discontinuous gas exchange A movement through a fluid through elastic storage energy Energy stored
ventilatory pattern seen in some interactions with the surface of an within a deformed object, which is
insects in which prolonged periods of object. released when the object regains its
apnea are followed by brief but rapid dual breather An animal that can relaxed configuration.
ventilation of the tracheal system. breathe either air or water. Also electrical gradient A charge gradient
dissociation constant (Kd) A measure called a bimodal breather. across a membrane arising from
of the tendency of a complex to duodenum The most proximal region unequal distribution of charged
dissociate into its components; of the small intestine, directly particles.
calculated as the ratio of the product following the stomach. electric organ A trans-differentiated
of the concentrations of the duty cycle In cytoskeletal movement, muscle of fish that generates electric
dissociated components to the the proportion of time in a cross- pulses for detecting objects or
concentration of the complex once bridge cycle that a motor protein defense.
the reaction reaches equilibrium binds its cytoskeletal tract. electrical energy The energy
(e.g., for the reaction AB Δ A ⫹ B, dynamic range The range between the associated with gradients of charged
Kd ⫽ [A][B]/[AB]). minimum and maximum signal that particles.
7
GLOSSARY
electrical synapse A junction between eventually gives rise to tissues such and is involved in the stress
neurons in which the signal is as the external surfaces, including response; also called adrenaline.
transmitted as an electrical charge the gut lining. epithelium The outermost cellular
rather than via a neurotransmitter endometrium The innermost layer of layer of eumetazoans.
(see also chemical synapse). the uterus composed of well- equilibrium For a chemical reaction,
electrocardiogram (ECG, EKG) A vascularized epithelial tissue; see also the state in which there is no net
recording of the electrical activity of myometrium. change in the reactants; products and
the heart. endoplasmic reticulum (ER) An substrates continue to interconvert,
electrochemical gradient A gradient intracellular organelle that forms a but at equal rates.
composed of the concentration network through which secretory equilibrium constant (Keq) The mass
gradient of an ion and the membrane products and plasma membrane action ratio of a chemical reaction
potential; the driving force for the components pass. when the reaction is at equilibrium.
movement of that ion across the endoskeleton More commonly referred equilibrium potential The membrane
membrane. to as the skeleton, an internal potential at which an ion is at its
electrogenic A transport process that framework of bones, cartilage, and equilibrium distribution across a
results in a change in electrical tendons that provides support and membrane.
charge across a membrane. resistance for muscular movement. eructation Gaseous release from the
electrolyte A charged solute, such as endosymbiont An organism that lives stomach (belching).
Na⫹, K⫹, and Cl⫺. within another organism. erythrocyte A type of vertebrate blood
electron transport system (ETS) A endosymbiosis A relationship whereby cell that contains hemoglobin (red
series of protein complexes with an organism lives within another cell blood cell).
mobile carriers that produce a proton or organism, and both parties benefit erythropoiesis Production of red blood
gradient across the inner from the relationship. cells from erythroblasts, usually in
mitochondrial membrane. It builds endothelium The innermost layer of specialized erythropoietic tissues.
the gradient by pumping protons as it blood vessels. erythropoietin A hormone released
transfers electrons from reducing endotherm An animal that generates from the kidney that induces
equivalents to oxygen, forming water. and retains heat internally. erythropoiesis.
electroneutral A transport process endothermic reaction A reaction that esophagus The passage from the oral
that does not change the electrical has a positive ⌬H, requiring heat. cavity (mouth) to the stomach.
charge across a membrane. end systolic volume (ESV) The volume essential nutrient A nutrient that
electroreceptor A sensory receptor of blood in the heart at the end of cannot be made by the animal and
that responds to electric fields or systole; the minimum volume of therefore must be obtained from the
discharges. blood that the heart contains during diet.
electrotonic conduction Conduction the cardiac cycle. esterase An enzyme that breaks an
via graded potentials. energetics The study of processes that ester bond.
emergence A phenomenon in which involve the interconversion of energy. estivation A form of dormancy in
the patterns and properties of a energy The ability to do work. which the reduced metabolic rate
complex system are the result of the energy metabolism The sum of occurs in response to dehydration.
interactions of the component parts metabolic reactions that pertain to estradiol-17␤ The dominant estrogen
of that system, and are not the production or utilization of in most species.
necessarily predictable from the energy. estrogens A class of steroid hormones
operation of those components in enteric branch (also enteric division; that act predominantly in females to
isolation. enteric nervous system) Part of the stimulate reproductive maturation
empirical An observation arising from vertebrate autonomic nervous system and control the reproductive cycle.
direct measurement of a parameter. involved in regulating the activity of estrous cycle A reproductive cycle
end diastolic volume (EDV) The the gut. composed of four phases: proestrus,
volume of blood in the heart at the enterosymbiont A symbiotic organism estrus, metestrus, and diestrus.
end of diastole; the maximum volume that lives within the gastrointestinal ethology The study of animal
reached during the cardiac cycle. tract. behavior.
endergonic reaction A reaction that enthalpy The heat content of a system, eupnea Normal breathing.
requires an input of free energy, for symbolized as H. Chemical reactions euryhaline Tolerant of a wide range of
which ⌬G is positive. are often expressed as a change in external salinities, or more precisely
endocardium The internal layer of the enthalpy (⌬H). osmolarities.
heart. entropy A thermodynamic parameter eurytherm An animal that is tolerant
endocrine A signaling pathway in that reflects the degree of disorder in of a wide range of external
which the signaling molecule is a system. temperatures.
released into the blood and affects a environmental estrogen An estrogen- evaporation Volatilization of liquid
distant cell of a different type. like endocrine disruptor. water to gaseous water, with the
endocrine disruptor An enzyme A biological catalyst composed absorption of heat.
environmental chemical (often of protein (sometimes RNA), evaporative cooling The heat loss that
humanmade) that alters cell signaling frequently incorporating a cofactor results when heat is absorbed from
by acting as an analogue or into its structure. the body to enable surface water to
antagonist of an endocrine hormone. enzyme induction An increase in the evaporate.
endocrine gland Type of gland that levels of an enzyme: one way to evolution The process of descent with
secretes hormones into the blood. achieve an increase in catalytic modification, or genetic change in
endocrine system The collective name activity. taxa over time; may be adaptive,
for the group of glands and other eosinophil A type of white blood cell maladaptive, or neutral.
tissues that secrete hormones into that is involved in the immune excess postexercise oxygen
the circulatory system. response to parasites an in allergic consumption (EPOC) A period of
endocytosis Invagination of the plasma reactions. elevated metabolic rate thought to be
membrane resulting in the formation ependymal cells Cells that line the necessary to allow the muscle to
of a vesicle; used to internalize ventricles of the brain. recover from ionic and metabolic
membrane proteins or capture epididymis The structure where sperm disturbances that arose as a result of
extracellular solids (phagocytosis) or mature and are stored in the intense exercise.
liquids (pinocytosis). vertebrate testis. exchanger See antiport.
endoderm The innermost primary epinephrine A catecholamine that can excitable cell A cell that is capable of
germ layer in a developing embryo; act as a hormone or neurotransmitter producing an action potential.
8
GLOSSARY
excitation-contraction coupling (or EC fast axonal transport Process by fluorescence Absorbance of a high-
coupling) The processes that link which neurotransmitter-containing energy (low-wavelength) light
external stimulation of a muscle to the vesicles are moved from the cell body followed by release of a lower-energy
activation of actinomyosin ATPase, to the axon terminal of a neuron; (longer-wavelength) light.
resulting in muscle contraction. requires molecular motors. flux Flow of material through a
excitatory postsynaptic potential fast-glycolytic (FG) muscle fibers pathway.
(EPSP) An excitatory potential in a Muscle cells with a biochemical and follicle A multicellular unit composed
postsynaptic cell. mechanical protein profile suited to of somatic tissue surrounding an
excitatory potential A change in the short-duration, high-intensity ovum.
membrane potential in an excitable contractions that rely on glycolysis follicle-stimulating hormone (FSH)
cell that increases the probability of for energy; typically muscle fibers One of the two major gonadotropins
action potential initiation in that cell. that express type IIb myosin. of vertebrates; causes the ovarian
exergonic reaction A reaction that fast-oxidative glycolytic (FOG) muscle follicle to mature.
requires an input of free energy, for fibers Muscle cells with a follicular phase That portion of the
which ⌬G is positive. biochemical and mechanical protein ovulatory cycle where a follicle
exocrine gland A type of gland that profile suited to contraction of matures to release the ovum.
releases its secretions via a duct intermediate duration and intensity; food vacuole A phagocytic vesicle that
(usually into the external rely on a combination of glycolysis fuses with other vesicles and
environment). and oxidative phosphorylation for processing organelles to digest the
exocrine secretions Secretions from energy. Typically muscle fibers that nutrients.
exocrine glands; include chemical express type IIa or II x/d myosin foramen of Panizza A structure that
messengers and substances such as isoforms. connects the left and right aorta in
mucus, slime, and silk. feces The undigested matter expelled the crocodile heart.
exocytosis The transport of vesicles to, from the gastrointestinal tract. forebrain The anterior portion of the
and subsequent fusion with, the feedback A regulatory mechanism vertebrate brain, consisting of the
plasma membrane; serves to secrete whereby a step late in a pathway telencephalon and diencephalon.
vesicle contents into the extracellular causes a change earlier in the Also called the prosencephalon.
space or to introduce proteins into pathway, either decreasing use of the founder effect A phenomenon in
the plasma membrane. pathway (negative feedback) or which the genotypic distribution of a
exon A region of DNA that codes for a increasing its use (positive feedback). population is a result of historical
protein. fever A period of elevated whole body events that caused the population to
exoskeleton An external rigid temperature that arises from an be established by a small number of
structure on the outside of many immune response, typically as a result individuals; often associated with a
invertebrates that serves to restrict of some form of infection. Behavioral reduction in genetic diversity.
the movement of water and provide a fever results when a poikilothermic fovea A small region in the center of
solid framework that controls animal animal responds to an immunological the retina of a vertebrate eye that is
shape and provides resistance challenge by moving into an responsible for high-acuity vision.
needed for locomotion. environment that increases body Frank-Starling effect An increase in
exosymbiont A symbiotic organism temperature. the force of cardiac contraction in
that lives outside the animal. fibroblasts Cells that have a major role response to increasing venous return
exothermic reaction A reaction that in producing the extracellular matrix to the heart.
has a negative ⌬H value, releasing of most soft tissues. free energy The energy in a system
heat. Fick equation The equation relating that is available to do work.
expiration Exhalation. diffusive flux to the energetic gradient freezing-point depression A reduction
extension A movement that causes a (concentration, partial pressure, in the temperature at which a
limb to straighten across a joint, electrical, etc.) driving diffusion. solution freezes; e.g., in the presence
usually caused by contraction of an field metabolic rate (FMR) The of antifreeze molecules.
extensor muscle. metabolic rate of a free-roaming futile cycle A combination of
extensor A muscle that causes a limb animal, usually measured using enyzymatic reactions or processes
to straighten across a joint doubly labelled water. that lead to net breakdown of ATP
(extension). filapodia Thin, fingerlike extensions of and/or release of heat without
external respiration The process by the cell, supported by the actin changes in the carbon substrates.
which animals exchange gases with cytoskeleton.
the environment to supply oxygen to filtrate The solution that passes G protein Type of trimeric membrane
the mitochondria and to remove the through a filter, such as the primary protein, associated with specific
resulting carbon dioxide (see also urine that passes through the transmembrane receptors, that plays
respiration). glomerulus. a role in signal transduction. G
extracellular digestion Breakdown of flagella (singular: flagellum) proteins bind guanine nucleotides;
nutrients in the outside of the cell Microtubule-based extensions from a when bound to GDP the G protein is
resulting from secretion of digestive cell that move in a whiplike pattern; inactive, but when bound to GTP it is
enzymes. usually present alone or in pairs. active. The alpha subunit of the G
extracellular fluids The fluids outside flexion A movement of a limb that protein moves through the
of a cell but contained within the causes the limb to bend at the joint membrane and acts in subsequent
limits of the organism. (caused by a flexor muscle). steps in the signal transduction
extracellular matrix The protein and flexor A muscle that causes a limb to pathway.
glycosaminoglycan network found bend at the joint (flexion). G-protein-coupled receptor A
outside cells; includes cartilage, bone, fluid mosaic model The model of a transmembrane receptor that
and connective tissue. lipid bilayer membrane that includes interacts with a G protein.
extrarenal Occurring in a tissue other multiple types of lipids and proteins GABA (gamma-aminobutyric acid) A
than the kidney. and allows for their free rotation and neurotransmitter; primarily
eye A complex organ that detects light. lateral movement. inhibitory in the vertebrate central
fluidity The degree of free movement nervous system.
facilitated diffusion A mode of of membrane entities within the gallbladder An organ that stores bile
transport in which a protein allows membrane; often assessed using the produced in the liver.
an otherwise impermeable entity to dye DPH, which exhibits an gamete The germ cell of sexually
cross a membrane down its anisotropy that depends on reproducing species; small gametes
electrochemical gradient. membrane fluidity. are sperm and large gametes are ova.
9
GLOSSARY
gametogenesis Production of mature glottis A small flap of tissue located inversely proportional to the square
gametes in the ovary or testis. between the pharynx and trachea of root of its molecular mass.
ganglion (plural: ganglia) A cluster of air-breathing vertebrates. granular cells See juxtaglomerular
neuronal cell bodies. Ganglia act as glucagon A hormone produced by the cells.
integrating centers. vertebrate pancreas that inhibits granulosa cells The inner layer of
ganglion cell An interneuron in the glycogen synthesis and stimulates somatic cells of a follicle that
retina of vertebrates. glycogen breakdown, resulting in an surround the primary oocyte.
gap junction Aqueous pore between increase in blood glucose. gray matter Areas of the vertebrate
two cells that allows ions and small glucocorticoids Steroid hormones central nervous system that are rich
molecules to move freely from cell to involved in the stress response that in cell bodies (see also white matter).
cell; formed by proteins called regulate carbohydrate, protein, and growth factor A group of peptide
connexins in the vertebrates and lipid metabolism. hormones that stimulate cells to
innexins in the invertebrates. gluconeogenesis The production of proliferate (hyperplasia) or grow in
gas gland A region of the vasculature glucose from noncarbohydrate size (hypertrophy).
of the swim bladder that secretes precursors; the main part of the growth hormone A peptide hormone
gases. pathway is a reversal of glycolysis, derived from the anterior pituitary
gastric Pertaining to the stomach. enabled by three enzymes that that mediates somatic cell growth.
gastrovascular cavity A space that bypass the two irreversible steps in guanine A purine nitrogenous base
performs the functions of digestion glycolysis. component of nucleotides, including
and circulation; found in organisms glycogen A glucose polysaccharide nucleic acids.
such as cnidarians. that forms the main carbohydrate guanosine A nucleoside of guanine
gene A region of DNA that, when energy store of animals. and a ribose sugar.
transcribed, encodes a protein or an glycogenesis Synthesis of glycogen guanosine triphosphate (GTP) A high-
RNA. from glucose or glycolytic energy phosphate compound in
gene duplication The process of DNA intermediates. energy metabolism; also the
mutation by which a genome can glycogenolysis The breakdown of substrate for guanylate cyclase,
acquire an additional copy of genes. glycogen to form glucose- forming the second messenger cGMP.
generator potential A change in the 6-phosphate. guanylate cyclase Enzyme that
membrane potential in the sensory glycolipid A glycosylated lipid common converts GTP to cGMP in response to
terminal of a primary afferent in the extracellular side of some signaling molecules such as nitric
neuron. It is a graded potential plasma membranes. oxide; has soluble and membrane-
proportional to the signal intensity. If glycolysis The breakdown of bound forms.
it exceeds threshold, it will trigger carbohydrates to form pyruvate, or gustation Detection of ingested
action potentials in the axon of the when oxygen is limiting, other end chemicals: the sense of taste.
sensory neuron. products such as lactate. gustducin A G-protein-coupled
genetic drift A change in gene glycoprotein A protein that has been receptor involved in the sense of taste
frequencies in a population over time modified by the addition of that detects sweet tastants.
as a result of random events. carbohydrates. gut reactor theory Mathematical
genome All of the genetic material of glycosaminoglycan A explanation of the optimal function of
an organism; the complete set of nonproteinaceous component various types of digestive tracts,
DNA in both the nucleus and of the extracellular matrix. modeled after chemical reactors.
mitochondria. glycosuria High levels of glucose in the gyri (singular: gyrus) Wrinkles on the
genotype The specific genetic makeup urine. surface of the brains of many
of an organism. glycosylation The addition of mammals.
germ cell A cell that produces the carbohydrate groups to proteins,
haploid gametes of a sexually lipids, or carbohydrates within the H zone The central region of a
reproducing species. endoplasmic reticulum or Golgi sarcomere corresponding to the
gestation The period of embryonic apparatus. location of the thick filaments where
development within the uterus of a goblet cell A goblet-shaped mucus- there is no overlap with thin
viviparous or ovoviviparous species. secreting cell found in the intestinal filaments; the H zone reduces in size
giant axons Unusually large-diameter and respiratory surfaces. upon contraction.
axons that are present in some Goldman equation The equation that habituation A process by which
invertebrates and vertebrates. predicts the membrane potential repeated stimulation of a neuron
gills Respiratory surfaces that across a cell membrane resulting results in a decreased response.
originate as outpocketings of the from the distribution of multiple ions hair cell Ciliated sensory cells of
body surface; generally used for gas in relation to their permeabilities. vertebrates that react to mechanical
exchange in water. Golgi apparatus An intracellular stimuli (particularly to vibrations).
gland A specialized organ that secretes organelle involved in the processing They are the basis of the senses of
hormones. of proteins prior to export. hearing and balance, and of the lateral
glial cells (glia) A group of several gonadotropin A hormone that line systems of fishes and amphibians.
types of cells that provide structural regulates the activity of reproductive Haldane effect The effect of oxygen on
and metabolic support to neurons. tissues; FSH and LH are the main hemoglobin–carbon dioxide binding.
gliocytes A type of invertebrate glial gonadotropins in vertebrates, and half-life A period of time required for
cell. allatotropin and allatostatin are the half of a population of molecules to
globin The protein component of main gonadotropins in arthropods. be converted to another form; often
hemoglobins. gonads The organs that produce the applied to radioactive decay.
glomerular filtration rate (GFR) The gametes in males (testes) and females heart A muscular pumping structure.
total amount of filtrate per unit time (ovaries). heat The kinetic energy associated with
passing through the glomeruli into graded potential Changes in the the movement of atoms and
the tubules of the kidneys. membrane potential of a cell that molecules.
glomerulus A knot-like cluster of vary in magnitude with the stimulus heat capacity The amount of thermal
capillaries that acts as a biological intensity; results from the opening energy required to increase the
filter in the nephrons of many and closing of ion channels. temperature of 1 g of a substance by
vertebrate kidneys. It permits fluids Graham’s law Describes the rate of 1°C.
and small molecules to pass freely diffusion of a gas in liquid; states that heat of vaporization The heat needed
from the plasma to the tubule the rate of diffusion of a gas is to cause a liquid to become gaseous,
lumen. proportional to its solubility and expressed per unit mass.
10
GLOSSARY
heat shock proteins A class of reproductive tissues either hydrophilic A molecule is hydrophilic
molecular chaperones that increase simultaneously or sequentially. (“water loving”) if it dissolves more
in abundance in response to elevated hertz A frequency of 1 per second (1 easily in water than in an organic
temperature; the term includes Hz ⫽ 1 sec⫺1). phase, such as a lipid bilayer.
members of genetically related heterodimer A quaternary structure of hydrophobic A molecule is
proteins that are constitutive and do two dissimilar monomers. hydrophobic (“water hating”) if it
not increase in expression in heterothermy A thermal strategy in dissolves more easily in a lipid phase
response to thermal stress. which the body temperature (TB) than in water.
heater tissues A general term for varies either spatially or temporally. hydrophobic bond Weak interaction
tissues that serve to elevate regional heterotrimeric G protein See G between two nonpolar groups or
or systemic temperature of an animal, protein. molecules arising through their
such as the heater organ of billfish. hexose A general name for mutual aversion to water.
Heliobacter A bacterium that infects monosaccharides with six carbons; hydrostatic pressure Pressure exerted
gastric pits, creating conditions that includes glucose and fructose. by a fluid at rest.
can lead to a gastric ulcer. hibernation A form of dormancy that hydrostatic skeleton A closed water-
hematocrit The proportion of whole occurs as a result of low ambient filled sac that acts as a semisolid
blood that is occupied by red blood temperature and persists for long support for an animal.
cells. periods. hydroxyl ion OH⫺.
heme A metal-binding porphyrin hindbrain The posterior portion of the hypercapnia Higher than normal
derivative that is incorporated into vertebrate brain, consisting of the carbon dioxide levels.
enzymes (e.g., cytochromes) and cerebellum and brainstem. hyperglycemia An elevated blood
nonenzyme proteins (e.g., hippocampus A part of the vertebrate glucose level.
hemoglobin). brain that is involved in the hyperosmotic A solution that has a
hemerythrin An iron-containing formation of memories. higher osmolarity than another
respiratory pigment found in histamine An amino acid; a regulatory solution.
sipunculids, priapulids, brachiopods, molecule that is released from mast hyperplasia An increase in the
and annelids; lacks heme. cells in response to an immunological number of cells in a tissue or organ.
hemimetabolous insect Type of insect challenge. hyperpnea Rapid breathing.
that possesses immature stages histone A protein that reversibly binds hyperpolarization A change in the
(nymphs) that resemble the adults, to DNA, altering its ability to be membrane potential of a cell from its
except in lacking fully formed wings transcribed. normally negative resting membrane
(see also holometabolous insects). holocrine secretion A type of secretion potential to a more negative value; a
hemocoel Collective name for the in which entire cells burst, releasing relative increase in the negative charge
sinuses in the open circulatory their internal contents. on the inside of the cell membrane.
systems of many invertebrates. holometabolous insect An insect in hyperthermia An elevation in body
hemocyanin A respiratory pigment which juvenile stages, dissimilar from temperature (TB) above a desired
found in arthropods and molluscs the adult, undergo dramatic point.
consisting of one or more protein metamorphosis. hypertonic A solution that has a
molecules complexed directly to homeostasis A state of internal combination of osmolarity and solute
copper molecules. constancy that is maintained as a profile that leads to the efflux of
hemocytes Generalized term for blood result of active regulatory processes. water from the cell, resulting in a
cells. Most commonly used for the homeothermy A thermal strategy of an decrease in cell volume.
blood cells of invertebrates. animal (a homeotherm) that has a hypertrophy An increase in the size of
hemoglobin A respiratory pigment relatively constant body temperature cells in a tissue or organ.
consisting of a globin protein (TB). hyperventilation Breathing rate or
complexed to an iron-containing homeoviscous adaptation A process depth that is greater than needed for
porphyrin molecule called heme. whereby cells alter the composition either oxygen supply or carbon
hemolymph The circulatory fluid of of cellular membranes to ensure that dioxide removal.
arthropods. fluidity remains constant to hypocapnia Lower than normal
hemopoietic factor A regulatory compensate for the effects of a carbon dioxide levels.
protein that induces the synthesis of change in the external environment. hypoglycemia Low levels of glucose in
red blood cells; erythropoietin, for homing A movement that returns an the blood.
example. animal to its home range. hypometabolism A period when
Henderson-Hasselbalch equation The homodimer A molecule composed of metabolic rate is lower than the
mass action equation for the two identical subunits. normal resting rate.
dissociation of carbonic acid (H2CO3) homologues Genes that are descended hyposmotic A solution that has a lower
to bicarbonate (HCO3⫺) and hydrogen from a common ancestor, without osmolarity than another solution.
ions (H⫹); important in respiratory intervening duplication events (see hypothalamic-pituitary portal system
physiology. also paralogues). A system of blood vessels within the
Henry’s law One of the ideal gas laws; hormone Type of chemical messenger hypothalamus and pituitary that
describes the dissolution of a gas in a that is carried in the blood and thus carries hypothalamic hormones to
liquid, stating that the amount of gas can act across long distances. the pituitary, where they regulate the
dissolved in a liquid is related to the Classically defined as a substance release of pituitary hormones.
partial pressure and the solubility of released from an endocrine gland hypothalamus A region of the
that gas. and active at very low vertebrate forebrain that is involved
hepatocyte The dominant cell type in a concentrations. in controlling body temperature,
liver. hydration shell A coating of water thirst, hunger, and many other
hepatopancreas An invertebrate tissue bound to the surface of an ion or physiological processes. Regulates
that serves the same roles as the molecule. the function of the pituitary.
vertebrate liver and pancreas. hydrogen bond A class of weak hypothermia A decrease in body
Hering-Breuer reflex A respiratory (noncovalent) bond in which an temperature (TB) below a desired
reflex that reduces breathing in electropositive hydrogen atom is point.
response to overinflation of the lungs; shared by two electronegative atoms. hypotonic A solution that has a
involved in the termination of a hydrolysis The breaking of a covalent combination of osmolarity and solute
breath. bond by introducing a water profile that leads to the influx of
hermaphrodite An animal that molecule; –H is added to one product water into the cell, resulting in an
possesses both male and female and –OH to the other. increase in cell volume.
11
GLOSSARY
hypoventilation Breathing rate or inhibitory postsynaptic potential ionic bond A weak bond between an
depth that is less than required for (IPSP) An inhibitory potential in a anion and a cation.
adequate gas exchange. For air postsynaptic cell. ionoconformer An animal with an
breathers this usually involves inner ear A series of membranous internal ion profile that resembles the
insufficient breathing to allow the sacs that contain the organs of ion composition of the external water.
removal of carbon dioxide, rather hearing and balance in vertebrates. ionophore A molecule that forms pores
than insufficient for oxygen supply; inner hair cells One of two types of within membranes, allowing specific
causes elevated blood carbon dioxide hair cells found in the organ of Corti ions to cross.
(hypercapnia) and respiratory in the inner ear of mammals; ionoregulator An animal that
acidosis. involved in the sense of hearing (see maintains an internal ion profile
hypoxemia Lower than normal blood also outer hair cells). independent of the ion composition of
oxygen levels. inorganic ion An ion lacking carbon the external water.
hypoxia Lower than normal oxygen; atoms. ionotropic receptor A receptor protein
usually referring to environmental inositol trisphosphate (IP3) that acts as a gated ion channel.
oxygen levels (see also hypoxemia). A second messenger in the iris A ring of tissue located
phosphatidylinositol signaling immediately in front of the lens of a
I-band (isotropic band) The region of system. vertebrate eye that controls the
a muscle sarcomere where the thin inspiration Inhalation. amount of light entering the eye by
filaments that span a Z-disk do not instar A juvenile form of an insect that altering the size of the pupil.
overlap with the thick filament. resembles the adult form in gross ischemia A reduction in blood flow,
ice-nucleating agent A molecule or appearance. depriving a tissue of oxygen and
particle that initiates the formation of insulation An external or superficial nutrients.
ice at a subfreezing temperature. layer of material that reduces the islets of Langerhans Clusters of
ideal gas law The relationship heat loss from the animal to the endocrine cells in the pancreas that
between pressure, volume, and gas environment, such as fur, feathers, produce the hormones glucagon and
concentration. and blubber. insulin.
ileum The last section of the small insulin Peptide hormone that isocortex The outer layer of the
intestine, connecting the jejunem to homeostatically regulates blood forebrain in mammals.
the large intestine. glucose levels; released in response isoelectric point The pH at which an
imidazole group The amino group to increased blood glucose. ionizable molecule exhibits no net
found in histidine and other integral membrane protein A protein charge.
compounds that exhibits a pK value that is embedded within a cellular isoform A protein that has the same
near physiological pH, and is membrane, and can only be released function as another protein but
therefore important in the buffering with detergent treatment that differs in primary sequence either
of the pH of body fluids. disrupts the membrane. because it is encoded by a different
in situ An in vitro condition in which integrins A class of dimeric gene, or because it results from
the parameter under investigation is transmembrane proteins that is alternative promoter usage or
in a realistic setting. important in the interactions differential splicing (contrast with
in vitro Occurring outside a living betweens cells and the extracellular alleles).
animal or cell. matrix, mediating both adhesion and isometric contraction A muscular
in vivo Occurring within a living cell signalling. contraction that results in force
animal or cell. integument The outer layer of an production without a change in
inactivation gate One of the two gates animal, usually derived from length.
that open and close voltage-gated epithelial cells and their secretions. isopleth A contour line showing the
sodium channels. intercalated disc The intercellular value of a function of two variables
incipient lower lethal temperature contact between cardiomyocytes connecting the points where the
(ILLT) For a poikilotherm composed of gap junctions and function has a particular value; e.g.,
acclimated to a given temperature, it desmosomes. the relationship between pH and
is the lowest temperature that can be intercellular fluid See interstitial bicarbonate concentration as
tolerated. fluid. described by the Henderson-
incipient upper lethal temperature intermediate filaments One class of Hasselbalch equation.
(IULT) For a poikilotherm proteins that are used to make up the isosmotic Describes two solutions with
acclimated to a given temperature, it is cytoskeleton. the same osmolarity.
the highest temperature that can be interneuron A neuron that makes isotonic A solution with a profile and
tolerated. synaptic connections between other concentration of solutes that does not
incus (anvil) One of the three small neurons. result in a change in the volume of a
bones of the mammalian middle ear. internode The region of axonal cell.
indirect calorimetry Estimation of membrane that is covered with the isotonic contraction A muscular
metabolic rate (heat production) myelin sheath. contraction that results in shortening
using consumption of oxygen or interstitial fluid The component of the without force production.
production of carbon dioxide. extracellular fluid that exists between isovolumetric contraction (or
inducible Usually refers to a gene that cells. isovolumic contraction) A phase
can increase in expression in intrinsic protein See integral during the cardiac cycle in which the
response to regulatory conditions; membrane protein. heart contracts, but does not eject
can be applied to the encoded protein intron A region of DNA that is always blood because the valves are closed,
itself, as in “an inducible enzyme.” spliced out of the mRNA following and thus does not change in volume.
inflammation A element of an immune transcription. isozyme An isoform of an enzyme.
response associated with local heat inulin A molecule that is used to assess
production. glomerular filtration rate because it is jejunum An intermediate region of the
ingested energy Term used to describe neither secreted nor recovered by the small intestine, flanked by an
the total energy content of a diet, kidney tubule. anterior duodenum and a posterior
includes both digestible energy and ion An atom or molecule with a net ileum.
indigestible energy. charge. juvenile hormone (JH) A class of
inhibitory potential A change in the ion channels Transmembrane proteins invertebrate hormones derived from
membrane potential that decreases that permit transfer of ions or isoprenes; secreted from the corpus
the probability of action potential molecules through an aqueous pore allatum, JH maintains juvenile
initiation in an excitable cell. down an electrochemical gradient. traits.
12
GLOSSARY
juxtaglomerular apparatus A group lateral inhibition Process by which a lipogenesis Conversion of fatty acids and
of cells located near the distal tubule sensory stimulus at one location glycerol to acylglycerides including
and the glomerular afferent inhibits the activity of adjacent monoacylglycerides, diacylglycerides,
arterioles. neurons. Lateral inhibition enhances triglycerides, and phospholipids.
juxtaglomerular cells Secretory cells contrast and improves edge detection lipolysis Breakdown of acylglycerides
of the afferent glomerular arterioles in sensory systems. and phospholipids.
that respond to low blood pressure lateral line system A lipophilic Hydrophobic or nonpolar.
by secreting renin (also known as mechanoreceptive organ in fishes lipoprotein A complex of lipids and
granular cells). and amphibians that senses proteins; central to the transport of
vibrations in the water surrounding lipids between tissues.
kcat See turnover number. the animal. Contains hair cells load A force that opposes muscle
keratan A glycosaminoglycan found in grouped into structures called contraction.
the extracellular matrix. neuromasts. locomotor module A set of
keratin Cytoskeletal protein that leak channel A passive ion channel in musculoskeletal components that
forms one type of intermediate the cell membrane that allows the work together to perform a single
filament; common in hair, nails, and movement of ions down their function, such as flying.
feathers. concentration gradients. long-term potentiation A long-lasting
ketogenesis The production of ketone leaky epithelia An epithelial layer with enhancement of the postsynaptic
bodies. cell-cell connections that permit response as a result of high-
ketolysis The breakdown of ketone paracellular transport. frequency stimulation of the
bodies to form acetyl CoA. lengthening contraction A type of presynaptic neuron.
ketone bodies Substances such as muscle contraction in which external loop of Henle A region of a
acetone, acetoacetate, and ␤- forces cause the muscle to lengthen mammalian kidney tubule that
hydroxybutyrate and other products while force is being generated. connects the proximal and distal
derived from acetyl CoA; produced by length-tension relationship Describes tubule; central to the production of
fatty acid oxidation under food the influence of sarcomere length on hyperosmotic urine.
deprivation conditions. force development in muscle; muscle lower critical temperature (LCT) The
kidney An organ responsible for generates optimal force when lowest environmental temperature at
producing urine, thereby regulating sarcomere length is about 2 µm (in which a homeotherm can survive for
the levels of nitrogenous wastes, most muscles), and tension declines long periods; the lower limit of its
extracellular fluid solute properties, at higher or lower sarcomere lengths. thermoneutral zone.
and osmolarity. lens A clear object that can refract lumen The internal cavity of a
kinesin A motor protein associated light. In the eye, the lens bends multicellular unit, such as a kidney
with microtubules (see also dynein). incoming light rays, helping to form a tubule or gastrointestinal tract.
kinetic energy The energy associated focused image on the retina. lungs Respiratory surfaces that
with movement. leukocytes Vertebrate white blood originate as invaginations of the body
kinocilium The long cilium of a cells; cells in blood that are involved surface. Generally used for gas
mammalian hair cell (involved in the in the immune system. exchange in air.
detection of sound). Leydig cell A testosterone-producing luteal phase The portion of an
Kleiber’s rule The observation that cell interspersed in the interstitium of ovulatory cycle after the follicle has
metabolic rate is related to body the testes. expelled the ovum and before a
mass to the exponent 0.75. ligament A form of connective tissue second follicle matures.
Km See Michaelis constant. that joins two bones. lymph A fluid consisting of an
knockout animal An animal that has ligand A chemical that specifically and ultrafiltrate of blood and immune
been subjected to genetic reversibly binds to a receptor or cells that travels through the
manipulation leading to the inability enzyme. lymphatic system of vertebrates.
to express a native gene. ligand-gated ion channel An ion lymph hearts The pumping structures
Krebs cycle See tricarboxylic acid channel that opens or closes in of the lymphatic system, present only
cycle. response to the binding of a specific in some vertebrates (including fish,
K-type strategy A life history strategy chemical. amphibians, and reptiles).
whereby an animal produces few limbic system A group of structures in lymph nodes Small bean-shaped
offspring and invests heavily in their the vertebrate brain that is involved organs found in various locations in
development (see also r-type in processes including emotions and the lymphatic system of tetrapods;
strategy). memory. they filter lymphatic fluid and
Lineweaver-Burk equation A plot of produce lymphocytes.
lactation Production and release of the reciprocals of reaction velocity lymphatic system In the vertebrates, a
milk from the mammalian mammary (1/V) and substrate concentration network of vessels or sinuses
gland. (1/[S]); generates a linear relationship (depending upon the species) that
lamella A general term referring to a for enzymes with hyperbolic kinetics. carries lymph back to the primary
morphology that resembles stacks of lipase An enzyme that breaks down circulatory system. In many species it
leaves. lipid; includes triglyceride lipases, also performs an immune function.
lamellipodia Flat, sheetlike extensions lipoprotein lipase, and lymphocytes Leukocytes that are
of the cell, supported by the actin phospholipase. involved in adaptive immunity in
cytoskeleton. lipid A class of organic molecules that vertebrates.
laminar flow A pattern in which the share hydrophobicity; includes fatty lysosomes Organelles responsible for
layers of fluid move in parallel, acids, phospholipids, triglycerides, the breakdown of damaged and
usually relative to the surface of an and steroids. unnecessary membranous
object. lipid bilayer The model for a plasma compartments and membrane
larva A pre-adult developmental stage membrane in which the hydrophobic proteins.
that bears little resemblance to the faces of two monolayers of
adult form. phospholipids are associated. macula densa A group of cells in the
latch state A condition in smooth lipid raft A thickened region of the juxtaglomerular apparatus that
muscle in which force is generated plasma membrane; often senses the sodium chloride
with less than expected ATP accumulates cholesterol, concentration of the tubular fluid.
consumption; usually attributed to a phospholipids with long chain fatty macrophage A type of white blood cell
more efficient mechanism of cross- acids, and proteins with long that ingests foreign invaders and
bridge cycling. transmembrane domains. dead or dying cells.
13
GLOSSARY
magnetite A crystalline aggregation of when the melting point and the metalloprotein A protein with a metal
a magnetic metal (usually iron); freezing point are not the same ion integrated into its structure;
found in some magnetoreceptors. temperature, this hysteresis suggests enzymatic metalloproteins typically
magnetoreceptor A sensory receptor the presence of a solute that acts in a involve their metal in oxidation-
that responds to magnetic fields. noncolloidal manner, such as an reduction reactions.
malleus (hammer) One of the three antifreeze protein. metamorphosis The transition
small bones of the mammalian membrane fluidity A state that allows between distinct developmental
middle ear involved in transmitting the two-dimensional movement of stages, typically from a larva to an
sound vibrations to the inner ear. lipids and proteins within a lipid adult.
Malpighian tubule The functional bilayer membrane. metazoan A multicellular animal.
equivalent of a kidney tubule in membrane potential The electrical methemoglobin An oxidized form of
insects, releasing the urine into the gradient across a cellular hemoglobin that can no longer carry
gut. membrane. oxygen.
mantle cavity A cavity formed by the membrane recycling The exchange of micelle A lipid monolayer that rolls
body wall (mantle) of molluscs; membrane lipids and protein onto itself to form a sphere with a
generally contains the respiratory between the plasma membrane and hydrophobic inner core and
structures. the internal membrane network. hydrophilic exterior.
mass action ratio Ratio of products to menarche The age at which a female Michaelis constant (Km) The
substrates; when more than one mammal with a menstrual cycle concentration of substrate that yields
product (or substrate) is involved, experiences her first menstruation. half maximal velocity in an enzymatic
their concentrations are multiplied meninges Membranes covering the reaction.
together. When a reaction is at vertebrate central nervous system. Michaelis-Menten equation V ⫽ Vmax
equilibrium, the mass action ratio Mammals have three meninges; × [S]/([S] ⫹ Km).
equals the equilibrium constant (Keq). birds, reptiles, and amphibians have microclimate The external
mass-specific metabolic rate The two; and fish have one. environment within a confined space,
metabolic rate of an animal (usually menses In female mammals, the typically distinct from the broader
described as oxygen consumption) periodic shedding of the endometrial conditions, such as a subterranean
expressed relative to body mass. layer of uterine tissue that occurs if burrow; typically used to describe the
mastication Mechanical disruption of there is no implantation of a fertilized conditions experienced by an
food in an oral cavity (chewing). ovum; also known as menstruation. organism (see also
maximum reaction velocity (Vmax) menstrual cycle The estrous cycle of microenvironment).
The maximal enzymatic rate humans and some other primates. microelectrode A very small electrode
calculated from a substrate-velocity menstruation See menses. used to record electrical signals from
curve; can be estimated by the mesangial cells Contractile cells cells.
enzymatic rate observed when between the capillaries of the microenvironment Like a
product is absent and substrate glomerulus, which control blood flow, microclimate, but can apply to the
concentrations are optimal. and thereby control blood pressure environment surrounding anything
mean arterial pressure (MAP) The within the glomerulus. from individual molecules to whole
weighted average of the systolic and mesencephalon See midbrain. animals.
diastolic pressures, taking into mesoderm The middle of the three microfilaments A polymer of ␤-actin
account the relative length of each of primary germ layers in a developing used to construct the cytoskeleton.
these phases of the cardiac cycle. embryo; eventually gives rise to microglia One of the glial cells of the
mechanical energy A form of energy tissues such as bone, muscle, and vertebrate central nervous system.
arising from the movement or connective tissue. microtubule A large, hollow tube
position of an object; can be either messenger RNA See mRNA. consisting of a polymerized tubulin;
kinetic energy (as in a moving leg) or metabolic acidosis or alkalosis A used to build the cytoskeleton.
potential energy (as in a loaded decrease or increase, respectively, in microtubule-associated protein (MAP)
spring). blood pH as a result of metabolic A protein that binds to microtubules
mechanogated channel (or activity. to alter structural or functional
mechanically gated channel) An metabolic depression A reduction in properties.
ion channel that opens or closes in metabolic rate below resting levels; microtubule-organizing center (MTOC)
response to the stress (or stretch) on associated with a period of A multiprotein complex near the
a membrane. dormancy. center of the cell from which
mechanoreceptor A sensory receptor metabolic flux The flow rate through a microtubules grow.
that detects forces applied to cell metabolic pathway. microvilli Fingerlike extensions from
membranes (such as touch or metabolic rate The rate of heat individual cells, supported by
pressure). Can be used to describe production by a tissue or organism, microfilaments, which serve to
either the receptor protein or cells usually approximated by oxygen increase surface area.
containing these receptors. consumption or carbon dioxide micturition Urination.
medulla oblongata A region of the production. midbrain The middle portion of the
vertebrate brainstem containing metabolic water The water produced vertebrate brain consisting of the
centers that regulate heart rate, by the metabolic breakdown of tectum and tegmentum. Also called
breathing depth and frequency, and macromolecules. the mesencephalon.
blood pressure. Also called the metabolism The sum of all chemical middle ear A part of the vertebrate ear
medulla. reactions in a biologic entity. that consists of the tympanic
medullary cardiovascular center The metabolizable energy The proportion membrane and one or more small
region within the medulla that of digestible energy retained by the bones (in mammals, the incus,
regulates cardiac function. body; the remainder is malleus, and stapes) that help to
medullary respiratory center The unmetabolizable energy lost in amplify sounds.
region within the medulla that excretory products. milieu intérieur The internal
regulates breathing depth and metabolon A group of enzymes that environment of a cell or organism.
frequency. are spatially localized within the cell mineralocorticoids Steroid
melatonin A hormone found in all and perform a function together. hormones involved in water and ion
animal groups that regulates sleep- metabotropic receptor A receptor that balance.
wake cycles. signals via a signal transduction mitochondria Organelles within most
melting point The temperature at pathway (see also ionotropic eukaryotic cells that produce energy
which a solid can become a liquid; receptor). by oxidative phosphorylation;
14
GLOSSARY
organized in many tissues as a mucous cells Cells that secrete a myosin light chain A protein that
network or reticulum. complex mucopolysaccharide onto binds the motor protein myosin II,
mitochondria-rich cell Usually refers the surface of a tissue; goblet cells regulating its structure or function.
to the epithelial cells specialized for are a type of mucous cell found in myosin light chain kinase (MLCK) An
ion pumping, which have abundant the intestinal and respiratory enzyme associated with hexameric
mitochondria to meet the energy surfaces. myosin that phosphorylates myosin
demands of active transport (see also mucus A mucopolysaccharide mixture light chain.
chloride cell). secreted from specialized epithelial myosin light chain phosphatase
M-line The midpoint of a sarcomere cells onto the external surface of a (MLCP) An enzyme associated with
where the thick filament lacks tissue. hexameric myosin that
myosin heads. multipolar neurons Neurons with dephosphorylates myosin light chain.
mobile element A region of DNA that many processes leading from the cell myotome A repeating segment in the
can be excised and inserted body; most of these processes are body musculature of adult fish; also,
elsewhere within the genome. dendrites, but one may be an axon. the embryonic form of muscle
molal (molality) Moles of an ion or muscarinic acetylcholine receptors derived from a body segment, or
molecule expressed relative to G-protein-coupled receptors that bind somite.
kilograms of solvent (usually water). acetylcholine. myotube An early stage of muscle
molar (molarity) Moles of an ion or muscle A multicellular tissue differentiation in which multiple
molecule expressed relative to liters composed of myocytes, fibroblasts, myoblasts fuse together to form a
of solvent (usually water). and vascular cells; the contraction of multinucleated contractile tubular
mole 6.02252 × 1023 molecules of a the myocytes leads to force cell.
substance; the molecular weight of a generation or shortening.
substance is the mass of one mole of muscle fiber A single muscle cell; Na⫹/K⫹ ATPase An ion transporter
that substance. can be mononucleated (as in that expels 3 Na⫹ out of a cell and
molecular chaperone A protein that cardiomyocytes) or multinucleated imports 2 K⫹, driven by the energy of
uses the energy of ATP hydrolysis to (as in skeletal muscle fibers). ATP hydrolysis.
help fold or stabilize denatured muscle spindle fiber A muscle stretch nares Nostrils.
proteins; includes heat shock receptor. natriuretic Leading to the appearance
proteins. mutation A heritable alteration in the of sodium in the urine.
molecular phylogeny The evolutionary nucleotide sequence of genomic near-equilibrium reaction A reaction
relationships among organisms as DNA. in which the products and substrates
reconstructed based on molecular myelin See myelin sheath. in vivo are near the concentrations
sequence data. myelin sheath The insulating that would arise if the enzymatic
monoacylglyceride (or monoglyceride) wrappings of vertebrate axons that reaction were to reach equilibrium.
A single fatty acid esterified to a are composed of multiple layers of The reaction is regulated by changes
glycerol molecule. glial cell plasma membrane. in the concentrations of substrates
monocyte A large white blood cell that, Invertebrate axons have analogous and products.
in the tetrapod immune system, wrappings, but they are not generally negative feedback loop A regulatory
ingests foreign particles such as termed a myelin sheath. mechanism whereby a step late in a
microbes; when it leaves the blood myelination The process of forming pathway causes a decrease in the
stream it differentiates into a the myelin sheath around a activity of a step earlier in the
macrophage. vertebrate axon. pathway to reduce the flow through
monogastric stomach An animal that myenteric plexus A network of the pathway.
has a stomach with one (usually neurons found within the smooth nephridium A primitive type of kidney
acidic) compartment. muscle of the gastrointestinal tract tubule found in some invertebrates,
monomer A single subunit of a that controls its muscular and such as annelids and molluscs; can
multimer, such as a dimer or trimer. secretory actions. also refer to the embryonic kidney of
monosaccharide A sugar, usually myoblast A mononucleated, vertebrates.
composed of a 6-carbon (sometimes proliferating cell that can nephron The multicellular unit of the
5-carbon) ring, such as glucose. differentiate to form a muscle cell. kidney, consisting of the tubule and
monounsaturated fatty acid A fatty myocardium The muscle of the heart. the vasculature that serves it,
acid with a single double bond. myocyte A general term for a muscle typically a glomerulus.
monozygotic Arising from a single cell, including smooth muscle cells, Nernst equation An expression that
zygote. cardiomyocytes, and myofibers. describes the ion concentration
motor end plate The location on a myofiber A multinucleated skeletal gradient across a permeable
muscle that forms synapses with a muscle fiber. membrane in relation to the voltage
motor neuron; the muscle side of a myofibril A long bundle of actin, when the system is at equilibrium.
neuromuscular junction. myosin, and associated proteins in nerve A cordlike structure composed
motor neuron A neuron that transmits muscle cells. of a collection of neuronal axons
signals from the central nervous myogenic Muscle contraction initiated grouped together by connective
system to skeletal muscles. by a trigger arising directly within tissues.
motor proteins Mechanoenzymes, such the muscle, as in a myogenic heart. nerve net Description of the
as myosin, that use the energy of ATP myoglobin A type of hemoglobin found structure of the nervous system of
hydrolysis to move along cytoskeletal in muscle. cnidarians.
tracks. myometrium The smooth muscle nervous system Network of neurons
motor unit A group of muscle fibers layers of the uterus. and their supporting cells.
under the control of a single neuron. myosin A large multigene family of net energy The proportion of
mRNA Messenger RNA; the form of ATP-dependent motor proteins that metabolizable energy that is retained
RNA that is used as a template work in conjunction with actin. The by the body, excluding that lost to
during translation to form protein. thick filament of muscle is composed specific dynamic action.
mucin The lipopolysaccharide that is of myosin, which is organized into neurogenic A contraction that occurs
the main component of mucus. hexamers consisting of two myosin in response to a nervous stimulus.
mucosa Refers to the inside layer of a heavy chains (MHC) and four myosin neurogenic muscle A muscle that is
tissue or organ, often that surface light chains (two regulatory MLC and activated by neuronal stimulation.
exposed to the lumen of an organ, two essential MLC). neurohemal organ A region of
such as the gastrointestinal tract (see myosin heavy chain The motor multiple neurons that secrete
also serosa). protein that interacts with actin. hormones into the blood.
15
GLOSSARY
neurohormone A chemical messenger formation of ice at subzero orphan receptors Receptors whose
released from a neuron into the temperatures. ligand and function is not known;
blood. nucleoside A molecule composed of a identified based on structural
neuromast A structure consisting of a nitrogenous base (purine or similarity to known receptors.
cup filled with a viscous gel and pyrimidine) linked to a ribose or osmoconformer An animal that
several hair cells; the functional unit deoxyribose sugar. exhibits an internal osmolarity that
of the lateral line system of fishes and nucleotide A nucleoside with one or parallels that of the external
amphibians. more phosphate groups, such as ATP. environment.
neuromuscular junction The synapse nymph The larval form of a osmolarity Analogous to molarity, it is
between a motor neuron and a hemimetabolous insect that resembles the concentration of osmolytes in a
skeletal muscle cell. in most respects the adult form of the solution (osmoles per liter);
neurons (nerve cells) Specialized cells insect, except lacking functional abbreviated OsM.
in the nervous system that wings. osmole One mole of osmotically active
communicate using chemical and solutes.
electrical signals. Many, but not all, obliquely striated muscle A muscle osmolyte An osmotically active solute;
neurons are excitable cells that where striations run obliquely to the any solute that has a significant effect
generate action potentials. axis of shortening. on osmotic pressure.
neuropeptides Polypeptides that act as odorant Molecules that can be detected osmoregulator An animal that exhibits
neurotransmitters. by the sense of smell. an internal osmolarity that is
neurosecretory cell Neurons that odorant binding protein Proteins controlled independently of the
produce and secrete neurohormones found in the mucus of the nasal osmolarity of the external
into the blood, typically in a region epithelium that bind to odorants and environment.
called a neurohemal organ. transfer them to odorant receptors. osmosis The movement of water
neurotransmitter A chemical odorant receptor protein A G-protein- across a membrane from an area
messenger released from a neuron coupled receptor involved in the with a high activity of water to an
into the synaptic cleft. detection of odorants and thus the area with low activity of water.
neutral pH The pH at which the sense of smell. osmotic pressure A force arising due
concentration of H⫹ equals that of olfaction Detection of environmental to the tendency of water to move by
OH⫺. chemicals from outside the body: the osmosis.
neutrophils The most common type of sense of smell. osteoblast A bone precursor cell.
white blood cell in the vertebrate olfactory bulb A part of the vertebrate otolith A small mineralized granule
immune system. forebrain that is involved in (usually calcium carbonate) in the
nicotinic acetylcholine receptors processing olfactory sensations. inner ear of vertebrates. Involved in
Ligand-gated ion channels that open oligodendrocyte A vertebrate glial cell the sense of balance.
in response to acetylcholine binding. that forms the myelin sheath of a outer ear External portion of the
nitric oxide A gaseous neuron in the central nervous vertebrate ear (consisting of the
neurotransmitter and paracrine system. pinna and auditory canal in
chemical signal that is involved in ommatidium The functional unit of the mammals).
regulating many physiological arthropod compound eye. outer hair cells One of two types of
processes; important vasodilator in oncotic pressure The osmotic pressure hair cells found in the organ of Corti
vertebrates. of blood that is due to the in the inner ear of mammals;
nociceptor (or nocioceptor) A sensory concentration of large involved in amplifying sound and
receptor that responds to noxious macromolecules, primarily protein. protecting the inner hair cells from
stimuli of various types (e.g., extreme oocyte One of the intermediate stages loud sounds.
heat or cold, extreme pressure, in the process of producing an ovum oval window Membrane between the
harmful chemicals, tissue damage); during meiosis. middle ear and the inner ear of
pain receptor. oogenesis The production of an ovum. vertebrates. Vibrates to transmit
nocturnal Active at night. oogonia (singular: oogonium) After sound to the inner ear.
node of Ranvier A gap of exposed the primordial germ cell enters the oviparous An animal that produces
axonal membrane between two ovary, it differentiates into an eggs that hatch outside the body.
regions of myelin sheath. oogonium, which undergoes multiple ovoviviparous An animal that holds its
noncompetitive inhibition A mode of rounds of mitosis before entering eggs inside the body until the eggs
enzyme inhibition in which a meiosis. hatch, and then releases active
molecule inhibits an enzyme by open circulatory system A circulatory young.
acting at a site distant from the active system in which the blood passes ovulation The release of an ovum
site; noncompetitive inhibitors can through one or more unbounded following the rupture of a follicle.
increase the Km or reduce the Vmax. spaces called sinuses. ovum The larger of the two gametes of
noncovalent bond Includes four types operculum The stiffened flaplike cover a sexually reproducing species.
of weak bonds that stabilize of the gills of bony fishes. Although an ovum is often defined as
macromolecular structure. opsin A family of G proteins that is the gamete produced by a female, in
nonpolar Having low solubility in involved in visual phototransduction. reality this definition is backward: an
water or other polar solvents. optic chiasm Area in the vertebrate individual is a female if it has gonads
nonshivering thermogenesis (NST) brain where the optic nerves cross. that can produce an ovum.
Production of heat by chemical optic lobe Either of the two lobes of oxidant A molecule that accepts an
means without muscle contraction. the vertebrate midbrain that are electron from another molecule (the
Typically refers to heat production by involved in visual processing; also, in reductant). In doing so, the oxidant
brown adipose tissue; however, there arthropods the regions of the brain becomes reduced.
are other means of NST. involved in processing signals from oxidation A chemical reaction
norepinephrine (or noradrenaline) A the compound eyes. whereby a molecule donates an
catecholamine neurotransmitter; in organ of Corti Located in the cochlea electron to another molecule,
vertebrates, released by the of the inner ear; contains the hair becoming oxidized.
sympathetic nervous system. cells that are involved in the sense of oxidative phosphorylation The process
nuclease An enzyme that hydrolyzes hearing. by which mitochondria produce ATP
nucleic acids; includes DNases and ornithine-urea cycle A pathway by from the oxidation of reducing
RNases. which urea is produced from equivalents (NADH, FADH2). The
nucleator (or nucleating agent) A nitrogen arising from ammonia or electron transport chain expels
molecule or particle that triggers the glutamine. protons from the mitochondria to
16
GLOSSARY
produce a proton motive force, which parathyroid glands Glands located on moving blood through the circulatory
is then used by the F1F0 ATPase to the posterior surface of the thyroid systems of some animals.
produce ATP. gland that release parathyroid permeability The ability of a molecule
oxyconformer An animal that exhibits hormones in response to changes in to cross a barrier, such as a
a respiratory rate that declines when extracellular calcium. membrane.
oxygen pressure declines. parathyroid hormone Peptide hormone permease A transporter that mediates
oxygen debt See excess postexercise that regulates blood calcium levels. facilitated diffusion, but is neither a
oxygen consumption. parietal cells The acid-secreting cells channel nor a porin.
oxygen dissociation curve See oxygen within the gastric mucous pH scale A measure of acidity,
equilibrium curve. membrane. expressed as the negative log10 of the
oxygen equilibrium curve A curve parthenogenesis A mode of asexual proton concentration.
showing the relationship between PO2 reproduction whereby offspring are pH-bicarbonate plot (Davenport
and the oxygen saturation of blood produced by a female as a result of a diagram) A graphical depiction of
containing a respiratory pigment. variation on the meiotic pathway. the relationship between the pH and
oxygen carrying capacity The Because meiosis is involved, bicarbonate concentration of a
maximum amount of oxygen that can chromosomal recombination is solution. Usually used to describe
be carried by blood. Includes both possible and the parthenogenic these relationships in arterial blood.
dissolved oxygen and oxygen bound offspring are not clones of the phagocyte A cell that carries out
to respiratory pigments. parent. phagocytosis.
oxygen-transport pigment See respi- partial pressure (of a gas) The phagocytosis The endocytosis of large
ratory pigments. pressure exerted by one of the gases particles from the extracellular space.
oxyregulator An animal that exhibits a in a gas mixture. The sum of the phasic muscle A type of muscle that
constant respiratory rate despite a partial pressures of all the gases in a undergoes rapid contractions and
decline in oxygen pressure. mixture gives the total pressure. relaxations; a twitch muscle.
oxytocin A peptide hormone produced parturition The birthing process by phasic receptor A sensory receptor
by the anterior pituitary; induces the which offspring of viviparous and that produces action potentials only
contraction of smooth muscle during ovoviviparous females are expelled during part of the stimulus (usually at
parturition. from the reproductive tract. stimulus onset and removal).
parvalbumin A Ca2⫹-binding protein phenotype The physical characteristics
P50 The partial pressure at which a in the cytoplasm of some muscles, of an organism; the result of an
respiratory pigment is 50% saturated which buffers Ca2⫹ levels to interaction between the genotype and
with oxygen. accelerate relaxation. the environment.
pacemaker A cell or group of cells passive diffusion A type of passive phenotypic plasticity Production of
whose output of action potentials transport that does not require a different phenotypes by a single
occurs in a rhythmic pattern. protein carrier. genotype as a result of environmental
pacemaker cell An excitable cell that passive transport Movement across a cues; may be reversible or
spontaneously fires action potentials cell membrane without an energy irreversible (see also acclimation).
in a rhythmic pattern. investment other than the chemical pheromones Chemical messengers
pacemaker potentials Spontaneous gradient of the transported molecule; released by an animal into the
depolarizations of the resting includes both passive diffusion and environment that have an effect on
membrane potential that ultimately facilitated diffusion. another animal of the same species.
trigger action potentials within pattern generator A group of neurons phosphagens Energy-rich compounds
pacemaker cells. whose rhythmic firing coordinates a that transfer energy in reactions in
Pacinian corpuscle A type of rhythmic physiological process or which a large change in free energy
vertebrate skin mechanoreceptor. behavior, such as breathing or results when a phosphate bond is
pancreas A vertebrate organ that locomotion. broken.
produces endocrine hormones pentose A five-carbon phosphatase An enzyme that removes
including insulin and glucagon and monosaccharide, such as ribose a phosphate group from a molecule;
also produces exocrine secretions and deoxyribose. important in signal transduction
that are involved in digestion. peptide bond A carbon-nitrogen bond pathways because it reverses the
pancreatic ␤ cells Cells within the (–C–N–); most common in polymers phosphorylations catalyzed by
vertebrate pancreas that secrete the of amino acids. kinases.
hormone insulin. perfusion Movement of fluid through a phosphocreatine See creatine
panting A mode of thermoregulation tissue (e.g., flow of blood through a phosphate.
whereby an increase in the frequency capillary bed). phosphodiester bond –P–O–P–.
of respiration enhances heat loss pericardium The sac surrounding a phosphodiesterase An enzyme that
from the body core. heart. breaks down the phosphodiester
parabronchi Smallest airways of a perilymph The fluid found in the bonds of cyclic nucleotides such as
bird lung. cochlea of the inner ear. cAMP and cGMP.
paracellular transport Passage of peripheral chemoreceptors phosphoglycerides The major class of
solutes or water between cells; in Chemoreceptors located in the aortic phospholipids of biological
most epithelial tissues, tight junctions and carotid bodies of vertebrates that membranes, consisting of a glycerol
and other cell-cell junctions prevent detect changes in blood chemistry. backbone, two fatty acids, and a
paracellular movement of fluids. peripheral membrane protein A polar head group linked to the
paracrine A type of chemical protein that is weakly bound to the glycerol via phosphate.
messenger that is involved in local membrane through an interaction phospholipase An enzyme that breaks
signaling between nearby cells; with a lipid or integral membrane down phospholipids, releasing either
paracrine messengers move through protein. diacylglycerol, polar head groups, or
the interstitial fluid by diffusion. peripheral nervous system (PNS) All fatty acids, depending on the type of
paralogues Genes that are the result of of the neurons outside of the central phospholipase.
a gene duplication event within a nervous system. phospholipids Phosphoglycerides and
lineage (see also homologues). peripheral resistance See total sphingolipids.
parasympathetic nervous system Part peripheral resistance. phosphorylation The addition of a
of the vertebrate autonomic nervous peristalsis The rhythmic contractions phosphate group via a kinase,
system; generally active during of intestinal smooth muscle; involved expending ATP (e.g., a protein kinase
periods of rest; releases acetylcholine in propelling a bolus of food along catalyzes the phosphorylation of a
onto target organs. the gastrointestinal tract and in protein).
17
GLOSSARY
phosphorylation potential An plane-polarized light When light porphyrins Organic ring structures
expression of energy status; the mass arrives at a detector, it typically that bind metals, primarily iron but
action ratio for an ATPase reaction exhibits waves that run at all angles. also copper; heme is the most
([ATP]/[ADP][Pi]). Polarizing filters permit the passage common type of porphyrin in
photon The fundamental particle of of light waves that run in a specific animals.
electromagnetic radiation. Streams of angle (plane), generating plane- portal system Two capillary beds
photons can have differing polarized light. connected by a portal vein (e.g.,
wavelengths, in which case the plasma The liquid fraction of hypothalamic pituitary portal system;
resulting radiation is given different vertebrate blood. intestinal liver portal system).
names (e.g., X-rays, gamma rays, plasma membrane The lipid bilayer portal vein A blood vessel that carries
visible light). membrane that encircles a cell. blood from one capillary bed to
photopigments Molecules specialized plasticity The ability to change or another; part of a portal system.
for detecting photons; consist of a remodel a physiological process or positive feedback loop A regulatory
chromophore and an associated structure, as in neural plasticity. See mechanism whereby a step late in a
protein. also phenotypic plasticity. pathway causes an increase in the
photoreceptors Sensory receptors that pleiotropy A phenomenon in which a activity of a step earlier in the
detect photons with wavelengths in single gene is responsible for pathway to increase the flow through
the visible spectrum (i.e., light). Can be multiple, seemingly independent the pathway.
used to describe either the receptor phenotypes. posterior pituitary Lobe of the
proteins or the cells that contain them. pleural sacs A series of membranes pituitary gland; secretes antidiuretic
phototaxis Movement in response to that surround the lungs of hormone and oxytocin; also called
light, either toward (positive vertebrates. The pleural sacs enclose the neurohypophysis.
phototaxis) or away (negative the pleural cavity. postganglionic neuron A vertebrate
phototaxis). plug-flow reactor A type of chemical autonomic neuron has its synapse in
phylogenetic Pertaining to phylogeny. reactor in which the inflow moves the peripheral autonomic ganglia,
phylogeny A hypothesis regarding the as a bolus through the tubelike and extends an axon out into the
evolutionary relationships among reactor. periphery; forms a synapse with a
organisms; can be based on the pN The pH at which a zwitterion has preganglionic neuron.
analysis of various types of data (e.g., no net charge. postsynaptic cell A cell (either a
molecular, morphological). podocyte Cells surrounding the neuron or effector) that receives a
physiological dead space The volume capillaries of the glomerulus, with signal from a presynaptic cell across
of a respiratory organ that is not footlike extensions that form the a synapse.
involved in gas exchange; consists of filtration slits. post-tetanic potentiation (PTP) A
both the anatomical dead space and poikilothermy A thermoregulatory phenomenon in which a postsynaptic
the volume of any regions that, strategy whereby an animal (a cell will respond with an unusually
although capable of acting as gas poikilotherm) allows body large change in membrane potential
exchange surfaces, do not participate temperature (TB) to vary, usually in for several minutes following
in gas exchange (e.g., unperfused or relation to the ambient conditions. repeated action potentials in the
unventilated alveoli). Poiseuille’s equation An equation presynaptic cell.
physoclist Any fish whose swim describing the relationship between potential energy The energy that is
bladder lacks a connection to the gut. the flow, pressure, and resistance of available in a static system; elastic
physotome Any fish whose swim a fluid moving through a rigid tube, storage energy is a form of potential
bladder is connected to the gut via a including the factors influencing energy.
tube. resistance (length, cross-sectional power The rate of doing work.
piloerection The movement of hair or area, and viscosity). power curve The relationship between
feathers perpendicular to the skin in polar See hydrophilic. the velocity of muscle shortening and
response to muscular contraction. polymer A chain of repeating the force of contraction.
pilomotor Related to the nerves and molecules, such as a polysaccharide power stroke The part of a cross-
muscles that change the orientation or a polypeptide. bridge cycle in which structural
of hair. polymodal receptors Sensory receptor changes in myosin alter the relative
pineal complex Consists of the pineal cells that can detect more than one position of the actin flilament.
gland and related structures; type of stimulus. pre-Bötzinger complex The primary
involved in melatonin secretion and polypeptide A chain of amino acids respiratory rhythm generator of
the establishment of circadian linked by peptide bonds. mammals.
rhythms. polyphenism A form of irreversible preferred body temperature The
pinna The cartilaginous structures phenotypic plasticity, generally temperature at which an animal
forming the outer ear of mammals. involving alternative developmental functions best; achieved by
pinocytosis The endocytosis of fluids pathways. physiological mechanisms that alter
by the plasma membrane (see also polypnea Rapid breathing. heat production or loss (mainly in
phagocytosis). polysaccharide A chain of homeotherms) or by behavioral
pit organs The highly sensitive monosaccharides linked by glycosidic choice of habitat (mainly in
thermoreceptive organs of some bonds. poikilotherms).
snakes. polysynaptic Involving more than two preformed water The water that
pituitary gland A hormone-secreting synapses; used in the context of arrives in the diet as a liquid or
organ located at the base of the reflex pathways. trapped within solid foods; distinct
vertebrate brain; connected to the polyunsaturated fatty acid A fatty from metabolic water that is
hypothalamus. acid with two or more double bonds produced during the digestion of
pivotal temperature In an animal with along the carbon chain. foods.
environmental sex determination, it pons A region of the vertebrate brain preganglionic neuron A vertebrate
is a temperature at which equal that communicates information autonomic neuron that has its cell
numbers of males and females result. between the brainstem and the body in the central nervous system
placenta In eutherian mammals, the higher brain centers. Works with the and forms synapses in the peripheral
membrane derived from the medulla to regulate breathing. ganglia.
embryonic chorion that encircles the porin A channel that permits the preprohormone Large inactive
embryo, acting as the interface facilitated diffusion of large polypeptide that is a precursor to a
between embryonic and maternal molecules; e.g., aquaporin is a porin peptide hormone (see also
tissues. that transports water. prohormone).
18
GLOSSARY
pressure A force applied to a unit area protein kinase An enzyme that quaternary structure The three-
of a surface. attaches a phosphate to a protein, dimensional arrangement of a
presynaptic cell A neuron that using a molecule of ATP for energy protein composed of multiple
transmits a signal across a synapse and as a phosphate source. monomeric units.
to a postsynaptic cell. protein phosphatase An enzyme that
primary active transport Active removes a phosphate group from a radiant energy Thermal energy
transport that uses chemical or light protein. released from an object in relation to
energy directly, such as an ion- proteoglycan A molecule composed of its temperature.
pumping ATPase; distinct from protein and glycosaminoglycan. radiant heat transfer The emission of
secondary active transport, in which proteolysis The breakdown of thermal energy from a warm object
an entity is driven by electrochemical proteins, usually by hydrolytic to cooler surroundings.
transmembrane gradients of another cleavage of peptide bonds by a radiation The emission of energy from
entity being transported. protease. an object.
primary follicle A follicle that prothoracic glands A pair of ram ventilation A ventilatory strategy
continues to develop to release an endocrine glands that secrete in which the forward movement of
ovum, unlike other follicles that hormones that regulate ecdysis. the animal provides the propulsive
degrade and die during the protofilament A single chain of tubulin force needed for bulk flow of the
maturation process (atresia). that exists prior to the formation of ventilatory medium across the
primary oocyte The products of sheets or microtubules. respiratory surface. Seen in some
oogonia that have undergone the first proton motive force The fishes and insects.
meiotic division to become a diploid electrochemical gradient arising from range fractionation A strategy in
cell that will eventually produce an proton pumping by the mitochondrial which groups of sensory neurons
ovum. electron transport chain. work together to increase the
primary spermatocyte The products protozoans An historical term to dynamic range of a receptor organ.
of spermatagonia that have describe the phyla of early single-celled Each neuron has an overlapping, but
undergone the first meiotic division eukaryotes known now as protists. not identical, dynamic range,
to become a diploid cell that will proximal tubule The region of a allowing a wider range of stimulus
eventually produce a spermatozoan. mammalian or avian kidney tubule intensities to be coded by the
primary structure The sequence of a that lies between the Bowman’s population of receptors.
polymer without consideration of capsule and the descending limb of the rate constant The factor that allows
how it folds; typically refers to the loop of Henle. the prediction of an enzymatic rate
amino acid sequence of a protein. proximate cause The immediate or based on the concentration of the
primary urine The initial contents of direct cause of an organismal substrates.
the lumen of a nephron. In structure, function, or behavior; reaction norm The range of
vertebrates that possess a usually refers to the developmental or phenotypes that can be produced by
glomerulus, the primary urine is the physiological mechanism (see also a given genotype when it is exposed
filtrate. ultimate cause). to different environments.
proboscis A single extension from the pulmonary system A respiratory reactive oxygen species (ROS) A free
head, typically superior to the oral system consisting of lungs and the radical in which the unpaired
opening; the nose. associated vasculature. electron is associated with an oxygen
proenzyme A catalytically inactive pulmonary circuit The part of the atom.
precursor for an enzyme; usually tetrapod circulatory system that receptive field The area of the body
undergoes proteolytic processing to carries blood from the heart to and that, when stimulated by an
become the active enzyme. from the lungs. incoming sensory stimulus, affects
prohormone A polypeptide formed by pupa A developmental stage in the activity of a sensory neuron.
the cleavage of a preprohormone; a hemimetabolous insects that receptor A protein or cell that can
precursor to the formation of a separates the larva from the adult; detect an incoming stimulus.
peptide hormone. can include a period of quiescence. receptor adaptation The process by
prolactin An anterior pituitary pupil An opening in the center of a which sensory receptor cells become
hormone that is responsible for milk camera-type eye through which light less sensitive to sensory signals as
production in mammals, and more enters. signal duration increases.
general roles in ion and water purine A class of nitrogenous bases receptor potential A graded change in
balance in other vertebrates. with two rings; includes guanine and the membrane potential within an
pronephros A simple kidney adenine. epithelially derived sensory receptor
equivalent of larval forms of some Purkinje fibers The terminal branches cell. The receptor potential triggers
amphibians and fish. of the conducting fibers of the the release of neurotransmitter onto
proprioceptor A sensory receptor that mammalian heart. a primary afferent neuron, causing a
provides information about body P wave One of the waveforms of an postsynaptic graded potential. If this
position and movement. electrocardiogram; represents the postsynaptic potential exceeds
prosencephalon See forebrain. depolarization of the atria. threshold, it will trigger action
prostate gland A gland accessory pyloric sphincter The sphincter that potentials in the axon of the primary
associated with the reproductive tract regulates movement of material from afferent neuron.
of male vertebrates. the stomach to the duodenum. recruitment The stimulation of
prosthetic group A nonprotein pyrimidine A class of nitrogenous different collections of muscle fibers
component of an enzyme or other bases with one ring; includes in response to different activity
protein; e.g., a coenzyme (an organic cytosine, thymine, and uracil. patterns.
prosthetic group) or a metal. pyrogen An entity that causes a rectal gland An organ found in
protease An enzyme that breaks homeotherm to mount an immune cartilaginous fish that secretes salt to
peptide bonds of proteins to generate response that culminates in a fever. aid in osmotic regulation.
polypeptides or amino acids. redox balance (reduction-oxidation
proteasome A cytoplasmic Q10 A value that reflects the impact of a balance) A condition in which there
multiprotein complex that degrades 10°C change in temperature on an is no net change in the ratio of
damaged proteins tagged with a enzymatic or metabolic process; also reduced to oxidized reducing
ubiquitin molecule. known as the temperature coefficient. equivalents, typically NADH/NAD⫹.
protein A polymer of amino acids, QRS complex One of the waveforms of redox shuttle A multienzyme
usually folded into complex an electrocardiogram; represents the pathway used to transfer the energy
secondary structures. depolarization of the ventricles. of reducing equivalents from
19
GLOSSARY
glycolysis into the mitochondria for produce carbon dioxide (see also responsible for vision in dim light
oxidation. external respiration). (see also cone).
redox status The relative levels of respiratory acidosis or alkalosis Root effect A change in the oxygen
reduced to oxidized molecules of Decrease or increase in blood pH as a carrying capacity of blood as a result
interest; typically applied to result of changes in blood carbon of changes in pH.
metabolic biochemistry (e.g., dioxide (usually as a result of round window Membrane at the end
NADH/NAD⫹) but can also be used to changes in ventilation). of the cochlea; acts as a pressure
reflect the degree of oxidative stress. respiratory chain See electron release for the fluid of the inner ear.
reducing equivalents NAD(P)H or transport system. rRNA The form of RNA that is
FADH2. respiratory pigments Metalloproteins incorporated into the riboprotein
reductant A molecule that donates an that act as oxygen transport and complex known as a ribosome.
electron to another molecule (the storage molecules (e.g., hemoglobin). r-selection A life history strategy
oxidant). In doing so, the reductant respiratory quotient (RQ) The ratio of whereby parents invest minimally in
becomes oxidized. CO2 produced to O2 consumed; large numbers of offspring; best
reduction A chemical reaction indicative of the type of fuel being suited to rapidly exploit underutilized
whereby a molecule accepts an utilized. An RQ of 0.7 indicates fatty niches.
electron from another molecule, acids are the fuel, whereas an RQ of r-type strategy A reproductive
becoming reduced. 1.0 suggests carbohydrates are being strategy where parents produce
reductionism A philosophical oxidized. numerous offspring, with relatively
approach that asserts that complex resting membrane potential The little investment in their care.
processes can be understood in terms membrane potential of an excitable ryanodine receptor A Ca2⫹ channel
of their components. cell when action potentials or found in the sarcoplasmic reticulum
reflex arc A simple neural circuit that graded potentials are not being of muscle, which allows Ca2⫹ to
does not involve the conscious generated. escape into the cytoplasm to initiate
centers of the brain. resting metabolic rate (RMR) The muscle contraction.
reflex control pathway See reflex arc. metabolic rate of an animal at rest
refraction The bending of light as it under experimentally defined saliva A solution of enzymes, salts, and
passes from one medium to another. conditions (see also basal metabolic water secreted into the oral cavity to
refractive index The degree to which rate, standard metabolic rate). lubricate, dissolve, and disrupt food.
a material refracts light. rete mirabile A network of blood salt A neutral molecule composed of
refractory period A period in which vessels that serve to retain heat via an inorganic anion and inorganic
an excitable cell is less likely to countercurrent exchange. cation linked by an ionic bond, such
generate an action potential (see also retina A layer of light-sensitive cells as NaCl (table salt).
absolute refractory period, relative that lines the back of eyes. salt gland An extrarenal gland found
refractory period). retinal A derivative of vitamin A that in some marine and desert
regional heterothermy A acts as the light-absorbing vertebrates that secrete Na⫹ and Cl⫺
thermoregulatory strategy in which chromophore in animal to reduce body salt content.
regions of an animal’s body exhibit photopigments. saltatory conduction The mode of
significantly different temperatures. reversal potential The membrane conduction of action potentials in
regulators Animals that maintain a potential at which there is no net myelinated axons in which action
degree of constancy in an internal movement of an ion through open ion potentials appear to jump from one
physiochemical parameter (e.g., channels. node of Ranvier to the next.
osmolarity or temperature) despite Reynolds number A dimensionless sarcolemma The cell membrane of a
external changes in the parameter. number associated with an object muscle.
regurgitation The expulsion of that reflects how smoothly a fluid sarcomere The contractile unit of
stomach contents back up the flows over the surface of the object. striated muscle, typically measured
esophagus into the oral cavity. rhabdomeric photoceptors One of two from one Z-disk to the next.
relative refractory period A period types of animal photoreceptor cells. sarcomere length The distance
immediately following the absolute Arthropod photoreceptors are between two Z-disks of a sarcomere.
refractory period in which an rhabdomeric (see also ciliary sarcoplasm The cytoplasm of a muscle
excitable cell will generate an action photoreceptors). cell; also known as myoplasm.
potential only if exposed to a rhodopsin A photopigment consisting sarcoplasmic reticulum The
suprathreshold (unusually large) of the protein opsin chemically linked endoplasmic reticulum of muscle.
stimulus. to a vitamin A derivative called satellite cells A population of
relaxed endothermy A thermal retinal. omnipotent stem cells found on the
strategy in which an endothermic rhombencephalon See hindbrain. surface of striated muscle. When
animal allows its body temperature ribonucleic acid See RNA. stimulated, satellite cells can enter
to fall for a period of time. ribosomal RNA See rRNA. myogenesis to repair or replace
renal Pertaining to the kidney. ribosome A complex of RNA and muscle.
renal clearance The removal of an protein that carries out protein saturated (1) For respiratory pigments,
entity from the plasma by the kidney. synthesis. hormone receptors, and carrier
renal tubule Within a nephron, it is rigor A state of skeletal muscle in proteins, refers to a situation in which
the tube composed of a single layer of which cross-bridges remain intact all available proteins are bound to
transport epithelium. because ATP has been depleted from their ligand. (2) For fatty acids, refers
repolarization A return of the the cell. to fatty acid chains that lack double
membrane potential of a cell toward RNA A polymer of ribonucleic acids bonds.
the resting membrane potential similar to DNA except that they saturated fatty acid A fatty acid with
following a depolarization or contain ribose in place of deoxyribose no double bonds.
hyperpolarization. and uracil in place of thymine; scaling The relationship between a
resistance, electrical The force includes mRNA, tRNA, and rRNA. parameter, such as metabolic rate,
opposing the flow of charge through Involved in transferring information and body size.
an electrical circuit. from DNA and in protein synthesis. scaling coefficient The slope of a plot
resistance, vascular The force RNase An enzyme that degrades RNA of log body mass against log
opposing the flow of blood through either from the end (exonuclease) or parameter of interest, such as
the circulatory system. internally (endonuclease). metabolic rate.
respiration The process by which rod A type of vertebrate photoreceptor Schwann cell A type of glial cell in the
mitochondria consume oxygen and cell. In mammals, rods are vertebrates that forms the myelin
20
GLOSSARY
sheath around axons in the serum Blood plasma after the clotting sphingolipid One class of phospholipid
peripheral nervous system. factors have been removed. based on a sphingosine backbone.
sclera Tough outer surface of a set point In a homeostatically spinal cord Part of the vertebrate
vertebrate eye. controlled system, the level at which central nervous system extending
sclerites Plate-like sections of an the regulated variable is maintained. from the base of the skull through the
invertebrate exoskeleton. sexual reproduction A process in vertebrae of the spine. The spinal
SDA See specific dynamic action. which two cells (each with half the cord is continuous with the
second messenger A short-lived normal genetic complement as a hindbrain.
intracellular messenger that acts as result of meiosis and recombination) spinal nerves A series of paired nerves
an intermediate in a signal fuse to form one descendant cell. that exit at regular intervals along the
transduction pathway. shivering thermogenesis Heat spinal column.
secondary active transport Transport production through uncoordinated spiracles Small openings leading to the
of a molecule across a membrane stimulation of skeletal muscle respiratory system; spiracles are the
against its electrochemical gradient, contractile units. primary opening to the tracheal
driven by the cotransport of another signal transduction pathways system of insects. The same word is
molecule along its electrochemical Biochemical pathways in which a used for a nonhomologous structure
gradient. change in conformation of a receptor in elasmobranch fishes that provides
secondary structure The folding protein in the target cell is converted an alternate opening for the buccal-
pattern of a macromolecule; an ␣- to a change in the activity of that cell. opercular cavities.
helix is an example of the secondary sinoatrial node (SA node) A remnant spleen A vertebrate organ that is
structure of protein and DNA. of the sinus venosus found at the top involved with the immune, lymphatic,
secretagogue A chemical that induces of the right atrium of the mammalian and circulatory systems. It can act as
the secretion of another chemical, heart. a storage site for red blood cells, and
usually a cell signaling factor such as sinus venosus The chamber leading to removes damaged cells from the
a hormone. the atrium of the heart in circulation. It also generates immune
secretory granules Vesicles of nonmammalian vertebrates. cells called lymphocytes.
secretory product stored within a skeletal muscle A general term to standard conditions Accepted external
cell, prepared for release when the describe the striated muscle that conditions under which physical
cell receives the appropriate signal. works in conjunction with the parameters are assessed; may refer
semicircular canals Structures of the endoskeleton. to pressure, temperature,
inner ear responsible for the sense of sliding filament model A theory that concentration, or other such
balance and body orientation; part of describes the interaction between parameters.
the vestibular apparatus. actin and myosin during cross-bridge standard metabolic rate (SMR) The
seminal vesicles A pair of glands that cycling. metabolic rate of a poikilothermic
store sperm and secrete nutrients smooth muscle A type of muscle that animal at rest and post-absorptive,
and fluids that form the semen, has an irregular arrangement of thick measured at a defined external
emptying it into the vas deferens and thin filaments, and thus lacks temperature. (see also basal
upon ejaculation. sarcomeres. metabolic rate, resting metabolic
semipermeable membrane A sodium-potassium pump See Na⫹/K⫹ rate).
membrane that allows the free ATPase. stapes (stirrup) One of the three
movement of some molecules but solute The particles (ions or molecules) small bones of the mammalian
impedes the movement of others. dissolved in a solution. middle ear.
sensillum (plural: sensilla) Sense solution The fluid in which solutes are Starling curve See Frank-Starling
organs in the insect cuticle. Involved dissolved. effect.
in the senses of taste, smell, touch, solvent The liquid in which solutes are statocyst Hollow, fluid-filled sense
and hearing. dissolved. organ in invertebrates that detects
sensitization A process by which the soma The cell body of a neuron, the orientation of the body with
response of a neuron to a stimulus is containing the nucleus. respect to gravity.
increased. somatic motor division (of the nervous statolith Small dense granule (usually
sensory adaptation See receptor system) The portion of the of calcium carbonate) found in
adaptation. vertebrate peripheral nervous system statocysts.
sensory modality The category of that controls skeletal muscle. steady state A condition in which
sensory input that a sensory system spatial summation The process by there is flux through a reaction or
detects (e.g., light, sound, pressure). which graded potentials at different pathway without a change in the
sensory neuron A neuron that conveys points in the membrane (occurring at concentration of intermediates.
sensory information from the the same time) combine to influence stenohaline An animal that is tolerant
periphery to the central nervous the net graded potential of a cell. of a narrow range of external
system (see also afferent neuron). specific dynamic action (SDA) The salinities.
sensory receptor A tissue, cell, or heat produced during the digestive stenotherm An animal that is tolerant
protein that detects incoming sensory process; also known as the heat of a narrow range of ambient
information. increment. temperatures.
sensory transduction The process of spermatogenesis Production of stereocilia The specialized cilia of
converting incoming sensory spermatozoa. vertebrate hair cells; involved in the
information to changes in cell spermatogonia (singular: sense of hearing.
membrane potential. spermatogonium) After the stereopsis The ability to see in three
series elastic components Elements of primordial germ cell enters the dimensions.
a structure that can store elastic testes, it differentiates into a steroid hormones A large class of
energy when they are deformed. spermatagonium, which undergoes hormones derived from cholesterol.
serosa Referring to the outer layer of a multiple rounds of mitosis before steroids A diverse group of nonpolar
tissue or organ (see also mucosa). entering meiosis. organic molecules composed of
serotonin A neurotransmitter (biogenic spermatozoa The smaller gamete in a multiple carbon rings.
amine) involved in setting mood and sexually reproducing species; stoichiometry The quantitative
regulating blood flow to the brain. sperm. relationship between two entities.
Sertoli cells Elongated cells in the sphincter A ring of smooth muscle that stomach A general term for an
seminiferous tubules of the testis that controls the diameter of an opening, anterior region of a gastrointestinal
nourish the spermatids during controlling passage from one region tract, typically characterized by
spermatogenesis. to the next. acidic digestion processes.
21
GLOSSARY
striated muscle A class of muscle that tachycardia Rapid heartbeat. excitable cell to which the membrane
possesses thick and thin filaments tastants Chemicals that are detected must be depolarized in order for an
organized into regular arrays; by the sense of taste. action potential to be initiated.
includes cardiac muscle and skeletal taste bud Structure involved in threshold stimulus The smallest
muscle. gustation in the vertebrates. stimulus that can provoke a response
stroke volume The volume of blood TCA cycle (see tricarboxylic acid in a cell.
pumped by the heart in a single beat. cycle) thyroid hormone An iodine-containing
submucosa The tissue layer that lies tectum Dorsal region of the vertebrate hormone produced by the thyroid
beneath the mucosal layer. midbrain involved in coordinating gland that is involved in the
substrate-level phosphorylation An visual and auditory responses. regulation of metabolism.
enzymatic reaction that produces a teleost fish The most common tidal volume The volume of a
high-energy phosphate. subclass of the bony fishes. respiratory medium moved into or
sulci (singular: sulcus) The folds on temperature coefficient See Q10. out of a respiratory structure during
the surface of the brain in some temporal heterothermy A thermal a single breath.
mammals. strategy whereby a homeothermic tight epithelia An epithelial layer with
summation See spatial summation, animal exhibits periods of cell-cell connections that limit or
temporal summation. poikilothermy, typically to allow a prevent paracellular transport.
supercooling The reduction of reduction in metabolic rate; also tight junction A type of intercellular
temperature of a fluid below its known as relaxed endothermy. connection that is capable of
freezing point but without the temporal summation The process by preventing the free movement of
formation of ice. which graded potentials occurring at molecules between the cells.
surface tension The force of adhesion slightly different times combine to tissue An aggregation of related cells
that binds molecules of a fluid influence the net graded potential of linked together by various types of
together at the interface with air. the cell. intercellular connections.
surfactant Substance that lowers the tendon The connection between a titin A very large protein that runs
surface tension of liquids; secreted in muscle and a bone. along the thin filament in striated
the lungs of vertebrates. tension, muscular The force produced muscle, determining its length and
swim bladder A gas-filled organ that by a contracting muscle. orienting into the sarcomere.
fish use for buoyancy compensation. terminal cisternae An enlargement of tonic muscle A muscle type with a
sympathetic division See sympathetic the sarcoplasmic reticulum near the slow contraction that persists for long
nervous system. muscle plasma membrane, periods (see also phasic muscle).
sympathetic nervous system Part of specifically T-tubules. tonic receptor A receptor that
the vertebrate autonomic nervous tertiary structure The three- produces action potentials
system; active during periods of dimensional structure of a throughout the duration of a
stressful activity; releases the macromolecule, stabilized by stimulus.
neurotransmitters epinephrine and numerous weak bonds. tonicity The property of an
norepinephrine onto target organs. tetanus The sustained contraction of a extracellular solution that determines
symport A transporter that carries two muscle arising from multiple whether a cell will swell or shrink.
or more entities across a cell stimulations in close succession. torpor A type of dormancy
membrane in the same direction; thalamus One of the basal ganglia of characterized by a relatively short
also known as a cotransporter. the vertebrate brain that relays period of hypometabolism.
synapse The junction between a sensory information to the cerebral total lung capacity The volume of air
neuron and another neuron or cortex. in the lungs at the end of a maximal
effector cell; consists of a presynaptic theca The outer layer of somatic cells inspiration; the maximum amount of
cell, the synaptic cleft, and a surrounding a follicle, separated from air that can be held in the lungs.
postsynaptic cell. the inner granulosa cells by a basal total peripheral resistance The net
synaptic cleft The extracellular space lamina. resistance of the vasculature.
between a presynaptic cell and a thermal conductance The transfer of totipotent stem cell An embryonic cell
postsynaptic cell at a synapse. thermal energy either within an that has the capacity to differentiate
synaptic depression A decrease in object or from one object to another. into any type of cell when given the
neurotransmitter release in response thermal energy Energy associated appropriate cell signaling information.
to repeated action potentials. with heat production. trabeculae Any partition that divides
synaptic facilitation An increase in thermogenesis Heat production. or partially divides a cavity.
neurotransmitter release in response thermogenin The mitochondrial trachea (plural: tracheae) The single
to repeated action potentials. uncoupling protein found in large airway leading to the paired
synaptic plasticity The capacity of mammalian brown adipose tissue. bronchi of vertebrate lungs; also, the
synapses to change their structure thermoneutral zone The range of nonhomologous respiratory
and function. ambient temperatures over which an structures that are the main
synaptic transmission The process of animal does not need to alter conducting airways in arthropod
transmitting information across a metabolic processes to maintain tracheal systems.
neural synapse. internal constancy. tracheal system The respiratory
synaptic vesicles Neurotransmitter- thermoreceptor A sensory receptor structures of insects and some other
containing vesicles that release that responds to temperature. groups of air-breathing arthropods.
neurotransmitter into a synapse. thermoregulation The physiological tracheoles The terminal structures of
synergism A situation in which two strategy an animal uses to control arthropod tracheal systems across
agents or processes have a combined temperature within the desired which gas exchange takes place.
effect greater than the sum of the range. transcellular transport Movement of
effects of the two agents or processes thick filament A polymer of about 300 solutes or water across a cell layer
applied individually. myosin dimers that produces the through the cell itself, typically
systemic circuit The part of the contractile force in muscle. crossing both apical and basolateral
tetrapod circulatory system that thin filament A muscle-specific ␣-actin cell membranes.
carries blood from the heart to the polymer similar in structure to a transcription RNA synthesis using the
body and back. microfilament; serves as a framework DNA template of a gene.
systole The phase of the cardiac cycle that translates actinomyosin activity transducin An inhibitory G protein
in which the heart is contracting. into force generation. involved in visual signal transduction
systolic pressure The arterial blood threshold potential The critical value in the vertebrates.
pressure during systole. of the membrane potential in an transfer RNA See tRNA.
22
GLOSSARY
transgenic animal An animal that has tubulin The monomeric protein unitary displacement The distance a
been genetically modified to possess subunit of microtubules, itself a single motor protein moves during a
a heritable mutation. dimer of ␣-tubulin and ␤-tubulin. cross-bridge cycle.
transition state A temporary, turbulent flow A disordered pattern of unsaturated fatty acid A fatty acid
intermediate state in the fluid flow over the surface of an with one or more double bonds.
conversion of substrate to product object that reduces the efficiency of upper critical temperature The
when a molecule obtains enough movement of the object through the highest temperature at which a
energy to reach the activation fluid. homeothermic animal can live for
energy barrier. turnover number The number of extended periods; the upper limit of
translation Protein synthesis using times a single enzyme molecule the thermoneutral zone.
ribosomes and mRNA template. completes a reaction cycle each U/P ratio The ratio of an ion or
transmembrane receptor A receptor second; also known as the catalytic molecule concentration in the urine
protein that spans the cell constant (kcat ). (U) versus the plasma (P).
membrane; consists of an turnover rate The number of catalytic up-regulation Increase in protein
extracellular domain, a events in a given period of time. For an number or activity in a target cell
transmembrane domain, and an individual enzyme, it is synonymous (see also down-regulation).
intracellular domain. with the catalytic constant (kcat ). It can urea A nitrogenous waste possessing
transmural pressure The pressure also be used to describe the rate of two nitrogen atoms per molecule.
difference across the wall of a synthesis and degradation of a ureotele An animal with an excretory
chamber (e.g., a blood vessel, heart, metabolite, such as ATP. strategy in which urea dominates the
or airway). T wave The portion of an nitrogenous wastes.
transpirational water loss Water loss electrocardiogram (EKG) that ureter The tube connecting the kidney
arising from gas exchange across the represents the repolarization of the to the bladder.
respiratory surface. ventricle. urethra The tube carrying urine from
transpulmonary pressure The twitch fibers Muscle fibers that the urinary bladder to the excretory
difference between the intra-alveolar undergo a rapid opening.
pressure and the intrapleural contraction/relaxation cycle (a uric acid A nitrogenous waste
pressure in mammalian lungs. twitch), in contrast to tonic fibers. possessing four nitrogen atoms per
transverse tubule See T-tubule. twitch muscle A muscle that contracts molecule.
triacylglycerol (or triglyceride) Three and relaxes once after each neuronal uricolytic pathway A pathway of
fatty acids esterified to a glycerol stimulus; a phasic muscle. breakdown of uric acid present in all
molecule. tympanal organ Sensory receptor animals.
tricarboxylic acid cycle The cyclical involved in hearing in insects; insect uricotele An animal with an excretory
mitochondrial pathway that oxidizes ears. strategy in which uric acid is the
acetyl CoA to form 3 NADH, 1 FADH2, tympanic membrane Thin membrane dominant nitrogenous waste.
and 1 GTP; the pathway that that separates the outer ear from the urine A solution of nitrogenous waste
produces most of the CO2 arising middle ear. Helps to transfer sound produced by the kidney or kidney-
from metabolism. vibrations to the inner ear. like tissues.
trichromatic color vision The system
of three different photoreceptors by ubiquitin A small protein that is added van der Waals interactions A type of
which humans and some other to damaged proteins to mark them weak bond forming from the mutual
animals obtain color vision. for degradation by the proteasome. attraction of the nuclei of two atoms
trimer A molecule composed of three UCP See uncoupling protein. in a molecule.
subunits. ultimate cause Why an organism has vas deferens The duct through which
tRNA (or transfer RNA) A cloverleaf- a particular structure, function, or sperm are carried from the sites of
shaped RNA molecule that binds a behavior; usually involves synthesis in the epididymis to the
particular amino acid and understanding the evolutionary ejaculatory opening.
participates in translation, binding to advantage of the trait (see also vasa recta The straight blood vessels
a three-nucleotide sequence of mRNA proximate cause). arranged in a hairpin loop that run
(codon) to transfer the amino acid to ultrafiltration Process of filtration of a from kidney cortex to medulla and
a growing polypeptide. fluid through a size-selective back to the cortex. The countercurrent
trophoblast An outer layer of cells membrane under pressure; used to arrangement allows removal of salts
derived from the mammalian form the primary filtrate of the and water from the peritubule
blastocyst that forms the interface vertebrate kidney. Also causes the interstitium while maintaining
between the fertilized ovum and the formation of lymph from blood in intramedullary osmotic gradients.
uterine wall. vertebrates. vascular endothelium Thin layer of
tropic hormones (or trophic hormones) ultraviolet light Short-wavelength cells that lines blood vessels.
Hormones that cause the release of light (<~300 nm); its high energy can vasculature The blood vessels of the
other hormones. damage macromolecules. circulatory system.
tropomyosin A regulatory protein that uncoupling (of oxidative vasoconstriction Narrowing of a blood
stretches across seven actin phosphorylation) When vessel as a result of contraction of the
monomers in a thin filament, mitochondrial respiration continues vascular smooth muscle; decreases
controlling myosin’s access to its without the production of ATP. local blood flow.
binding site on the thin filament. uncoupling protein (UCP) A class of vasodilation Widening of a blood
troponin A trimeric regulatory protein proteins, which includes thermogenin vessel as a result of relaxation of the
bound to tropomyosin. It responds to (UCP1), that act by dissipating the vascular smooth muscle; increases
high [Ca2⫹] by inducing tropomyosin mitochondrial proton motive force. local blood flow.
to move into a position that allows unipolar neuron A neuron with one vasomotion Change in the diameter of
myosin to bind actin. process leading from the cell body; blood vessels; also known as
T-tubule An extension of the plasma this process generally splits into two angiokinesis.
membrane (sarcolemma) of some branches, one conveying information vasomotor response The changes in
muscles that serves to improve the toward the cell body and one diameter of blood vessels in response
conduction of the action potential conveying information away from the to vasodilatory or vasoconstricting
into the fiber. cell body. factors; also known as the
tubule, renal Also known as a kidney uniporter A class of transporter that angiokinetic response.
tubule, it is the single filtration unit of carries a single entity (ion, atom, vasomotor tone The degree of
the vertebrate kidney. molecule) with each transfer. contraction of the smooth muscles
23
GLOSSARY
surrounding the arterioles (see also visual cortex A part of the vertebrate weak bonds Ionic bonds, hydrogen
venomotor tone). brain that is responsible for bonds, van der Waals forces, and
veins Blood vessels that return blood processing visual signals. hydrophobic interactions.
to the heart. In vertebrates, blood visual field The area that is visible to white adipose tissue A lipid storage
flows from the capillaries into an eye, without changing eye tissue of mammals; distinct from
venules and then into veins. position. brown adipose tissue. Other
venomotor tone The degree of vital capacity The maximum amount vertebrates lack brown adipose
contraction of the smooth muscles of respiratory medium that can be tissue, and white adipose tissue is
surrounding the veins (see also moved into or out of the respiratory typically referred to simply as
vasomotor tone). system with each breath. “adipose tissue.”
ventilation Active movement of the vitamin A dietary compound that white matter Areas of the vertebrate
respiratory medium (air or water) serves as a precursor for prosthetic central nervous system that are rich
across the respiratory surface. groups of proteins, particularly in axons (see also gray matter).
ventilation-perfusion ratio (or enzymes. white muscle A muscle fiber type
ventilation-perfusion matching) vitellin The dominant protein found in specialized for rapid, high-intensity
The relationship between the yolk produced from vitellogenin. contractions that continue for a short
ventilation (flow of respiratory vitellogenin The major protein in the duration; usually composed of type
medium) and the perfusion (flow of yolk of an egg. IIb myosin isoforms.
blood) at a respiratory surface. viviparous Animal whose offspring work The transfer of energy that
ventricle A fluid-filled sac or cavity develop internally and are released occurs when force is exerted on a
(e.g., the spaces in the center of the as active young (see oviparous and body to cause it to move.
vertebrate brain; the muscular ovoviviparous). work loop A method used to assess
pumping chambers of the vertebrate Vmax The maximal rate of catalysis by whether a muscle is performing
heart). an enzyme; arises when all positive or negative work.
venule Small blood vessels located substrates are at optimal (saturating)
between capillaries and veins. concentrations and prior to the xeric A dry, dehydrating environment.
vesicle A membrane-bound formation of product.
compartment that buds off from the VO2max The maximal sustainable rate of yolk A deposit of lipid and protein
intracellular membranous network, oxygen consumption exhibited by an (largely vitellin) associated with an
often encased in coat proteins such as animal. The experimental means to ovum.
clathrin. assess VO2max differs among
vestibular apparatus The organ of disciplines. Z-disk The protein plate at the end
balance in the vertebrates. volatile fatty acids Fatty acids of chain of a sarcomere that serves as the
villi Undulations and folds in a tissue length less than 2–6 carbons; also insertion site of actin thin filaments.
that serve to increase surface area; known as short chain fatty acids. zona pellucida A thickened
most commonly seen in the voltage-gated ion channel A glycoprotein extracellular matrix of a
gastrointestinal tract. membrane protein containing an mammalian ovum; it binds the sperm
viscosity An internal property of a fluid aqueous pore that can be opened in to initiate the acrosomal reaction.
that results in resistance to flow. response to changes in the zwitterion A molecule with groups that
Thick liquids have high viscosity. membrane potential. can become positive and others that
viscous effects The antagonism to vomeronasal organ A vertebrate sense can become negative.
movement of an object due to the organ adjacent to the mouth and zygote The single cell arising from the
interaction of its surface with the nasal cavities that is involved in fertilization of an ovum by a sperm.
fluid through which it moves. detecting pheromones.
24
25
Introduction to Physiological Principles
Physiological research exploded in the 1960s as a result of teams of researchers collaborate as multidisciplinary
several related events. Advances in diverse technologies, teams, exploring projects that would otherwise be prohibi-
from nuclear medicine to molecular genetics, paved the tative. The ease of travel and growth of the worldwide re-
way for new approaches to studying animal diversity. Pop- search community created opportunities for physiologists
ulation demographics led to massive hiring of university- to study unusual animals in exotic places.
based scientists, creating a critical mass of researchers It was during this period that Dr. Per Scholander, a
interested in understanding the physiological diversity of renowned animal physiologist and director of the Scripps In-
animals. It became commonplace to see international stitute of Oceanography (University of California, San Diego),
From Chapter 1 of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
26
Research vessel, Alpha Helix.
spearheaded an initative that would allow teams of interna-

tional researchers to work together to study biological prob-
lems in remote locations. After many years of effort and
negotiation with researchers, universities, and government
agencies, the Alpha Helix program was launched.
The Alpha Helix was an oceanic research vessel named
after the structural model of DNA proposed by Watson and
Crick only 10 years earlier. It was purchased in 1964 by the
Scripps Institute of Oceanography through a $1.5 million Elephant seal.
grant from the U.S. National Science Foundation. The ship
was built to provide technically sophisticated laboratories The trip home passed through the Galapagos Islands,
for experimental biologists to use as the ship explored the where researchers studied the same animals that Darwin
unusual natural habitats of the world. Although launched studied a century earlier. The cruises over the next 15 years
and funded by the U.S. government, it supported the re- took researchers back to these same locations, and to oth-
search of both American and international scientists. On ers such as the Bering Sea (cold-water fishes), New Guinea
her maiden voyage in 1966, the Alpha Helix carried 12 crew (tropical animals), Guadalupe Island (fish and elephant
members and 10 scientists around the world on a “quest of seals), Antarctica (polar animals), the eastern Pacific (reef
biological and medical knowledge.” The Alpha Helix pro- animals, sharks, whales), Australia (sea snakes), Hawaii
gram was a career-changing experience that inspired a (deep-sea fishes), and the Philippines (nautilus). Many of
whole generation of animal physiologists. these animals had never been studied, and their physiolog-
The ship was the floating laboratory for three or four ical properties were largely mysterious at that time.
expeditions each year, bringing together teams of scien- The Alpha Helix exemplified the explosion of work in
tists with complementary interests and expertise. The inau- animal physiology that began in the 1960s. The Alpha Helix
gural expedition of the Alpha Helix was a six-month program continued until 1980, at which point government
expedition to the Great Barrier Reef, where researchers support ended and the ownership of the vessel was trans-
studied coral reefs, tropical mangrove forests, and the ani- ferred to the National Science Foundation. The vessel itself
mals that lived in the sea and on land. Three months after remains in active duty, based at the University of Alaska, and
returning from Australian waters, a new expedition was is used for international oceanographic research. The Alpha
launched to South America. The Alpha Helix traveled up the Helix program gave hundreds of researchers the opportunity
Amazon River to study the behavioral and evolutionary to learn firsthand about the diversity of the natural world and
properties of fish and terrestrial animals in the neotropics. how organisms function in their various environments.2
27
Overview
In the words of the renowned Genotype Evolution
physiologist Knut Schmidt-
Nielsen, animal physiology is Adult Phenotype
“the study of how animals
Molecules
work.” Animal physiologists
study the structure and function Cells
of the various parts of an ani-
mal, and how these parts work Development Tissues Physiology Reproduction
and
together to allow animals to behavior
perform their normal behaviors Organs
and to respond to their environ-
Organ
ments. One hallmark of animal systems
physiology is diversity. More
than a million different species
of animals live on Earth, each Environment Random Natural
processes selection
of which has acquired through
evolution countless unique
properties. Each physiological
process is a product of the activ-
ities of complex tissues, organs, Figure 1 An overview of the factors influencing the phenotype of
adult animals
and systems that can arise
through complex patterns of genetic regulation of influence the adult phenotype. Organisms may
countless cells. change their behavior as a result of learning, or al-
Despite this great diversity, there are many ter their physiological responses through modifica-
commonalities within physiology—unifying themes tion of their phenotypes. Ultimately, the phenotype
that apply to all physiological processes. First of all, (morphology, physiology, and behavior) of an ani-
physiological processes obey physical and chemical mal influences its reproductive success. Differential
laws. Second, physiological processes are regulated survival of organisms with distinct phenotypes may
to maintain internal conditions within acceptable result in evolutionary change in the genotype of a
ranges. This internal constancy, known as homeo- population over many generations.
stasis, is maintained though feedback loops that
sense conditions and trigger an appropriate re-
sponse. Third, the physiological state of an animal Physiology: Past and Present
is part of its phenotype, which arises as the product
of the genetic makeup, or genotype, and its inter- Modern animal physiology is a discipline con-
action with the environment. Fourth, the genotype cerned with the whole range of processes that af-
is a product of evolutionary change in a group fect animal function. Although animal physiology
of organisms—populations or species—over many is an experimental science that can trace its roots
generations. back more than two millennia to the ancient
Most physiological studies examine how vari- Greeks, it plays an important role in modern biol-
ous processes affect the physiological phenotype of ogy as the intellectual glue that holds disparate bi-
an animal (Figure 1). Both the genotype of an or- ological fields together.
ganism and its environment interact through devel-
opment to produce the phenotype of the adult
organism. The phenotype is itself the product of
processes at many levels of biological organization, A Brief History of Animal Physiology
including the biochemical, cellular, tissue, organ, Although Greek thinkers such as Hippocrates
and organ system levels. Together these processes (460–circa 377 B.C., the father of medicine) and
interact to produce complex behaviors and physio- Aristotle (384–322 B.C., the father of natural his-
logical responses. The environment can, in turn, tory) were not primarily experimental physiolo-
28
gists, Hippocrates’ emphasis on the importance of William Harvey (1578–1657) identified the
careful observation in the treatment of disease and path of blood through the body, and showed that
Aristotle’s emphasis on the relationship between contractions of the heart power this movement.
structure and function make them important fig- Although Harvey could not see the fine capillaries
ures in the history of physiology. Claudius Galenus that connect arteries and veins using the crude
(A.D. 129–circa 199), known as Galen, was the first magnifying glasses that were available at the
to use systematic and carefully designed experi- time, he postulated that they must exist to form a
ments to probe the function of the body. Galen closed circulation for the blood around the body.
made extensive use of dissection and vivisection of Harvey showed how dissections, close observa-
nonhuman primates such as Barbary apes and tion of living organisms, and careful experiments
other mammals to test his physiological ideas. For could be combined to teach us about the func-
example, Galen performed experiments in which tions of the body.
he tied off the ureters (the tubes leading from the Prior to the 18th century, physiologists fell into
kidney to the bladder), and observed that the kid- one of two camps. The iatrochemists believed that
neys swelled. From this observation he concluded body function involved only chemical reactions,
that the kidneys play a role in the formation of whereas iatrophysicists believed that only physi-
urine. Similarly, he tied off the laryngeal nerve cal processes were involved. In the late 17th and
(which leads to the vocal cords) of a living pig, at early 18th centuries a Dutch physician, Hermann
which point the pig stopped squealing. From this Boerhaave, and his Swiss pupil, Albrecht von
experiment, he concluded that the brain and nerves Haller, proposed that bodily functions were a com-
regulate the voice. This experimental work, combination of both chemical and physical processes.
bined with his practice as a physician to the Roman By uniting these two approaches, these researchers
gladiators, allowed him to formulate detailed de- were among the earliest proponents of physiology
scriptions of anatomy and elucidate the basis of as we understand it today.
many physiological processes. Although much of In the 19th century physiological knowledge
Galen’s work was fundamentally incorrect when began to accumulate at a rapid rate. For example,
viewed from a modern perspective, his emphasis in 1838 Matthias Schleiden and Theodor Schwann
on careful observation and experimentation makes formulated the “cell theory,” which states that or-
him the founder of physiology. ganisms are made up of units called cells, a discov-
During the Middle Ages the medical traditions ery that paved the way for modern physiology.
of the ancient Greeks were practiced and further Claude Bernard (1813–1878) discovered that he-
developed by physicians in the Muslim world, moglobin carries oxygen, that the liver contains
most notably Ibn al-Nafis (1213–1288), who was glycogen, that nerves can regulate blood flow, and
the first to correctly describe the anatomy of the that ductless glands produce internal secretions
heart, the coronary circulation, the structure of (hormones) that are carried in the blood and influ-
the lungs, and the pulmonary circulation. He was ence distant tissues. One of Bernard’s most impor-
also the first to describe the relationship between tant contributions was his concept of the milieu
the lungs and the aeration of the blood. interieur (internal environment); he postulated
The Renaissance brought a new flowering of that living organisms preserve a distinct internal
physiological research in the Western world. Jean- environment despite changes in the external envi-
Francois Fernal (1497–1558) outlined the current ronment. This concept—the ability to maintain a
state of knowledge of human health and disease. constant internal environment—was later devel-
Andreas Vesalius (1514–1564), author of the first oped more fully by the American physiologist Wal-
modern anatomy textbook, demonstrated that ter B. Cannon (1871–1945), who coined the term
Galen had made many errors in both anatomy and homeostasis.
physiology. Because Galen was thought to have Until the 20th century, physiologists made lit-
done everything that was necessary to understand tle distinction between animal physiology and
the workings of the body, many medical practi- medical physiology. Most physiological experi-
tioners of the time shunned physiological re- ments on animals were performed with the goal of
search. Thus, by showing that Galen was not improving the understanding of the human body
entirely correct, Vesalius’s work triggered the both in health and in illness. But in the 20th cen-
modern study of anatomy and physiology. tury biologists became interested in applying the
29
newly emerging physiological knowledge to ani- Any attempt to survey the major figures in the
mals living in diverse environments, and in trying history of animal physiology excludes countless
to understand the nature of physiological diversity. other researchers who have made important con-
Per Scholander (1905–1980) was one of the tributions to the field.
first and most influential of these comparative
physiologists. Scholander studied a remarkable
diversity of physiological responses, including the
mechanisms involved in diving vertebrates, the re- Subdisciplines in Physiological
sponses of warm-blooded animals to cold environ- Research
ments, and how fish fill their swim bladders Modern physiological knowledge is the product of
(air-filled organs that fish use for buoyancy). the efforts of multitudes of scientists with diverse
Scholander also organized the influential expedi- interests and expertise. Typically, an animal phys-
tions of the Alpha Helix in the research program iologist specializes in one or two subdisciplines of
described in the opening essay of this chapter. physiology, with an awareness of the central is-
The contributions of C. Ladd Prosser sues in other, related subdisciplines. There are
(1907–2002) include the discovery of so-called three main ways to categorize physiological sub-
central pattern generators. These groups of disciplines: by the biological level of organization,
neurons coordinate many rhythmic behaviors, in- by the nature of the process that causes physio-
cluding breathing and walking. Prosser also dis- logical variation, and by the ultimate goals of the
covered the relationship between muscle diameter research.
and conduction speed, and during World War II he
worked on the effects of radiation on animal life as
part of the Manhattan Project. Physiological subdisciplines can be
Knut Schmidt-Nielsen (1915–2007) devoted his distinguished by the biological level
career to understanding how animals live in harsh of organization
and unusual environments. In his classic early work Since physiology is concerned with biological func-
on the adaptations of the camel to desert life, he tion at many levels of organization (Figure 2), one
showed that the camel’s nose contains a countercur- of the most common ways to distinguish branches
rent exchanger that allows it to recapture moisture of physiology is by reference to these levels.
from exhaled air, resulting in an almost 60% reduc-
tion in water loss compared to other mammals. • Cell and molecular physiologists study
George Bartholomew (1923–2006) is the founder phenomena that occur at the cellular level,
of the field of ecological physiology, or the study of although these effects have important con-
how an organism interacts with its environment. sequences for higher levels of organiza-
Bartholomew combined the study of animal behav- tion. Cell and molecular physiologists
ior, ecology, and physiology to assess the evolution- might include researchers studying molec-
ary significance of adjustments or adaptations in ular genetics, signal transduction, meta-
animals to their environments. He identified the in- bolic biochemistry, or membrane biophysics.
dividual as the principal unit of natural selection, • Many physiologists focus their efforts on
and emphasized the importance of variation in specific physiological systems. A systems
physiology. physiologist is concerned with how cells
Peter Hochachka (1937–2002) and George and tissues interact to carry out specific re-
Somero (1941–) founded the field of adaptational sponsibilities within the whole animal. In
biochemistry. By applying the concepts and tech- fact, each of the chapters in Part Two of this
niques of biochemistry to the questions of compar- text is focused on a physiological system.
ative physiology, they have extended to the Thus, there are respiratory physiologists,
subcellular level our understanding of how ani- sensory physiologists, and so on.
mals adapt to hostile environments, providing in- • An organismal physiologist is most often
sights into the biochemical mechanisms that allow concerned with the way an intact animal un-
animals to live in habitats as diverse as the deep
sea, the Antarctic oceans, high mountain peaks,
and tropical rain forests.
30
Organisms
Organ systems
Molecules
Populations Cells
Organs
Atoms
Tissues
Communities Ecosystems Biosphere
Figure 2 Levels of biological organization Chemists and biochemists study the

properties of atoms and molecules. Molecular biologists study the properties of molecules and
cells. Physiologists study the interactions between molecules, cells, tissues, organs, and organ
systems to understand the structure and function of an organism. Ecologists study the interactions
of organisms, populations and communities to understand the properties of ecosystems, and
ultimately the biosphere.
dertakes a specific process or behavior. For An organismal characteristic such as meta-

example, an organismal physiologist might bolic rate is the product of multiple physio-
study changes in animal metabolic rate in logical systems interacting in complex ways.
response to a stressor, such as temperature. Some organismal physiologists specialize in
31
particular groups of animals: thus, there are Physiological subdisciplines can be

marine mammal physiologists, avian physi- distinguished by the process that
ologists, fish physiologists, and so on. generates variation
• An ecological physiologist studies how the Many physiologists are interested in how biologi-
physiological properties of an animal influ- cal functions change over time or in response to
ence the distribution and abundance of a changes in the environment. Thus, physiology can
species or population. For example, an eco- also be divided on the basis of the mechanism by
logical physiologist may study how the nutri- which changes or differences in physiological
ent distribution in the environment influences processes arise.
the growth rate of an animal. While organis-
mal physiologists may focus their research on • A developmental physiologist studies how
an interesting group of animals, ecological structures and functions change as animals
physiologists are more concerned with how grow through the various life stages from
an interesting environment affects diverse embryo to reproductive maturity, to senes-
animals within that environment. cence and death. These developmental path-
ways transform omnipotent stem cells into
• An integrative physiologist attempts to un-
specialized cells, forming multicellular tis-
derstand physiological processes at a vari-
sues and physiological systems. To under-
ety of levels of biological organization and
stand the diversity in animal morphology
across multiple physiological systems. For
and function, it is important to appreciate
example, an integrative physiologist might
how these structures arise in development.
study how variation in hemoglobin genes
contributes to differences in oxygen deliv- • An environmental physiologist assesses how
ery and how those differences in the ability animals mount physiological responses to
to extract oxygen from the environment environmental challenges. For example,
contribute to the geographical distribution changes in temperature have the potential to
of the species. affect many physiological systems in complex
ways. An environmental physiologist is con-
Of course, there is a great deal of overlap among
cerned with the way an individual animal or-
these subdisciplines, and making distinctions
ganizes or reorganizes its physiology to
among them is often difficult. In fact, few physiolog-
survive the environmental challenge.
ical researchers confine themselves exclusively to
investigating a single level of biological organiza- • An evolutionary physiologist is primarily
tion. Often a physiologist interested in a process at concerned with explaining how specific
one level of organization also studies its function at physiological traits arise within lineages
the next lower level. This approach, known as re- over the course of multiple generations.
ductionism, assumes that we can learn about a sys- Thus, evolutionary physiologists may be in-
tem by studying the function of its parts. Although a terested in the origins of variation within
reductionist approach can be extremely illuminat- populations of a single species, or the basis
ing, and has been the basis of many important bio- of differences between closely related
logical discoveries, ultimately many processes have groups of animals.
characteristics that are not apparent simply by ex-
amining the component parts. This feature of com-
plex systems is called emergence, which is just
Animal physiology can be a pure or an
another way of saying that the whole is often more
applied science
than the sum of its parts. The emergent properties Physiological research can be distinguished on the
of a system are due to the interactions of the com- basis of the ultimate goal. The research of an
ponent parts of the system, and can be difficult to applied physiologist is intended to achieve a spe-
predict by studying each part in isolation. Physiolo- cific, practical goal. For example, physiologists
gists are usually interested in these emergent prop- study some animals because of their economic im-
erties, and thus physiologists study how molecules, portance. Thus, veterinary medicine relies on
cells, and tissues interact to produce the complex physiological research to improve the health of
system that is an organism. agricultural animals and household pets. Simi-
32
BOX 1 METHODS AND MODEL SYSTEMS

August Krogh Models in Animal Physiology
A model species is an organism that is proteins. Xenopus oocytes are large, so scientists can
studied by a wide community of researchers be- easily introduce foreign RNA by microinjection. The RNA
cause (1) it has features that are conducive to experi- is then translated and the protein sent to the appropri-
mentation and (2) understanding a process in the model ate location. For example, microinjection of RNA coding
provides insight into how the process works in other for membrane proteins causes the oocyte to translate
species of interest. Each model species has been cho- the protein and insert it into the membrane where its
sen because it demonstrates a combination of features functional properties can be assessed.
that make it well suited to some studies, though not all Many animals are useful models because of their de-
studies. This approach of using an animal model with velopmental biology. Nematodes are small animals
features that are favorable for scientific study is known composed of only a few thousand cells. The development
as the August Krogh principle: For every biological prob- from fertilized egg to adult has been studied to the point
lem there is an organism on which it can be most conve- that the fate of each cell has been mapped. Researchers
niently studied. can microinject substances into a designated cell at a
The importance of specific model systems changes specific developmental stage, knowing that specific cell
over time, as technologies advance and genomic data- will divide and differentiate into a specific tissue or or-
bases expand. An animal that was inconvenient to study gan. Zebra fish are useful models because the embryo
in the past may be much easier to study now. For exam- grows quickly and remains transparent for much of its
ple, mice became more useful models in developmental early development. This allows researchers to follow
physiology when transgenic mouse technologies be- complex cellular changes in living animals. Such studies
came readily available. are aided by transfection of genes encoding fluorescent
Knowledge gained from model systems is useful only if proteins that can be monitored more easily.
that information is relevant to other species. Most com- One important factor that determines the utility of a
monly, a model was originally chosen because of parallels model species is the ease with which genes can be
with human biology. Although the major model animals modified. The ability to generate mutations that result in
are quite different in appearance, much of the genetic and the gain or loss of a function allows physiologists to ex-
structural machinery that underlies development is simi- plore the importance of structural features. For many
lar among animals. The early patterns of embryonic de- years, random mutagenesis was the only way to gener-
velopment are similar in most vertebrate models, such as ate mutants. During this period, invertebrates and
zebra fish, chickens, mice, and humans. However, there small fish were used because it was possible to conduct
are always concerns about the phylogenetic distance be- large-scale screening projects to identify interesting
tween model systems. For this reason, each taxon has one mutants. More recently, genetic approaches to physiol-
or more species that have been trumpeted as a model. ogy have been facilitated by two trends. First, the prolif-
Some animals are useful models because they have eration of techniques for targeted mutagenesis makes it
unusual anatomical features. Perhaps the most famous easier to work on animals with long generation times,
example of such a model system is the squid giant axon. because large-scale screening is not needed. Second,
Squid are relatively simple animals that have certain ax- there is a rapid growth in the number of species for
ons large enough to be easily seen and readily manipu- which we have genomic information. Models become a
lated. The oocytes of the African clawed frog (Xenopus lot more convenient to use in genetic studies when we
laevis) are useful as models for the expression of foreign know their entire genome.
larly, much physiological research is aimed at un- In contrast to a medical physiologist, who uses
derstanding the human body. Although the ulti- animals to understand the human condition, a
mate goal of medical physiology is to understand comparative physiologist studies animals to ex-
human disease, medical physiology relies on other plore the origins and nature of physiological diver-
species as model systems (see Box 1, Methods and sity. Comparative animal physiology thrives on the
Model Systems: August Krogh Models in Animal breadth of physiological diversity, all the while
Physiology). searching for unifying themes.
33
cules, or solubility of gases in solution. Physiologists

2 CO N CEP T C HE C K
often borrow concepts and techniques from the
1. How would you define physiology? physical and chemical sciences, including engi-
2. Who were some of the major figures in neering, to help them understand how animals
physiology prior to the 20th century? work.
3. How do 20th-century comparative physiologists
differ from earlier physiologists?
4. What are the subdisciplines of physiology?
Mechanical theory helps us understand
how organisms work
5. How do some of the other sciences help us to
understand physiological processes? Each material has physical properties that are
useful in some contexts but not others. It would be
a mistake for an engineer to design a skyscraper
from Styrofoam, or a kite of concrete. Likewise, bi-
Unifying Themes in Physiology ological materials, or biomaterials—proteins, car-
In spite of the vast and diverse nature of animal bohydrates, and lipids—also have characteristic
physiology, several unifying themes and princi- physical properties that make them useful for
ples apply to all of its subdisciplines (Table 1). some processes but not others. For example, some
proteins are rigid and inflexible whereas others
readily deform. The physicochemical characteris-
tics of these biomaterials are determined by their
Physics and Chemistry: The Basis molecular properties. For example, a network of
of Physiology proteins can be made more rigid by additional
To understand physiology you need a basic under- bonds that cross-link proteins together. Cells use
standing of chemistry and physics. Animals are enzymatic reactions to fine-tune the physical
constructed from natural materials and thus obey properties of macromolecules. The macromole-
the same physical and chemical laws that apply to cules combine to form cells, which are collected to-
everything that we see around us. Temperature, gether to form tissues. Thus, the mechanical
for example, exerts its effects on physiology by al- properties of a tissue, such as bone, are conferred
tering the nature of chemical bonds in biomole-
Table 1 Unifying themes in animal physiology.
Unifying theme Examples

Physiological processes Mechanical engineering rules apply to physical properties of animals.
obey the laws of physics Chemical laws, including the effects of temperature, govern interactions between
and chemistry. biological molecules.
Electrical laws describe membrane function of all cells, including excitable cells.
Body size affects many physiological processes.
Physiological processes Homeostasis is the maintenance of internal constancy.
are usually regulated. Negative feedback loops help maintain homeostasis.
Positive feedback loops generate an explosive response.
The physiological Even identical genotypes can result in different phenotypes.
phenotype is a product Phenotype changes with normal development.
of the genotype and the Phenotype changes with environmental and physiological challenges.
environment. Phenotypic plasticity is the ability of a phenotype to change in response to environmental
conditions.
A genotype is the product The definition of adaptation is context dependent.
of evolution, acting In the strictest evolutionary sense, adaptation refers to a trait that confers an increase
through natural selection in reproductive success.
and other evolutionary Adaptation can also refer to phenotypic changes that improve the performance of a
processes. physiological system, without underlying evolutionary change.
Not all physiological differences are adaptations.
34
by the molecular properties of the components of the produced by tissue metabolism, and thus the meta-
bone-forming cells, the nature of the connections be- bolic rate of the animal as a whole depends on the
tween cells, and the interactions between tissues. mass of tissues. Metabolic heat is lost across the sur-
In addition to mechanical properties, other en- face of the body. Since heat production varies with
gineering concepts such as flow, pressure, resis- body mass and heat loss varies with body surface
tance, stress, and strain play important roles in area, a larger animal has more difficulty shedding
physiology. An engineer designing a system to metabolic heat than does a smaller animal.
pump water from a deep well takes into consider- It has long been known that metabolic rate of
ation factors such as the pressure gradients, fluid animals does not increase proportionately with
dynamics, the power of the pump, and resistance body mass. That is, animals differing 10-fold in
in the plumbing. A cardiovascular physiologist has body size differ less than 10-fold in metabolic rate
the same concerns in trying to understand how the (Figure 3). In the late 1800s, Max Rubner reported
heart delivers blood through the blood vessels. that the metabolic rate of dogs of various sizes was
constant when body surface area was taken into
account. For many years, it was thought that the
Electrical potentials are a fundamental relationship between body mass and metabolic
physiological currency rate was related to the ratio of surface area to vol-
Just as we use electricity to power many of the ma- ume. In the 1930s, Max Kleiber examined the in-
chines we use in our daily lives, animals use elec- fluence of body size on metabolic rate of birds and
tricity to power cellular activities. Cells establish a mammals. Based on these data, he formulated the
charge difference across biological membranes by allometric scaling equation, relating body mass
moving ions and molecules to create ion and elec- (M) and metabolic rate (y)
trical gradients. All cells and many organelles y ⫽ aM b
within cells rely on this potential difference, or
membrane potential, to drive processes that are where a is the normalization coefficient and b the
needed for survival. Animals also use changes in scaling coefficient. Kleiber’s work suggested the
electrical potentials to send signals within and be- value for b was closer to 0.75 (3/4) rather than the
tween cells, helping to coordinate the complex value of 0.67 (2/3) expected from Rubner’s studies.
processes of the body. Muscles and neurons, two These data, and many studies since, suggest that al-
cell types that are found only in animals, use lometric scaling of metabolism is not easily ex-
changes in membrane potential to send signals. plained by simple differences in ratio of surface
Thus, electrical theory has played an important area to volume. Despite the complexity of size-
role in helping physiologists to understand the dependent physiological properties, or perhaps
way that neurons and muscles work.
Biochemical and physiological patterns 1000 Elephant

Metabolic rate (watts)
Line of
are influenced by body size 100
unity Horse
Human
From tiny zooplankton weighing less than a mil- Chimpanzee
10
ligram to blue whales weighing over 100,000 kg, Goose
animals vary greatly in body size, and these dif- 1
Rat
ferences have profound effects on physiological
0.1
processes. One reason is that the ratio of the surface Small birds
Mouse
area to volume changes with body size. Consider an
animal shaped like a sphere. With a radius r, its 0.01 0.1 1 10 100 1000 10,000
Body mass (kg)
mass, or rather its volume (V) ⫽ (4/3)πr3 and its sur-
face area (A) ⫽ 4πr2. Since surface area increases by Figure 3 Metabolic rate of various birds and
the power of two, and volume increases by the mammals plotted against body weight on a double
power of three, the surface area is proportional to logarithmic scale The line of unity shows the relationship
that would be expected in the absence of allometric scaling. In
the volume to the 2/3 power, or V 0.67. This relation- this figure, an animal that is 10 times larger than another has a
ship between surface area and volume has an im- metabolic rate that is only about 7 times greater.
portant influence on thermal biology. Heat is (Source: Adapted from Schmidt-Nielsen, 1984)
35
because of the complexity, allometric scaling re- regulate a particular variable. For example, your
mains one of the dominant themes in comparative body temperature remains relatively constant only
animal physiology. Normally reticent physiologists because numerous physiological processes actively
have been inspired to engage in animated, and change, adjusting the rates of heat production and
sometimes vitriolic arguments about both the exact heat loss. For example, when you stand in the cold
value of b and the underlying mechanisms. air, your muscles may shiver to produce heat that
replaces the heat lost to the environment. Thus,
muscle activity changes in order to maintain con-
stant body temperature.
Physiological Regulation The nature of the physiological response to an
Most organisms are faced with environmental vari- environmental change depends on many factors.
ation. Temperature, food availability, and the phys- Short-term challenges can often be dealt with us-
iochemical environment around an animal may ing existing physiological systems. When a dog is
change with the time of day, the season, or the move- too hot, it can move to a cooler location or pant to
ment of an animal across the landscape. Multicel- shed heat in its breath. These are effective short-
lular animals can be classified according to the term behavioral and physiological approaches to
strategies they use to cope with changing conditions. reducing thermal stress. However, they are not ef-
Conformers allow internal conditions to fective long-term strategies. A dog hiding in the
change when faced with variation in external con- shade cannot hunt for food, and panting conflicts
ditions. For example, the body temperature of a fish with oxygen delivery during running. Instead,
will be low in cold water and high in warm water. dogs cope with long-term changes in temperature,
Thus, each of the cells in a fish’s body must cope such as seasonal cycles, by growing fur in the au-
with the effects of changes in external temperature. tumn and shedding fur in the spring.
Regulators maintain relatively constant in- This example illustrates several principles that
ternal conditions regardless of the conditions in govern physiological changes. First, some physio-
the external environment. Your body temperature logical strategies are effective in the short term but
is likely to be approximately 37°C whether you are less useful for the long term. Holding your breath
in a warm room or standing outside on a very cold may be fine for diving to the bottom of a lake, but
day. Your body has mechanisms to maintain its in- it will not help you cope with low oxygen levels
ternal temperature, and thus the vast majority of while you climb Mount Everest. Second, some
the cells in your body do not have to cope with the strategies require a significant investment in re-
effects of changes in ambient temperature. sources and need longer to take effect. Hair
Each strategy has its benefits and costs. Be- growth, for instance, is a relatively slow process
cause physiological responses demand metabolic that requires metabolic energy. Third, some stres-
energy, conforming is much less expensive than sors are sufficiently predictable that animals re-
regulating. However, environmental changes can model physiology in anticipation of the stress, and
have deleterious effects on physiology, so regulat- often in predictable cycles. Many physiological
ing provides a much more stable internal environ- processes change daily, showing a circadian
ment. Animals may be regulators with respect to rhythm. Some changes are seasonal, such as the
one internal parameter, but conformers with regrowth and shedding of fur. Other patterns, such as
spect to another parameter. For example, lizards human reproductive cycles, are linked to the lunar
conform to external temperature but regulate their cycle. In some cases, cyclical physiological changes
internal salt concentrations within a narrow range. proceed without any environmental input, but gen-
erally they arise in response to specific environ-
mental cues, such as temperature or photoperiod.
Homeostasis is the maintenance
of internal constancy
The maintenance of internal conditions in the face
Feedback loops control
of environmental perturbations is referred to as
physiological pathways
homeostasis. The word homeostasis does not im- To maintain homeostasis, animals must (1) de-
ply that there is no change in the organism, only that tect external conditions and (2) if necessary ini-
the animal initiates specific responses to control or tiate compensatory responses that (3) keep vital
36
areas buffered against unfa-

+ Heat production –
vorable change. Animals most
often maintain homeostasis
Cold Hot
using a reflex control path- Reduced exposure Normal exposure Elevated
way. A change in the inter- Tb Tb Tb
nal or external environment
provides a stimulus. The
stimulus then causes a re- – Heat dissipation +
sponse. For instance, when
you depress the gas pedal of Figure 4 Antagonistic controls Your body temperature is held relatively constant by
your car (the stimulus), the antagonistic loops. If cold conditions cause a decrease in your body temperature, this triggers
an increase in heat production and a reduction in heat dissipation. When body temperature
car accelerates (the re- increases, heat production pathways are inhibited and heat dissipation pathways are
sponse). If you take your foot stimulated, correcting body temperature.
off the gas (remove the stim-
ulus), the car will slow down.
Animals fine-tune physiological responses by Positive feedback loops cause
using antagonistic controls: independent regu- explosive responses
lators that exert opposite effects on a step or path-
Some physiological systems are controlled by
way. In the car analogy above, the gas pedal and
positive feedback loops. Unlike negative feed-
the brake are examples of antagonistic controls.
back, which minimizes changes in the regulated
You can cause the car to decelerate by taking your
variable, positive feedback loops maximize changes
foot off the gas or depressing the brake, but the
in the regulated variable. For example, the mus-
car’s response will be greater if you use both in
cles in the stomach are normally regulated to con-
combination. Animals control body temperature
tract and relax in a regular pattern to gently mix
by regulating both heat production and heat dissi-
food. However, when a toxin is detected, a positive
pation (Figure 4). Hormones mediate many antag-
feedback loop is triggered to induce forceful con-
onistic controls. Insulin and glucagon are
tractions that propel the food back up the esopha-
antagonistic controllers of glucose levels.
gus to induce vomiting. Pathways involving
positive feedback loops begin slowly but rapidly
Negative feedback loops increase in intensity. In a positive feedback loop
maintain homeostasis there must also be a signal that allows the animal
to stop the process at the proper time, so that the
In a negative feedback loop, the response
action does not spiral out of control.
sends a signal back to the stimulus, reducing the
intensity of the stimulus. For example, when you
eat, the incoming food causes the stomach to
swell. The change in stomach volume and early Phenotype, Genotype,
digestion products trigger a negative feedback and the Environment
loop, acting through your brain, to reduce your The physiological properties of an animal are as-
appetite. pects of the animal’s phenotype. Physiological
Many physiological systems have a set-point, traits, like other characteristics of animals, are de-
a preferred physiological state defended through termined in large part by the genes of the
feedback loops. Your body temperature has a set- genome—the genotype—but are also influenced
point of approximately 37°C. When temperature by the way the genes are regulated, particularly in
rises, your body may sweat to cool you down, response to external conditions.
whereas a decrease in body temperature may trig- An individual genotype has the capacity to
ger shivering to warm you back to your set-point. produce considerable variation in cellular proper-
Although the set-point for human body tempera- ties. Although the same genes are found in each
ture is near 37°C, the exact body temperature set- cell, they are regulated in combinations to allow
point varies between individuals and changes animals to develop distinct tissues. During this
throughout the day. process of tissue formation, called morphogenesis,
networks of genes are turned on and off in precise
37
patterns to create the appropriate phenotype. For

example, when the fertilized egg of a frog develops
into a tadpole, a developmental program is turned
on to produce the gills and a tail. When the tadpole
undergoes metamorphosis, another program is
triggered that results in the formation of the lungs
and legs, and death of the cells in the gills and tail.
In addition to orchestrating the normal develop-
mental program, the genotype controls the way
animals can alter their phenotype in response to
physiological and environmental conditions. For
example, changes in the expression of genes allow
your muscles to change in size and strength in re-
lation to exercise training. The differences in
genotype among animals are central to the pheno-
typic variation upon which natural selection acts.
Every individual genotype has a capacity to differ
in complex, often unpredictable ways because of (a) Daphnia reared (b) Daphnia reared
the way the genes respond to external conditions. in the absence in the presence
of predator extract of predator extract
Figure 5 Phenotypic plasticity and

A single genotype results in more than polyphenism Alternative morphs of the water flea,
one phenotype Daphnia pulex. When genetically identical individuals are
reared in the absence of predator extracts, these features
A single genotype can result in multiple pheno- are absent. When reared in the presence of chemical
types, depending on the environmental conditions extracts of predators, Daphnia pulex have a large helmet-
that the animal experiences. For example, if iden- shaped head and a long spiky tail.
tical twins were raised in different places, it is pos-
sible that one twin might grow taller than the they develop with much smaller heads and a
other due to differences in diet. This ability of a shorter, less spiky tail (Figure 5). Adult water fleas
single genotype to generate more than one pheno- retain these morphologies even if the predator ex-
type, depending on environmental conditions, is tracts are removed from the water.
called phenotypic plasticity. We observe this
phenomenon most commonly at the population
level, where individuals with similar genotypes Acclimation and acclimatization result
can have different phenotypes depending on envi-
in reversible phenotypic changes
ronmental conditions. The term phenotypic plas- Most animals are able to remodel their physiolog-
ticity encompasses a wide range of changes in ical machinery in response to external conditions.
phenotype, some reversible and some irreversible. Physiologists use the related terms acclimation
Developmental plasticity, or polyphenism, is a and acclimatization when referring to processes
form of phenotypic plasticity in which develop- that cause reversible changes in the phenotype of
ment under different conditions results in alterna- an organism in response to an environmental
tive phenotypes in the adult organism that cannot change. The word acclimation refers to the
be reversed by subsequent changes in the environ- process of change in response to a controlled en-
ment. The similar concept of a reaction norm, or vironmental variable (usually in a laboratory set-
the range of phenotypes produced by a particular ting), while the word acclimatization refers to the
genotype in different environments, applies to process of change in response to natural environ-
phenotypes that exist as a continuum. For exam- mental variation. For example, if you take a fish
ple, when water fleas (Daphnia pulex) are reared from water at 15°C and leave it in water at 5°C,
in the presence of predators (or even chemical ex- you will observe a variety of changes in muscle
tracts of predators) they develop large, armored, biochemistry, metabolic rate, and other physiolog-
helmet-shaped heads and an elongated spiny tail. ical parameters. This process would be referred to
When they are reared in the absence of predators, as acclimation. In contrast, if you compare a fish
38
that you capture in the summer from a lake with a ural selection, that is, a change in a population or
mean temperature of 15°C with a fish that you group of organisms over evolutionary time. Many
capture in winter from a lake at 5°C, you will ob- evolutionary biologists argue that the word
serve many of the same changes, but in this case adaptation should only be used in this context.
the process would be termed acclimatization. Ac- However, physiologists often use the word
climatization may be the result not just of the tem- adaptation as a synonym for the word acclimation.
perature change, but also of changes in day One usage is in the context of phenotypic plasticity:
length, food availability, and any other environ- a beneficial change in an individual’s physiology
mental parameters that vary between summer that occurs over the course of its lifetime. For exam-
and winter. In general, both acclimation and ac- ple, a medical physiologist might discuss exercise
climatization are reversible physiological changes. adaptations: the changes in the muscles and heart
that occur during exercise training. In this text,
adaptation is used in the context of evolutionary
adaptation, but it is important that you learn to
Physiology and Evolution make the distinction between this definition and
One of the fundamental challenges of animal phys- the way the term is used by other scientists and the
iology is to understand and account for the great general community.
diversity of animal body forms and the strategies To an evolutionary physiologist, an adaptation
that animals use to cope with their environments. is a trait that arose via a process such as natural
Consider the neck of a giraffe, which, in relation to selection and conveys an increase in reproductive
its body size, is far longer than the neck of its clos- success. Thus, an evolutionary adaptation is the
est living relative, the okapi. When a physiologist result of processes that occur over the course of
thinks about the neck of a giraffe, what question many generations, rather than within the lifetime
first springs to mind? A respiratory physiologist of a single individual. The evolution of insecticide
might wonder: how can a giraffe breathe through resistance in insects provides an excellent exam-
such a long neck? A cardiovascular physiologist ple of the principles of adaptive evolution. Over the
might wonder: how can a giraffe’s heart pump last 50 years, chemical insecticides have been
blood all the way up to its head? These mechanis- used to kill insects that harm crops or carry dis-
tic questions are amenable to the experimental ease. For instance, organophosphates have been
methods of physiology and can be addressed using used for decades to control populations of insects,
many of the techniques and conceptual ap- such as the common house mosquito Culex pipi-
proaches we discuss in this text. In contrast, an ens. Organophosphates kill mosquitoes by inhibit-
evolutionary physiologist might wonder: why does ing acetylcholinesterase, an enzyme that is vital
a giraffe have a long neck? This question actually for neuronal transmission. The insecticides kill off
encompasses two different kinds of thinking. If we all or most of the susceptible mosquitoes, but
wish to address the proximate cause of the gi- those few rare individuals with beneficial muta-
raffe’s long neck, we might examine the genes that tions survive and reproduce. This differential sur-
specify the size or number of vertebrae in the vival changes the structure of the population.
skeleton. Alternatively, we might wish to under- Resistant populations of Culex pipiens have
stand the ultimate cause of the giraffe’s long evolved in two ways. Some mosquitoes have mu-
neck: whether long necks provided an evolution- tations in the acetylcholinesterase gene, which
ary advantage to the ancestors of the giraffe. To makes the enzyme more tolerant of the insecticide.
address these ultimate questions we need to con- Other mosquitoes have extra copies of the esterase
sider the impact of evolutionary change and the gene, which encodes an enzyme that converts the
adaptive significance of the physiological traits organophosphate into a less toxic form. These mu-
that we study. tations are vital for survival in the presence of the
insecticide, but in the absence of insecticide the in-
dividuals carrying these mutations are at a disad-
What is adaptation? vantage. Those that overproduce esterase use
Adaptation has two distinct meanings within the energy that could serve other physiological func-
context of physiology. The most common usage tions; those with the mutated acetylcholinesterase
refers to the product or process of evolution by nat- have an enzyme that does not function quite as
39
well as the nonmutant (or wild type). Thus, these diversity. One of the best ways to understand
genotypes are superior to wild-type genotypes how an animal works is to establish in which
only when the insecticides are present. ways the animal is similar to other organisms.
We can distill several general principles about Some animal traits are shared among all organ-
the process of evolutionary adaptation from the isms, some among all animals, and some among
evolution of insecticide tolerance in mosquitoes: related animals (lineages). Other traits are truly
unique to the species under study.
1. For evolution to occur, there must be varia-
When a new species of insect is discovered
tion among individuals in the trait under
deep in the heart of the Amazon jungle, we al-
consideration.
ready know many of its features. Like all eukary-
2. The trait must be heritable—genetically deter- otic organisms, it will possess a genome of DNA,
mined and passed on to offspring. proteins of the same 20 amino acids, and phos-
3. The trait must increase fitness—the reproduc- pholipid membranes. Like other animals, its
tive success of the individuals that have the cells will be connected to each other with pro-
trait. teins such as collagen and elastin, and it will
4. The relative fitness of the different genotypes have nerves and muscles that allow it to sense
depends on the environment. If the environ- the world around it and move from place to
ment changes, the trait may no longer be place. Like other invertebrates, it will lack a
beneficial. spinal cord. Like other arthropods, it will have
an exoskeleton of chitin. Like other insects, it will
Not all differences are evolutionary have six legs and paired wings. We can be rea-
adaptations sonably certain of these features because the
new species of insect has an evolutionary history
Not all evolution is adaptive. For example, genetic
that included, at some point in the last billion
drift, or random changes in the frequency of par-
years, ancestors that it shared with other in-
ticular genotypes in a population over time, can
sects, invertebrates, metazoans, and ultimately
result in substantial differences in the phenotype
all eukaryotic organisms. Thus, species that are
of two populations, independent of any adaptive
closely related to each other are likely to share
evolution. Genetic drift is most likely to occur in
more common features than do species that are
small populations and is a result of happenstance,
distantly related.
not of differences in fitness. If a forest fire kills
most of the individuals of a population, the few
survivors may happen to display a different
genotype frequency than the ancestral popula- 2 C O N C EP T CH E CK
tion. After a number of generations, the derived 6. What are the major unifying themes in
population may differ from the ancestral popula- physiology?
tion, but not for any reason related to natural se- 7. What is homeostasis?
lection and fitness. This example of genetic drift is 8. Compare and contrast negative feedback with
known as the founder effect. positive feedback.
9. What is a phenotype?
Evolutionary relationships influence 10. What are some of the ways in which an
morphology and physiology individual’s phenotype can change?
Although it is easy to be overwhelmed by the di-

versity in animal form and function, animal biol-
ogists strive to understand the nature of this
40
Summary
Physiology: Past and Present k Body size can have a profound influence on an-
k Throughout history, physiological advances imal physiology.
have been made because of detailed observa-
k Conformers allow their internal environment to
tions of living and dead animals, united with
change, whereas regulators maintain their in-
carefully planned experiments to elucidate how
ternal environment relatively constant in the
animals work.
face of external change.
k Advances in physiology have followed in step
k Homeostasis is the maintainance of an internal
with advances in physics, chemistry, and mo-
state that is constant or within tolerable limits.
lecular biology, which have allowed physiolo-
gists to gain an ever-increasing understanding k Homeostasis is maintained by reflex control
of animal structure and function. pathways that include antagonistic controls,
negative feedback, and positive feedback.
k Physiology can be divided into several subdisci-
plines. It can be divided based on the level of bi- k Negative feedback loops tend to minimize the
ological organization that the researcher change in the regulated variable, while positive
studies, what kind of physiological variation feedback loops tend to amplify the change.
the researcher studies, or the purpose of the
k An animal’s phenotype is the result of a com-
research.
plex interaction between its genotype and its
k Physiological processes can be reduced to environment. Because of phenotypic plasticity,
their component parts at a lower level of bio- one genotype may produce many phenotypes,
logical organization and each part studied in depending on the effects of the environment.
isolation. Emergent properties of the system
k Polyphenism is a type of phenotypic plasticity in
result from the interactions of these parts and
which the environment that an organism en-
are not always evident when the parts are
counters as it develops influences the pheno-
studied in isolation.
type of the adult. These changes are usually
Unifying Themes in Physiology irreversible.
k A number of important unifying themes apply
k Acclimation and acclimatization are types of
across all of the subdisciplines of physiology.
phenotypic plasticity in which the environment
(1) Physiological processes obey physical and
causes reversible changes in an organism’s
chemical laws. (2) Physiological processes are
phenotype.
often regulated. (3) Genotype and phenotype
are linked. (4) Phenotypes are the product of k The genotype of an animal is the result of evo-
evolution. lutionary processes, including adaptation and
genetic drift.
k Physiological processes obey physical and
chemical laws, and physiologists often use the-
ories and ideas from physics, chemistry, bio-
chemistry, and molecular biology to help them
understand how organisms work.
41
Synthesis Questions
1. Home heating systems such as a furnace are help the herpetologist understand the nature
regulated via negative feedback. Describe how of this variation.
such a system might work. 3. What physical, chemical, or physiological con-
2. A herpetologist (a biologist who studies rep- straints may lead to allometric scaling?
tiles and amphibians) brings two frogs into 4. Why do physiologists need to understand evo-
your lab. One frog is blue, and the other is lution?
green. For each of the main subdisciplines
5. Compare and contrast adaptive evolution and
that were described in this chapter, outline the
genetic drift.
kinds of investigations you might perform to
For Further Reading

See the Additional References section at the end This entertaining autobiography provides a
of the chapter for more references related to the personal glimpse into the life and work of one of
topics in this chapter. the 20th century’s greatest animal physiologists.
Physiology: Past and Present Schmidt-Nielsen, K. 1998. The camel’s nose:
Memoirs of a curious scientist. Washington,
The following four papers are essays on the DC: Island Press/ Shearwater Books.
history of important subdisciplines in physiology.
Each provides insight into the major questions Unifying Themes in Physiology
and suggestions for the future of the field.
The following works summarize some of the
Costa, D. P., and B. Sinervo. 2004. Field important unifying themes in animal physiology.
physiology: Physiological insights from
animals in nature. Annual Review of Feder, M. E., A. F. Bennett, W. W. Burggren, and
Physiology 66: 209–238. R. B. Huey. 1987. New directions in ecological
physiology. Cambridge: Cambridge University
Feder, M. E., A. F. Bennett, and R. B. Huey. 2000. Press.
Evolutionary physiology. Annual Review of
Ecology and Systematics 31: 315–341. Mangum, C. P., and P. W. Hochachka. 1998.
New directions in comparative physiology
Somero, G. N. 2000. Unity in diversity: A and biochemistry: Mechanisms, adaptations,
perspective on the methods, contributions, and and evolution. Physiological Zoology 71:
future of comparative physiology. Annual 471–484.
Review of Physiology 62: 927–937.
Tracy, C. R., and J. S. Turner. 1982. What is This fascinating book attempts to unify the
physiological ecology: A collection of disparate fields of developmental biology and
commentaries by noted physiological ecologists. evolution. It contains many important themes
Bulletin of the Ecological Society of America 63: that are relevant to animal physiology.
340–346. Gerhart, J., and M. Kirschners. 1997. Cells,
embryos and evolution: Toward a cellular
These two short books summarize the history of and developmental understanding of
medical physiology and some of the most phenotypic variation and evolutionary
important contributors to its development. adaptability. Malden, MA: Blackwell
Franklin, K. J. 1949. A short history of Science.
physiology. London: Staples Press.
Leake, C. D. 1956. Some founders of physiology.
Washington, DC: American Physiological
Society.
42
This book of the collected essays of J. B. S. This brief review summarizes the mechanisms of
Haldane includes his famous essay on the insecticide resistance in mosquitoes.
problems of biological scaling. Raymond, M., C. Berticat, M. Weill, N. Pasteur, and
Haldane, J. B. S. 1985. On being the right size C. Chevillon. 2001. Insecticide resistance in the
and other essays, J. M. Smith, ed. Oxford: mosquito Culex pipiens: What have we learned
Oxford University Press. about adaptation? Genetica 112–113: 287–296.
These works address the concept of phenotypic This readable book discusses the physiological
plasticity from a variety of viewpoints. implications of animal size.
Piersma, T., and J. Drent. 2003. Phenotypic Schmidt-Nielsen, K. 1984. Scaling: Why is
flexibility and the evolution of organismal animal size so important? Cambridge:
design. Trends in Ecology and Evolution 18: Cambridge University Press.
228–233.
Pigliucci, M. 2001. Phenotypic plasticity— This book provides a comprehensive introduction
Beyond nature and nurture. Baltimore: Johns to physics and engineering principles as applied
Hopkins University Press. to physiology.
West-Eberhard, M. J. 2003. Developmental Vogel, S. 1988. Life’s devices. Princeton, NJ:

plasticity and evolution. Oxford: Oxford Princeton University Press.
University Press.
Additional References
Alexander, R. M. 1985. The ideal and the feasible: Physical Gould, S. J., and E. S. Vrba. 1982. Exaptation: A missing term
constraints on evolution. Biological Journal of the Linnean in the science of form. Paleobiology
Society 26: 345–358. 8: 4–15.
Bartholomew, G. A. 1986. The role of natural history in Jorgensen, C. B. 1983. Ecological physiology: Background
contemporary biology. BioScience 36: 324–329. and perspectives. Comparative Biochemistry and
Bennett, A. F. 1997. Adaptation and the evolution of Physiology, Part A: Molecular and Integrative Physiology
physiological characters. In Handbook of physiology: A 75: 5–7.
critical, comprehensive presentation of physiological Kingsolver, J. G., and R. B. Huey. 1998. Evolutionary analyses
knowledge and concepts, ed. W. H. Dantzler (Section 13: of morphological and physiological plasticity in thermally
Comparative Physiology), vol. 1, 3–16. Bethesda, MD: variable environments. American Zoologist 38: 545–560.
American Physiological Society. Kleiber, M. 1975. The fire of life, 2nd ed. Huntington, New
Calder, W. A., III. 1984. Size, function, and life history. York: Krieger.
Cambridge, MA: Harvard University Press. Prosser, C. L. 1986. Adaptational biology: Molecules to
Crespi, B. J. 2000. The evolution of maladaptation. Heredity organisms. New York: Wiley.
84: 623–639. Schmidt-Nielsen, K. 1984. Scaling: Why is animal size so
Endler, J. A. 1986. Natural selection in the wild. Princeton, important? Cambridge: Cambridge University Press.
NJ: Princeton University Press. West, G. B., J. H. Brown, and B. J. Enquist. 1999. The fourth
Feder, M. E., A. F. Bennett, and R. B. Huey. 2000. dimension of life: Fractal geometry and allometric scaling
Evolutionary physiology. Annual Review of Ecology and of organisms. Science 276: 122–126.
Systematics 31: 315–341. Wieser, W. 1984. A distinction must be made between the
Garland, T., Jr., and P. A. Carter. 1994. Evolutionary ontogeny and the phylogeny of metabolism in order to
physiology. Annual Review of Physiology 56: 579–621. understand the mass exponent of energy metabolism.
Gibbs, A. G. 1999. Laboratory selection for the comparative Respiratory Physiology 55: 1–9.
physiologist. Journal of Experimental Biology 202:
2709–2718.
Credits
Credits listed in order of appearance.
1 Photo Researchers, Inc., Francois Paquet-Durand/Photo
Researchers, Inc.
2 Frans Lanting/National
Geographic Stock.
3 Minden Pictures, FRANS LANTING/Minden Pictures.
3 Jonathan Blair-Corbis.
43
Chemistry, Biochemistry, and Cell Physiology
About 4.5 billion years ago the planet Earth coalesced from with the capacity for catalysis and self-replication. At some
clumps of debris floating through space after the Big Bang. point around 4 billion years ago, these purely chemical
For another billion years Earth’s surface was a harsh place; processes produced the earliest life-form, the progenote.
asteroid bombardment and volcanic eruptions were con- The progenote was likely a chemoautolithotroph, capable of
stantly remodeling the face of the planet. Yet it was during surviving without oxygen and living on inorganic sources of
this tumultuous period that life on Earth began. Some re- energy and carbon. The closest living relatives to the
searchers believe that organic molecules arose from a pri- progenote are likely the archaea. These modern prokaryotes
mordial soup of methane, ammonia, and water, energized by can survive in the harshest environments that now exist on
atmospheric electrical discharges. Others believe that the Earth, such as sulfuric hot springs and deep-sea vents.
first organic molecules arose from chemical reactions of The progenote was the ancestor to all organisms on the
products of deep-sea volcanoes. Regardless of the origins of planet and, as a result, it is likely that many of the ubiquitous
the first small organic molecules, the pathway to living or- biological features arose in the progenote. The dependence
ganisms required the formation of larger macromolecules on water, the role of nucleic acids, the use of only 20 amino
44
A species of domain Archaea found in deep-sea vents.
acids in proteins, and the basic pathways of intermediary

metabolism are shared attributes of all living organisms.
Within the first billion years, the progenote gave rise to
three distinct types of organisms: eubacteria, archaea, and Connective tissue.
eukaryotes. Each lineage diversified independently over the
next 3 billion years. The two prokaryote lineages, eubacteria The transition from single-cell organisms to multicellu-
and archaea, remained single-cell organisms with little in- lar organisms occurred independently in the ancestors of
tracellular organization. In contrast, the ancestral eukary- plants, fungi, and animals. Each lineage found different so-
otes experienced evolutionary changes that resulted in the lutions to the challenge of building multicellular tissues.
production of membranous, subcellular compartments, The strategy used by fungi and plants relies on a cell wall for
thereby increasing intracellular organization. This began resistance to osmotic swelling and intercellular connec-
when the earliest eukaryotes found a way to package their tions. Animal cells, in contrast, found other solutions to
DNA into a membrane-bound compartment: the nucleus. these physical challenges. Na/K ATPase appeared early
Later, around 3 billion years ago, a eukaryote engulfed a bac- in animal evolution, enabling animal cells to regulate cell
terium that resembled a modern purple bacterium. Although volume, ionic balance, and osmotic balance. Collagen, one
the purple bacterium was probably ingested as food, it devel- of the vital proteins used to construct tissues, also arose
oped a symbiotic relationship with its host, replicating with very early in metazoan evolution. Once these physical asso-
the host cell. Over time, the bacterial endosymbiont lost its ciations were established, more elaborate pathways for in-
capacity to exist outside the cell, and the host cell became re- tercellular communication became possible and necessary.
liant on the metabolic contributions of the endosymbiont, the Even plants and fungi use chemical messengers to commu-
ancestor of mitochondria. By 2 billion years ago the diverse nicate, but animals possess much more complicated mech-
groups of protists were established. The protists include or- anisms for cell-to-cell signaling.
ganisms like the euglena (with features of both animals and We cannot understand the basis of animal diversity
plants), the trypanosomes (the single-cell flagellate para- without an awareness of the evolutionary origins of animals.
sites of blood that cause malaria), and amoebas (ciliated On the one hand, many cellular processes are similar across
cells that are the namesake of amoeboid movement). These broad taxa, so what we learn from studies on model species
protists were once called protozoans because they were of fungi and plants tells us a lot about how these features
considered to be primitive animals, but we now recognize the work in animals. On the other hand, each lineage evolved
protists to be a group of over 50 different phyla that emerged novel ways of using similar machinery to face the chemical
prior to the origins of the three main eukaryote kingdoms: and physical stresses imposed by the environment. By un-
plants, fungi, and animals. The term metazoan, which arose derstanding how different taxa solved similar problems, we
to distinguish multicellular animals from the single-cell pro- can better understand the constraints on animal cell func-
tozoans, is now used synonymously with “animal,” although tion and evolution. Modern animal physiology builds upon
some taxonomists separate sponges, the most primitive an- studies of organisms in diverse taxa to understand the cel-
imals, from true metazoans (eumetazoans). lular origins of diversity in animals.2
45
Overview entropy, states that the universe is becoming

more chaotic. Both laws describe the constraints
Physiology is the study of how animals work and that exist when energy is transferred between sys-
how they solve the challenges of surviving in the tems. With any spontaneous transfer of energy,
natural environment. Though we often think of some energy is diverted in a way that increases
animal physiology as a study of organs, systems, the entropy of a system, another form of energy.
and whole animals, it is important to recognize Although each chemical reaction conforms to
that reasons for many of these features can be these principles, living organisms are able to delay
traced back to underlying rules of chemistry, bio- the inevitable increase in chaos, or entropy. The
chemistry, and cell biology. Many of the properties survival of living organisms depends upon an abil-
of organs and systems emerge from regulation of ity to obstruct the natural processes that lead to
cellular processes, such as energy production, chemical breakdown.
membrane transport, cellular anatomy, and gene
expression (Figure 1). While the physiology of an
animal is much more than the sum of these molec-
Energy
ular and cellular processes, an awareness of how
cells work is vital to understanding complex phys- Energy is the ability to do work. In our world,
iological processes. gasoline is an important form of chemical energy.
We know that if the fuel tank of a car is full of gaso-
line, we have the potential to use this fuel to move
Chemistry the car from place to place. Burning the gasoline
causes the pistons in the engine to move, turning
In the purely chemical world, chemical reactions the drive-shaft and ultimately the wheels. This fa-
proceed according to the rules of thermodynam- miliar analogy illustrates many important princi-
ics. The first law of thermodynamics, also called ples that govern energy transfers or energetics.
the law of conservation of energy, states that en- The gasoline in the tank has potential energy
ergy can be converted from one form to another trapped within its chemical structure. When gaso-
but the total amount of energy in the universe is line is ignited, the resulting explosion releases
constant. The second law, also called the law of heat and carbon dioxide, moving the piston in its
ATP
ATP
ATP
Energy production Membrane transport
Cellular anatomy Gene expression
Figure 1 Cells and tissues Many cellular processes underlie physiological systems.
46
cylinder. This type of energy is kinetic energy, • Thermal energy is a form of kinetic energy
the energy of movement. that is reflected in the movement of parti-
The standard SI (Système International) unit of cles, and serves to increase temperature.
energy is the joule, although the imperial unit, the • Chemical energy is a form of potential en-
calorie, persists in the scientific literature. A joule ergy that is held within the bonds of chem-
is defined many ways, depending on the circum- ical structures.
stances. In electrical terms, a joule (J) is the amount
of energy used when 1 watt of power (W) is ex-
pended for the period of 1 second (1 J 1 W sec). Food webs transfer energy
Conversely, a watt is defined as a joule per second. Most biological processes are essentially transfers
You are probably most familiar with the units of of energy from one form to another. When you see
energy from your household electrical bill, with and smell a rose, the perception is essentially a
energy consumption expressed in kilowatt hours cascade of chemical and electrical energy trans-
(1 kW h 3.6 × 106 J). In more biological terms, fers between the sensory system and the brain. We
a piece of toast with butter has about 300 kJ of en- are more familiar with the concept of energy
ergy, which is enough energy to allow you to run transfers in the context of food webs. Plants cap-
for about 6 minutes or light a 100-watt bulb for ture the energy of photons and use it to create sug-
about 1 hour. ars. Herbivorous animals eat the plants, and
All energy is kinetic energy, potential energy, carnivores eat the herbivores. At each level, some
or a combination of both. However, in the context potential energy in the diet is assimilated to form
of biological systems it is more useful to classify animal tissues. Some potential energy is converted
types of energy by other categories. to heat, which is either lost to the environment or
retained within the animal. Dietary potential en-
• Radiant energy is energy that is released
ergy is also transferred to kinetic energy, when an-
from an object and transmitted to another
imals use nutrients to fuel locomotion. A portion of
object by waves or particles. The sun is the
the potential energy in the diet is locked in chem-
most obvious source of radiant energy,
ical structures that can’t be liberated by the ani-
emitting light that serves as an energy
mal, and is excreted in waste products. Light is the
source for photosynthetic organisms. Other
ultimate source of dietary energy for most ani-
forms of radiant energy occur in animals,
mals; it also provides the energy that allows ani-
such as the infrared radiation given off
mals to use vision and perceive color.
from warm-bodied objects. Radiant energy
The chemical energy transferred between
is important in the thermal biology of ani-
trophic levels is stored within molecules in the
mals.
bonds between atoms. Chemical reactions liberate
• Mechanical energy is a combination of po- energy from one bond in order to produce other
tential and kinetic energy that can be used bonds. We discuss the nature of chemical bonds,
to move objects from place to place. A flying and the role of energy in bond formation, a bit
bird uses its wings to produce the mechan- later in this chapter. However, other forms of en-
ical energy necessary for flight. A kangaroo ergy are also critical components of biological
uses its legs to store mechanical energy in function.
the form of elastic storage energy. Recoil
of the springs helps the kangaroo hop.
Many forms of mechanical energy have im- Energy is stored in electrochemical
portant roles in animal locomotion. gradients
• Electrical energy is a combination of po- Molecules within a system tend to disperse or
tential and kinetic energy that results from diffuse randomly within the available space. Imag-
the movement of charged particles down a ine starting a dozen spinning tops in the center of
charge gradient. a box. The tops collide frequently at first, eventu-
ally dispersing randomly throughout the box.
Two aspects of diffusion govern the proper-
ties of many biological processes. First, diffusion is
47
certain to lead to a random distribution of mole- is expressed in the electrical unit of volts. In cells,
cules, but the rate of diffusion can be slow. Many membranes are the electrical barrier and the elec-
physiological systems function to reduce the re- trical gradient is called the membrane potential.
liance on slow rates of diffusion. Second, the ten- The nature of the molecule determines
dency of molecules to diffuse is a source of energy whether the potential energy of the gradient is pri-
that cells can use to drive other processes. Living marily electrical or chemical. If a molecule is un-
organisms can invest energy to delay the in- charged, then it can only form a chemical
evitable tendency toward randomness. In the pre- gradient. A charged molecule can form a chemical
vious example, you could prevent the spinning gradient and influence the electrical gradient. For
tops from randomly distributing by moving each instance, if the concentration of Na is greater out-
top back to the center position. Your efforts to reside the cell than inside, there is both an electrical
verse the random distribution reflect an energetic gradient (more positive charges outside the cell)
investment on your part. Similarly, biological sys- and a chemical gradient (more Na ions outside
tems can invest energy to move molecules out of a the cell). Consequently, these gradients are often
random distribution. The resulting diffusion gra- discussed as electrochemical gradients.
dient is a form of energy storage that the cell can
use for other purposes. Of particular importance
are the gradients established across biological
Thermal energy is the movement
membranes. Transmembrane gradients created
of molecules
by cells differ in terms of the nature of the mole- It is impossible to ignore the importance of ther-
cules (Figure 2). A chemical gradient arises mal energy, or heat energy, in discussing chemical
when one type of molecule occurs at a higher con- or biological processes. When a system gains ther-
centration on one side of a membrane. The mag- mal energy, there is an increase in the movement
nitude of the chemical gradient is expressed as a of molecules within that system. This type of
ratio of the concentrations of the specific molecule movement has a profound effect on molecular re-
on either side of the membrane. For example, you activity and the rate of chemical reactions.
might say that a given molecule is 10-fold more Most chemical reactions involve changes in
concentrated outside the cell. The second type of thermal energy. Exergonic reactions release en-
gradient, an electrical gradient, arises if the dis- ergy and endergonic reactions absorb energy. To
tribution of charged molecules is unequal on ei- understand the reasons for these changes in energy,
ther side of an electrical barrier in a circuit. The let’s consider a simple reaction in which a single
electrical gradient across the barrier is dependent substrate, S, becomes a single product, P:
on the distributions of all the charged molecules
S→P
combined. The strength of the electrical gradient
At any given time, each molecule
of S is vibrating in solution, experi-
Positive charge
Negative charge
encing subtle changes in its struc-
+ + ture. A single molecule of S at times
+ + moves quickly (lots of kinetic energy)
and at other times moves slowly
+ +
(less kinetic energy). Occasionally, a
Plasma
membrane molecule of S has so much kinetic
(bilayer)
+ +
energy that it is able to assume a
+ + specific structure that is vulnerable
to a more significant change. This
+ + structure, intermediate between P
+ + and S, is called the transition state.
The energy required for a molecule
(a) Chemical gradient (b) Electrical gradient to reach the transition state is the
Figure 2 Storage of potential energy in electrochemical gradients activation energy, or EA. Once a
Animals can use the energy stored as (a) chemical gradients or molecule reaches the transition
(b) electrical gradients, or membrane potential. state, it is equally likely to revert to
48
the substrate, S, or convert to the product, P. The All chemical reactions are reversible under the
progression of the reaction from S to P, expressed right conditions. The reaction of S to P is favored
in terms of energy content, is shown in Figure 3. only because the activation energy barrier is lower
Since the free energy content, (G), of S is greater for S than it is for P. Because free energy was re-
than the free energy of P, the chemical reaction leased when S was converted to P, free energy
leads to a change in free energy (G), calculated must be absorbed if P is to be converted to S. The
as reverse reaction, with its positive G, is an ender-
gonic reaction. If both S and P are present, at any
G Gproducts Gsubstrates
point in time both forward and reverse reactions
In this reaction (Figure 3), P has a lower free en- occur simultaneously. The net reaction is the dif-
ergy, making G negative. S is converted to P, and ference between the forward rate and the reverse
the difference in free energy, or G, is released to rate. Because energy is released in one direction
the environment, primarily as heat. Thus, an ex- and absorbed in the other, the balance between
ergonic reaction is defined in thermodynamic forward and reverse directions depends on tem-
terms as a reaction with a negative G. An ender- perature. At high temperatures, endergonic reac-
gonic reaction has a positive G. tions become more feasible. Thus, temperature
influences chemical reactions in two ways. In-
creasing temperature allows more molecules to
reach activation energy, and increases the likeli-
Number of S molecules
hood of endergonic reactions.
Chemical Bonds
Most biologically available energy is stored in the
form of chemical bonds. Covalent bonds hold in-
dividual atoms together to form a molecule. These
Low EA High strong bonds involve the sharing of electrons be-
Enthalpy of S molecules tween two atoms. Noncovalent bonds organize
(a) molecules into three-dimensional structures. In
general, noncovalent bonds are called weak
bonds or sometimes weak interactions to further
distinguish them from strong bonds.
Transition state
Free energy (kcal/mol)
Activation Covalent bonds involve shared electrons

S energy (EA )
Each element has a characteristic arrangement of
electrons that influences the types of bonds it can
Difference in form. Specifically, for the six common biological
P E content of elements, each atom has at least one unpaired
substrate and
product (ΔG) electron in its outer electron shell. Atoms with un-
Chemical reaction paired electrons can readily form covalent bonds
(b)
with other atoms with unpaired electrons. These
atoms share electrons so readily that they are
Figure 3 Chemical reactions, substrates, rarely present in elemental form. Atoms with
products, and thermal energy (a) A collection of
more than one unpaired electron can form multi-
substrate molecules, S, possesses an average energy level and
ple covalent bonds. For instance, molecular oxy-
an average arrangement of electrons around its nucleus. But
at any given time, some S molecules are energy-rich and
gen has two oxygen atoms joined by a double
others energy-poor. (b) Occasionally a molecule of S might covalent bond. Many atoms are covalently bonded
absorb enough energy from the surroundings (perhaps from a to more than one other atom. Methane, for exam-
molecular collision) that it achieves the transition state (S*). At ple, is composed of four hydrogen atoms cova-
this point it could revert to S, or change into a novel product P. lently bound to a single carbon atom. Each type of
49
covalent bond has a characteristic bond energy, lecular interactions: van der Waals forces, hydro-
the energy required to either form or break the gen bonds, ionic bonds, and hydrophobic bonds
bond. The greater the bond energy, the stronger (Figure 5).
the bond. Multiple bonds possess more bond en- The electrons in a bond between two atoms
ergy than single bonds. Large molecules are built can be shared unequally. This asymmetry in elec-
from a collection of individual atoms attached by tron distribution creates a polarity, or transient di-
covalent bonds. Functional groups are combina- pole, within the molecular structure. One region is
tions of atoms and bonds that recur in biological slightly negative (), and the other is slightly pos-
molecules (Figure 4). itive ().
When an atom with a transient dipole encoun-
ters another atom, the distribution of electrons in
Weak bonds control macromolecular the second atom is altered. The weak interaction
structure between the two dipoles is the van der Waals in-
Weak bonds arise between atoms with asymmet- teraction. Van der Waals interactions are effec-
rical distributions of electrons either within the tive only over a very narrow range of atomic
atom or between atoms. Four types of weak bonds distances. When two atoms are far away, the di-
can be distinguished based on how they form mo- pole of one atom has no effect on the electron
cloud of the other. As the atoms approach, the at-
traction between the atoms increases. When the
Functional groups Covalent bonds atoms get too close, their electron shells repel each
O atom away from the other. The van der Waals ra-
dius is the distance at which the attractive force is
C OH Carboxyl S S Disulfide
at its greatest. Each atom has a characteristic van
der Waals radius.
Hydrogen bonds arise from the asymmetric
H sharing of electrons between two atoms. They are
N H Amino C O Ester critical to the organization of water molecules. In
a single water molecule, each hydrogen atom is
O
covalently linked to the oxygen atom. However, the
O O oxygen atom is just a bit better at attracting the
OH Hydroxyl P O P Phosphodiester
OH OH van der Waals interaction Hydrophobic bond
C H Methyl C S Thioester
H H
H O
Hydrogen bond H C H H C H
O H C H H C H
C O C Ether H C H H C H
P OH Phosphoryl
C H C
OH
H C H
Ionic bond
H C H
H H O
SH Sulfhydryl N C Peptide H C H
N H
+ –O C
C
O
H
Figure 4 Important functional groups and Figure 5 Weak bonds Four types of weak bonds are
bonds Although there are many types of bonds and involved in building macromolecules: hydrogen bonds, ionic
functional groups, those illustrated here are particularly bonds, van der Waals forces, and hydrophobic interactions.
common in macromolecular structure.
50
electron of hydrogen. More precisely, hydrogen’s Weak bonds are sensitive to temperature
electron spends a bit more time closer to the oxy-
Bond energy reflects the amount of thermal energy
gen atom than the hydrogen atom. Consequently,
required to break (or form) a bond. Weak bonds are
the hydrogen is slightly positive (), and the oxy-
more vulnerable to the effects of temperature be-
gen atom slightly negative (). The attraction be-
cause their bond energies are much lower than the
tween the of hydrogen in one water molecule
bond energies of covalent bonds. Whereas covalent
and the of oxygen in another water molecule
bonds have energies of formation of 200–900
constitutes a hydrogen bond (Figure 6).
kcal/mol, weak bonds have energies of formation
In some cases, a nucleus is so good at attract-
less than 5 kcal/mol. The three-dimensional macro-
ing electrons that when a bond breaks, an electron
molecular structures of proteins, membranes, and
from one atom remains with the other to create
DNA, which primarily depend upon weak bonds,
ions. Electronegative ions, or anions, possess ex-
are also sensitive to temperature. As a result, rising
tra electrons, whereas electropositive ions, or
temperature can cause macromolecules to unfold,
cations, have lost electrons. Anions and cations
or denature, when these weak bonds break. How-
can interact to form an ionic bond. Most of the
ever, not all weak bonds are affected by tempera-
molecules we think of as salts, acids, and bases
ture the same way. Hydrogen bonds, ionic bonds,
rely on ionic bonds to join anions and cations.
and van der Waals forces each have positive energy
Van der Waals forces, hydrogen bonds, and
of formation and tend to break when temperature
ionic interactions form on the basis of mutual at-
increases. In contrast, hydrophobic bonds have
traction between two charged or slightly charged
negative energy of formation and are strengthened
atoms. However, hydrophobic bonds form be-
by thermal energy.
tween atoms because of a mutual aversion to wa-
ter. Whole molecules or specific regions of large
molecules can be hydrophobic (“water-fearing”).
The bonds within hydrophobic molecules share 2 C O NC E P T C H E CK
electrons equally and therefore do not possess sig- 1. What are the five main forms of energy used by
nificant dipoles. With little internal charge, they animals? Provide biological and nonbiological
cannot interact effectively with the more polar examples of processes that represent conversion
molecules such as water. of energy from one form to another.
2. What are the four types of weak bonds, and
how do they differ from each other and from
covalent bonds?
δ– 3. What is the difference between (a) thermal
energy and temperature and (b) exergonic and
O
exothermic?
H δ+ H
δ+ H δ+
δ– H δ+ δ– H δ+
O
δ–
O Properties of Water
O
δ+ Most cells are composed primarily of water. Aquatic
H H
H organisms also live in water, and even the cells of
δ+ H δ+ δ+
O δ– terrestrial organisms are bathed in the aquatic en-
δ–
vironment of their extracellular fluids. Many physi-
O H δ+ ological processes arose to meet the challenges of
H
δ+
the physical and chemical properties of water.
H
δ+
The properties of water are unique
Figure 6 Water dipole and hydrogen bonds
Oxygen atoms in water strongly attract the electron of the
A solvent is the most abundant molecule in a liquid,
hydrogen atom. The result is a small charge difference (). whereas the other molecules within the liquid are
The hydrogen atom is slightly positive () and the oxygen solutes. Collectively, the solutes and solvents con-
atom is slightly negative (). These charges influence the stitute the solution. In biological systems, the sol-
way that water molecules interact. vent is usually water. Water’s unusual combination
51
of physicochemical properties, which can be attrib- dense than liquid water and tends to float. These
uted to its ability to form hydrogen bonds, have physical properties of water have important ef-
special significance in biological processes and con- fects on aquatic ecosystems. In temperate regions
strain the direction of biological evolution. Liquid of Earth, a layer of ice forms on the surface of lakes
water is actually a network of interconnected wa- in early winter. The ice layer insulates the lake wa-
ter molecules. Each water molecule interacts ter from the air conditions, creating a more stable
strongly with other water molecules, creating in- environment for aquatic organisms. Temperature
ternal cohesiveness. At the interface between air also alters the density of liquid water. Because the
and water, the attraction between water molecules density of water is greatest at 4°C, the deepest
creates a force called surface tension. This pre- parts of large water bodies tend to be a constant
vents most water molecules from spontaneously 4°C, whereas surface waters can be colder or
escaping to the air. Many animals take advantage warmer, depending on the latitude and season.
of surface tension to move over water (Figure 7). Other physical properties of water have an im-
Their mass exerts a force on the water, but it is not portant impact on biological processes. Water has
great enough to disrupt the molecular interactions a higher melting point (0°C) and a higher boiling
between water molecules. point (100°C) than other solvents. In most habit-
The organization of water molecules changes able locations on Earth, then, water is a very sta-
in relation to temperature. At high temperatures, ble liquid. Water’s high heat of vaporization, the
the water molecules possess enough thermal en- amount of energy required to cause liquid water to
ergy to escape the restraining force of surface ten- boil or evaporate, makes sweating an effective
sion. At this point, the water “boils,” and water cooling strategy for mammals. A great deal of en-
molecules can escape as gaseous water (steam). In ergy is absorbed when liquid water vaporizes. Wa-
contrast, low temperatures stabilize water struc- ter on the skin absorbs a lot of thermal energy
ture as a result of the formation of additional hy- from the body in the process of evaporation.
drogen bonds. Water solidifies, or freezes, when
each water molecule forms four hydrogen bonds
to create a stable lattice of water molecules.
Solutes influence the physical properties
Changes in temperature also influence the
of water
density of water. Although frozen water molecules Many solutes can dissolve in water because they
incorporate more hydrogen bonds, the geometry can form hydrogen bonds with water molecules.
is such that the water molecules are held further Water-soluble molecules in solution are often sur-
apart than in liquid water. Consequently, ice is less rounded by a coat of water molecules called the
hydration shell. The hydration shell increases
the functional size of the molecule, and influences
how the solute interacts with other molecules in
complex biological systems.
In the tissues of most animals, the most com-
mon solutes are inorganic ions. K is the most abun-
dant cation inside cells, and Na is the most
abundant cation in the extracellular fluid. However,
in some species, particularly marine animals, the
most abundant solutes are organic ones such as
urea, amino acids, and sugars. Each type of solute
can exert specific, distinct effects on the chemical
properties of other molecules within the solution.
However, all solutes, regardless of their chemical
nature, exhibit four basic properties, known as
colligative properties. Solutes reduce the freezing
Figure 7 Surface tension The basilisk lizard is able point of the solution, and increase the boiling point,
to run across the surface of water. The surface tension of the vapor pressure, and the osmotic pressure of the
water can support the lizard because the force is distributed solution. The colligative properties depend only on
over the large surface area of the feet. the concentration of solutes, not their size or charge.
52
In a solution with high concentrations of that forms around many molecules enlarges the
solutes, cooling to 0°C will not induce freezing. The functional size of the molecule, restricting its mobil-
thermal energy of the system is low enough to form ity. Other factors that influence how the solute inter-
the extra hydrogen bonds, but the solutes block the acts with the solvent, such as charge and solubility,
formation of hydrogen bonds necessary to form the also affect the rate of diffusion. Each solute has an
ice crystal. When solutes are present, the solution experimentally determined diffusion coefficient
must be cooled below 0°C before the extra hydro- (Ds), which is influenced by the structural properties
gen bonds can form. The freezing point of biologi- of the solute. The rate of diffusion of a solute (dQs /dt)
cal fluids, such as cytoplasm or blood, is always depends on the diffusion coefficient of the solute (Ds),
lower than freshwater, and sometimes even as low the diffusion area (A), and the concentration gradi-
as seawater. The difference in the freezing point of ent (dC/dX). The relationship between these param-
body fluids and the aquatic environment has im- eters is defined by the Fick equation:
portant ramifications for aquatic animals.
dQs dC
Similar mechanisms are responsible for the ef- Ds A
dt dX
fects of solutes on the vapor pressure and boiling
point of water. A water molecule can escape liquid Small solutes, such as inorganic ions, are able
water only at the water-gas interface. When solute to traverse the width of the cell, typically about
molecules are also present at the surface, they re- 10 µm, in a fraction of a second. The time required
duce the likelihood that a water molecule will es- for a molecule to diffuse a given distance increases
cape. We discuss the fourth colligative property, with the square of the distance. If a molecule takes
osmotic pressure, after we discuss a related con- 1 sec to diffuse 0.1 mm, it would take about 3 h to
cept: diffusion. diffuse 1 cm. Many biological processes depend on
diffusion, such that physiological and anatomical
strategies have evolved to prevent these processes
Solutes move through water by diffusion from becoming “diffusion limited.”
The direction of diffusion of molecules in a solution
depends on the concentration gradient, but the rate
of diffusion depends on many additional factors.
Solutes in biological systems impose
Molecules move more rapidly when the gradients
osmotic pressure
are steeper. The properties of the solute itself also in- The semipermeable membranes of cells allow
fluence the rate of diffusion. If solute molecules are some molecules to cross while restricting the
relatively large, they have a more difficult time mov- movement of others. Imagine a situation where
ing through the restrictive structure of water. Large two identical solutions of pure water exist on ei-
molecules like proteins diffuse much more slowly ther side of a membrane that allows free move-
than small molecules like K. The hydration shell ment of water molecules only (Figure 8). On each
NaCl
Semipermeable
membrane
Gravity
H2O
H2O
Osmotic
H2O H2O pressure
(a) (b) (c) (d)
Figure 8 Osmotic pressure The two solutions differing in solute concentration are
separated by a semipermeable membrane. The movement of water creates osmotic pressure.
Movement will continue until the force of gravity is equal to the osmotic pressure.
53
side of the membrane is approximately 55.5 mol tion is hyposmotic. When the osmolarity is the
of water per liter. Water molecules freely cross the same on both sides of the cell membrane, the so-
membrane in both directions. If you added NaCl to lution is isosmotic.
one side of the membrane, a concentration gradi-
ent would be created for Na and Cl. Since the Differences in osmolarity can alter cell
membrane is permeable to water alone, only wa- volume
ter molecules could move across to equalize the
Biologists usually make distinctions between os-
concentration gradients. There would be a net
molarity, which is related to the osmotic pressure,
movement of water molecules from the side with
and tonicity, which is the effect of a solution on
pure water to the side with solutes. This would in-
cell volume. Tonicity depends on differences in os-
crease the volume on the side with solutes. Even-
tually, the net movement of water would stop molarity, but also on the types of solutes and the
permeability of the membrane to those solutes.
when the force generated by the movement of wa-
To understand the distinction between osmo-
ter equaled the force of gravity, which prevents the
larity and tonicity, consider the following example
water column from getting any higher. In cells, the
(Figure 9b). A cell that is placed in an isosmotic
movement of water is restricted not by gravity but
salt solution neither shrinks nor swells (an
by the flexibility of the cell membrane. In either
case, the force associated with the movement of isotonic solution). If more salt is added, the cell
loses water and shrinks. Thus, this solution is both
water is the osmotic pressure, the fourth colliga-
hyperosmotic and hypertonic. Imagine now that
tive property of solutes.
small amounts of urea, a permeant solute, are
The ability of solutions to induce water to
added to the isotonic salt solution. The urea would
cross a membrane is expressed as the osmolarity,
equilibrate across the cell membrane, and thus
expressed in units of osmoles per liter (OsM). Os-
prevent the net movement of water in or out of the
molarity is analogous in many respects to molar-
cell; this is an isotonic solution. Of course, if the
ity (M). Whereas molarity is a reflection of the
concentration of specific molecules in a solution, cell were placed in a solution containing only urea,
the movement of urea into the cell, combined with
osmolarity depends on the total concentration of
the high internal salt concentration, would draw
particles in solution. The osmolarity of a solution
water into the cell, causing it to swell or even
of known molarity can be calculated on the basis
of the number of particles derived from each mol- burst; this is a hypotonic solution.
ecule. If a solution has only one solute, and that
solute does not dissociate, then molarity and osmo-
larity are equivalent. For instance, 1 mol/l (or 1 M) pH and the Ionization of Water
glucose solution has an osmolarity of 1 osmol/l (or A small proportion of the H2O molecules in any so-
1 OsM). Some solutes dissociate into multiple par- lution dissociates into ions by breaking one of the
ticles. Each mole of NaCl produces 1 mol of Na covalent bonds between oxygen and hydrogen. In
and 1 mol of Cl. Thus, a 1 M NaCl solution has an reality, water is in equilibrium with itself.
osmolarity of 2 OsM. Knowledge of the concentra-
H2O H2O Δ H3O OH
tion and valency of the solutes would allow you to
estimate osmolarity, but in reality the osmolarity is For simplicity, the cation is treated as a proton
somewhat less. Some of the salt does not dissoci- (H) rather than a hydronium ion (H3O). The dis-
ate, and some of the water molecules become association of water into ions is reversible. Both the
sociated with the hydration shell of the ions. The forward reaction (water dissociation) and the re-
osmolarity and osmotic pressure of a solution are verse direction (water formation) occur simultane-
physical properties of a solution. However, in a bi- ously. Only a very small proportion of water
ological setting the absolute osmolarity is often molecules are dissociated at any given time, about
less important than the osmolarity of an extracel- 1 in 55,500,000 water molecules at room temper-
lular fluid relative to the osmolarity of the intracel- ature (25°C). Under these conditions (pure water
lular fluid (Figure 9a). If a cell is placed in a at 25°C), the concentration of protons arising from
solution with greater osmolarity, then the solution water dissociation is 107 M. For the sake of con-
is considered hyperosmotic (relative to the cell). venience, the concentration of protons is usually
Similarly, if a cell is placed in pure water, the solu- converted to the pH scale. The pH of a solution is
54
Na+ Na+
Cl– Cl–
Cell Cell
Isosmotic Isotonic
Solution Solution
More salt More water Salt Urea
added added added added
Urea
Hyperosmotic Hyposmotic Hypertonic Isotonic

Solution Solution Solution Solution
(a) Osmolarity (b) Tonicity
Figure 9 Osmolarity versus tonicity (a) A cell is swell. (b) The effects of solutes on cell volume depend on the
in an isosmotic solution when the solution has an osmotic ability of the solute to enter the cell. If NaCl is added to an
pressure equal to that of the cell cytoplasm. If salt is added to isosmotic solution, the cell shrinks and the solution is
the solution it becomes a hyperosmotic solution. Water leaves considered hypertonic. If urea is added to the solution, there is
the cell, causing the cell volume to shrink, until the osmotic little change in cell volume because urea can cross the cell
pressures are again equal. If the salt concentration is reduced, membrane. Thus, adding urea to this solution makes it
as would be the case if more water was added, the solution hyperosmotic, but it is also isotonic.
becomes hyposmotic. Water flows into the cell, causing it to
calculated as the negative logarithm of proton con- molecules dissociate, raising the pH to 7.28. In
centration (denoted as [H]). Thus, the pH of pure each of these situations, water remains neutral,
water at 25°C is pH 7 (log 107). As we see later but the pH at neutrality, or pN, varies inversely
in this chapter, the negative logarithmic scale, des- with temperature. In practice, pure water changes
ignated by the prefix p, is also a convenient way to its pH at a rate of 0.014 units per degree Celsius.
express low concentrations of other ions, such as
pOH for [OH] and pCa for [Ca2].
Acids and bases alter the pH of water
Pure water is never anything but neutral. How-
Neutrality is not always at pH 7 ever, ionizable solutes can influence the pH of a so-
A solution is considered neutral when [H] lution. An acid releases one or more protons.
[OH], or pH pOH. Pure water at 25°C possesses Hydrochloric acid (HCl) is an acid because it disso-
107 M concentrations of both H and OH: pH 7 ciates into H and Cl. A base causes a reduction
and pOH 7. The temperature of a solution of in the [H] of the solution. When the base sodium
pure water alters the proportion of water mole- hydroxide (NaOH) is dissolved into water, it rap-
cules with enough thermal energy to break the co- idly dissociates into Na and OH. The extra OH
valent O–H bond. For instance, at 45°C almost arising from NaOH dissociation rapidly interacts
twice as many H2O molecules dissociate, lowering with H to form H2O, reducing the [H] and in-
the pH to 6.72. At 5°C, about half as many H2O creasing pH.
55
The degree to which acids and bases change This simple equation is useful for understand-
the pH of a solution depends on the ease with ing many different biochemical and physiological
which the molecule dissociates under physiologi- principles. For example, the pK value reflects the
cal conditions. Inorganic acids such as HCl and strength of acids and bases. A strong acid will give
H2SO4 are considered strong acids because they up its proton even when the concentration of pro-
readily release their protons to the solution. Simi- tons in the surrounding area is very high (low pH).
larly, NaOH and KOH are strong bases because Thus, the pH must be very low to prevent a strong
they readily dissociate to release OH. Many bio- acid from dissociating. The pK value is low for a
logical molecules are weak acids or weak bases, strong acid, less than 3 for hydrochloric acid and
which are only partially ionized under physiologi- sulfuric acid. Similarly, strong bases, such as
cal conditions. sodium hydroxide and ammonium hydroxide,
If an acid is defined as something that releases have pK values greater than 11. The pK values for
a proton, then we can discuss acids with the gen- some common biological acids and bases are
eral formula of HA. Dissociation of the acid HA shown in Table 1.
produces H and the anion, A. We can describe a The equilibrium equation is a powerful tool for
reversible chemical reaction with the equation analyzing biological solutions. Once we know the
HA Δ H A values of three of the four parameters, we can cal-
culate the one that is unknown. To determine pH,
We define the relationship between the sub- we can rearrange the equation into the form
strate (HA) and products (H and A) as the mass
3A 4
action ratio, using the equation pH pK log
3 HA 4
3H 4 3 A 4
Mass action ratio
3HA 4
This rearrangement is known as the
Henderson-Hasselbalch equation, named after
To understand how these parameters change, the researchers who used the relationship to ex-
consider an experiment where the acid HA is added plain the behavior of CO2 (HA) and HCO3 (A),
to pure water. When first added to water, HA re- which is important in respiratory physiology.
mains intact and [A] is equal to zero; the mass ac-
tion ratio is also close to zero. However, very
quickly at least some of the acid dissociates. There Table 1 Acids and bases.
is an increase in both [H] and [A], and as a result
an increase in the mass action ratio. At some point Acid Reaction pK
the reaction slows, with [HA] reaching a minimum
Carbonic acid H2CO3 → HCO3 H 3.8
and [H] and [A] reaching a maximum. When this
HCO3 → CO3 H
10.2
occurs, the reaction is at equilibrium. It is impor-

tant to recognize that although there is no net Phosphoric acid H3PO4 → H2PO4 H 3.1
change in the concentrations of reactants, both for- H2PO4 → HPO42 H 6.9
ward and reverse reactions continue, but at equal
HPO4 2
→ PO43 H 12.4
rates. When the reaction is at equilibrium, the
mass action ratio attains a specific value, Keq, the Ammonium NH4 → NH3 H
9.3
equilibrium constant. Under most circumstances, Acetic acid CH3COOH → CH3COO H
4.8
the equilibrium constant is converted to its negative
Glycine (amino) R–NH3 → R–NH2 H 2.3
log (log10 Keq), analogous to the way we converted

[H] to pH. Thus, the equilibrium equation can be (carboxy) R–COOH → R–COO H 9.6
rewritten after log transformation as H H
3A 4

N N
pK pH log
3HA 4 Histidine R – C CH R–C CH + H+ 6.0
HC N HC N
Put another way, the pK is the pH at which half the
acid is dissociated, [A] [HA], [A]/[HA] 1 and H+
log [A]/[HA] 0.
56
Both pH and temperature affect the of the glycine molecule, or its pKCOOH. Adding more
ionization of biological molecules base causes deprotonation of the amino group. At
pH 9.6, exactly half the amino groups are proto-
Changes in pH can alter the dissociation of other
nated. This pH value is the equilibrium constant
molecules with ionizable groups. Let’s look at the
for the amino group of glycine, or its pKNH2. At still
amino acid glycine to explore how pH affects its
higher pH values, the carboxyl groups remain
structure (Figure 10). Glycine has a carboxyl
charged and the amino groups are fully deproto-
group that can be protonated (–COOH) or deproto-
nated, giving the glycine molecule a net negative
nated (–COO). It has an amino group that can be
charge. Midway between the two pK values, the
deprotonated (–NH2) or protonated (–NH3). The
glycine molecule has no net charge, as the charges
protonation state of the carboxyl and amino
on the carboxyl group (COO) balance the charges
groups in a molecule of glycine depends on the pH
on the amino group (NH3). Glycine and other mol-
of the solution.
ecules that have both negative and positive
We can observe the effects of pH on glycine
charges are called zwitterions.
structure by performing a titration, where an acid
The ionization state of molecules is very sensi-
or base is added to a solution. We start our titra-
tive to temperature. Let’s return to the previous ex-
tion by dissolving glycine in an acidic solution. At
ample where we titrated the ionizable groups of
very low pH, where [H] is high, both amino and
glycine. As pH rose to equal pKCOOH, protons became
carboxyl groups are protonated. The carboxyl
so scarce that half of the carboxyl groups lost their
group is uncharged (–COOH) and the amino group
proton. If we repeated the titration at lower temper-
has a positive charge (–NH3), giving glycine a net
ature, the pK value would change because the lower
positive charge. When we add base to the solution
temperature increases the strength of the bond
to increase pH, the protonation state of both of
holding the proton to the carboxyl group. At any
these groups begins to change. First, the carboxyl
given pH the colder glycine would be more proto-
groups become deprotonated (–COOH → –COO2
nated. Put another way, a higher pH would be re-
H). At pH 2.3, exactly half of the carboxyl groups
quired to lure half the protons off the carboxyl
in the glycine molecule are ionized. This pH value
group. Thus, the pK value increases as temperature
is the equilibrium constant for the carboxyl group
decreases. Each ionizable group has a characteristic
sensitivity to temperature, ex-
14 pressed as pK/°C. For example,
H+
13 H H
H H the ionization of phosphoric acid
N
12 N
O
O is relatively insensitive to tem-
11 H C C = H C C
– perature (pK/°C 0.005),
O– O
10 H
H whereas the ionization of the
9 pKa = 9.6 imidazole group of histidine is
8 more sensitive to temperature
(pK/°C 0.017).
pH
+ +
7 H H
H H H H
6 N
The protonation state of
N
O
5 H C C
O
many molecules can have im-
=H C C
4 OH O
– portant effects on molecular
H H
3 processes. Many of the effects of
2 pKa = 2.3 temperature and pH on cells
1
can be traced to the effects on
0
the protonation state of critical
Added base molecules. For example, many
proteins form structures that
Figure 10 Changing pH and the ionization state of acids and bases
The amino acid glycine occurs in several different ionization states that change with
depend on particular ionization

pH. At low pH (high [H ]) both the amino group and the carboxyl group are protonated. states of amino acids. Changes
As pH increases, the carboxyl loses its proton first, becoming half ionized at pH 2.3, its in pH or temperature can affect
pKa value. The amino group does not lose its proton until much higher pH values are how these proteins fold and
reached. Near neutral pH, glycine is primarily neutral. function. By actively regulating
57
temperature and pH, animals diminish the debilitat- some of the protons are liberated from acetic acid,
ing effects of changes in protonation state. the added NaOH has a reduced effect on the pH of
the solution. This buffering effect is evident over the
pH range of about 3.75 to 5.75, where the titration
Buffers limit changes in pH curve is quite shallow. Once pH reaches 5.75, most
A variety of mechanisms help cells regulate pH. of the acetic acid is in the deprotonated form (A),
The first level of defense is a buffer. A buffer is a which cannot act as a buffer. This pH range corre-
chemical found in a solution that dampens the ef- sponds to the greatest buffering capacity of the so-
fect of added acid or base on the pH of the solu- lution, and is centered on the pK value for the
tion. Buffers are often described as if they were buffer, about 4.75, where about half of the buffer is
single molecules. In reality we should think of protonated (HA) and half deprotonated (A).
them as buffer systems, because they are mixtures Animals use a variety of different molecules as
of at least two forms of a molecule, typically proto- buffers. The best buffers in animal cells have pK
nated and deprotonated. values that approach the pH of the compartment in
If we add a buffer to the solution, the protons which they are used. Phosphate (H2PO4 /HPO42)
liberated from the acid can associate with the is an important buffer in the cytoplasm of most
buffer. As a result, the addition of acid has less ef- cells, with a pKA of 6.9. The amino acid histidine
fect on pH than it does in the absence of buffer. Most contributes to buffering in many animal cells be-
buffer systems rely on weak acids, present in both cause the pK value of its imidazole side chain is
the acid form (HA) and the anion form (A). Fur- very close to intracellular pH. Histidine residues
thermore, a buffer works only over a particular within large proteins help buffer the cytoplasm
range of pH values. Acetic acid is a weak acid that against changes in pH. Many species use amino
can be used as a buffer. The effects of an acetic acids with imidazole groups to produce dipeptides
acid/acetate buffer are illustrated by the titration that serve as important intracellular buffers. The
curve shown in Figure 11. If you started your titra- dipeptides carnosine (histidine and -alanine),
tion at low pH, most of the acetic acid would be in anserine (1-methylhistidine and -alanine), and
the protonated form (HA). If you added small vol- ophidine (3-methylhistidine and -alanine) are
umes of NaOH, the pH would increase proportion- important buffers in the muscle of many species.
ately. Below pH 3.75, acetic acid would remain In air-breathing animals, the most important
mostly protonated (HA). If you add more base, the extracellular buffer is bicarbonate/CO2, but it
increase in pH would induce some acetic acid (HA) works by a different mechanism than a simple
to become deprotonated (HA → H A). Since A/HA buffer pair. In a closed test tube bicarbon-
ate/CO2 would have little buffering capacity at
physiological pH because its pK is much too low
10 (3.8). It works as a biological buffer because ani-
9 mals can expire CO2. As [H] increases, bicarbon-
ate is consumed and carbonic acid is produced
8
(H2CO3), which in turn forms H2O and CO2.
7
H HCO3 → H2CO3 → H2O CO2
6
When an animal expires CO2 as a gas, it is es-
Buffering
pH
5 sentially eliminating a weak acid from the body,

range
4 buffering against a change in pH.

3 Same amount of
base has different
2 effects on pH.
2 C O N C EP T CH E CK
1
4. What is the relationship between pK and pH?
0 5. How does temperature influence the pK of
Added base
water? What might this mean for animals that
Figure 11 Effects of buffers on changes in pH experience changes in body temperature?
Buffers blunt the effects of added bases (or acid) on the pH of
a solution.
58
6. What change in pH has a greater effect on proton that are metals, such as copper, iron, magne-
concentration: pH 6 to 7 or pH 7 to 8? sium, zinc, and selenium. Organic cofactors, or
7. What properties of a particle influence its rate of coenzymes, are usually derived from vitamins;
diffusion across a membrane? What membrane coenzyme A is derived from panthothenic acid,
properties influence this rate?
FAD from riboflavin, and NAD from niacin. Many
of the life-threatening diseases we associate with
vitamin deficiencies can be traced back to pertur-
Biochemistry bations of metabolism due to loss of function of
specific enzymes.
Animals control the inner workings of cells
through the use of enzymes, which interconvert
macromolecules to create building blocks and con- Enzymes accelerate reactions by reducing
trol the flow of chemical energy. A metabolic path- the reaction activation energy
way is a series of consecutive enzymatic reactions The laws of thermodynamics that govern chemical
that catalyze the conversion of substrates to prod- reactions in test tubes also apply to chemical reac-
ucts, with multiple stable intermediates. Flow tions in living cells (see Box 1, Mathematical Un-
through the pathway is called metabolic flux. derpinnings: Thermodynamics). Enzymes do not
Metabolic pathways can be either synthetic (ana- determine whether or not a chemical reaction is
bolic), degradative (catabolic), or a combination thermodynamically possible. However, enzymes
of both (amphibolic). Energy metabolism re- do have the ability to accelerate thermodynami-
volves around production of ATP and other energy- cally feasible reactions by factors of 108 to 1012.
rich molecules. Metabolism is the sum of all these Previously we discussed how substrate mole-
metabolic pathways within the cell, tissue, or or- cules in an uncatalyzed reaction must obtain suf-
ganism. Many metabolic pathways span multiple ficient energy to meet the activation energy
cellular compartments, allowing cells to create barrier (EA). Once the EA is met, the substrate can
distinct microenvironments. For example, the mi- adopt the transition state and then spontaneously
tochondria are specialized compartments with a change into the product. Although enzymatic re-
major role in energy metabolism. action uses the same substrate and yields the
In the following sections, we discuss the na- same product as an uncatalyzed reaction, it pro-
ture of enzymes and metabolic energy, and the duces a different intermediate at the transition
metabolism of three of the four major classes of bi- state. First, the enzyme (E) and substrate (S) bind
ological macromolecules: proteins, carbohydrates, to form the ES complex. After conversion to tran-
and lipids. The fourth class of macromolecules, sition states (ES*, EP*), the final product (P) is
nucleic acids, is discussed later in this chapter formed and then is released by the enzyme. This
when we consider genetics. is represented as shown:
S E Δ ES Δ ES* Δ EP* Δ EP Δ E P
The energy required to reach this intermediate
Enzymes state is lower than in the uncatalyzed reaction
Enzymes are biological catalysts that convert a (Figure 12). With a lower energy barrier, more of
substrate to a product. Enzymes, like other types the substrate molecules possess enough energy to
of catalysts, have three properties: (1) they are ac- reach the transition state, and the reaction is ac-
tive at very low concentrations within the cell; celerated. Like other chemical reactions, enzyme
(2) they increase the rate of reactions but they reactions are reversible, proceeding through the
themselves are not altered in the process; (3) they same set of reaction intermediates.
do not change the nature of the products. An enzymatic reaction begins with the sub-
Although some enzymes, called ribozymes, strate binding at a specific location called the
are made of RNA, most enzymes are composed of active site. Think of the active site as a pocket into
protein. Many enzymes possess nonprotein com- which the substrate fits. The enzyme can bind the
ponents, called cofactors. A cofactor that is cova- substrate only if it possesses the proper conforma-
lently bonded into the enzyme is called a tion. The three-dimensional folding of the enzyme,
prosthetic group. Some enzymes use cofactors maintained by weak bonds, forms the active site.
59
BOX 1 MATHEMATICAL UNDERPINNINGS

Thermodynamics
All chemical reactions, whether they oc- G. All reactions that occur spontaneously possess a
cur in test tubes or biological systems, are gov- negative G; free energy was released.
erned by the laws of thermodynamics. The first law of Chemists evaluate these parameters under standard
thermodynamics deals with conservation of energy. The conditions. The standard free energy, or G° is assessed
energy within a substrate is either transferred to the at 25°C, with each reactant, including H, present at a
product or released. The first law doesn’t tell us if the re- concentration of 1 M. The proton concentration used by
action will go forward or backward, only that the energy chemists equates to pH 0, which is not relevant to biolog-
transformations must be balanced. The second law of ical systems. When we use the laws of thermodynamics
thermodynamics provides a way of predicting if a reaction to discuss biological systems, the parameters must be
is likely to occur. It says that spontaneous processes altered to reflect normal cellular conditions. When bio-
occur in the direction that will increase randomness, or chemists adjust G for standard conditions, including a
entropy (S). Throughout this chapter we discuss many pH of 7.0, the symbol G°′ is used.
examples of increases in entropy. When table salt dis- It is important to distinguish between G and G°′
solves in water or ice melts, the molecules that were when discussing chemical reactions. The value of G°′ is
once in a well-ordered crystal begin to disperse. Diffu- a constant. It tells how much free energy is available when
sion also illustrates the principle of spontaneous in- a reaction begins under standard conditions. The value of
creases in entropy. Solutes at high concentration tend to G, the actual free energy of a reaction in a cell, depends
disperse to regions of lower concentration. Collectively, upon the concentrations of reactants. If a reaction is close
these laws tell us that the total energy of the universe is to equilibrium, then G equals zero. For the reaction
constant but that it tends toward randomness.
ABΔYZ
What does this mean for chemical reactions? As we
discovered earlier, spontaneous chemical reactions lib- the relationship between G, G°′, and concentration is
erate thermal energy. Some of this thermal energy is defined by the following equation where R is the gas
used within the system to increase randomness or en- constant:
tropy. The remainder of the thermal energy is called
free energy (G) because it is available for other pur- 3 Y4 3 Z4
¢G ¢G°¿ RT ln
poses. The equation relating enthalpy (H), entropy 3A 4 3 B4
(S), free energy (G), and temperature (T) was first
When the reaction is at equilibrium G 0 and the mass
proposed by J. Willard Gibbs in 1878.
action ratio is equal to Keq, the equation is reduced to
H G T S
0 G°′ RT ln Keq
From this equation, we see two factors that influence bi-
ological systems. First, the change in energy associated or
with randomness is dependent upon temperature. This is G°′ RT ln Keq
because the potency of a fixed amount of thermal energy,
or its ability to induce randomness, depends on temper- We can measure Keq directly by letting the reaction
ature. Thermal energy is more effective at inducing en- reach equilibrium. The value of G°′ can be calculated
tropy at low temperature. The second principle is more from the equation above. Knowing Keq and G°′, we can
apparent if we rearrange the equation to isolate G. calculate the amount of actual free energy G available
for a reaction at any concentration of reactants.
G H T S
Remember that G represents the maximal amount
The amount of free energy available in a reaction is the of free energy theoretically available from a reaction,
difference between the total energy change and the under a constant temperature and pressure that ap-
amount of energy associated with the change in ran- proximates conditions found in the cell. Cells use en-
domness. This equation allows us to predict if a reaction zymes to mediate chemical reactions and transfer as
will occur spontaneously. If a reaction is to occur spon- much energy as possible to other useful forms. Some
taneously, the amount of energy potentially released by enzymes mediate reactions that store energy as chem-
a reaction (H) must be greater than the energy used to ical energy, such as ATP or NADH. Free energy can also
increase entropy (T S). Recall that exothermic reac- be used to create electrochemical gradients. The ability
tions, those that release heat, have a negative H. Sim- to divert free energy into useful forms is central to the
ilarly, reactions that release free energy have a negative success of living organisms.
60
EA (uncatalyzed)
ES EP
Free energy
EA (catalyzed)
S
[P]
Change in
free energy
ΔP
Slope = V = ( )
Time
P
Time Time
Figure 12 Enzymes and EA Enzymes are biological Figure 13 Time course of enzyme reaction
catalysts that accelerate reactions without changing the Enzyme assays begin with the addition of substrate to the
nature of the product. When the substrate (S) binds the reaction. The enzyme rapidly converts the substrate (S) to
enzyme (E), the enzyme-substrate complex (ES) is formed. product (P). The buildup of [P] eventually slows the reaction,
The enzyme alters the substrate through a series of as P competes with S for the active site. The initial velocity (V)
transition states, ultimately releasing the product (P). The is the fastest because P has not yet accumulated.
rate is faster than the noncatalyzed rate because of the
lower activation energy (EA).
(S) or products (P). We use the reaction S → P to il-
lustrate the importance of substrate concentration
Once it binds the substrate, the enzyme induces a ([S]) in two experimental scenarios.
change in the molecular structure of the substrate, The first scenario illustrates how the buildup
perhaps as subtle as a shift in the distribution of of [P] influences the rate of the forward reaction
electrons across a particular bond or a twist in the (Figure 13). When the reaction begins, there is no
substrate molecule. By inducing these subtle product ([P] 0). As it proceeds, molecules of P ac-
structural changes in the substrate, the enzyme cumulate and eventually compete with molecules
makes the substrate more likely to spontaneously of S for the same active site. Finally, the reaction
undergo more significant changes. Many enzymes approaches equilibrium, where the forward and
require two or more substrates. These enzymes reverse reaction rates are equal and the mass ac-
accelerate reactions by bringing destabilized reaction ratio equals Keq. We can determine the initial
tants in close proximity. All together, these velocity of the forward reaction (V) from the slope
changes increase the probability that the substrate of the curve before P accumulates.
will undergo a major change in structure toward The second scenario illustrates how the initial
the formation of EP*. [S] influences the enzymatic rate (Figure 14). The
experiment previously described is repeated many
times using a wide range of starting [S]. Increasing
Enzyme kinetics describe enzymatic [S] from a low concentration to a higher concen-
properties tration causes a proportional increase in V. Under
Enzymes accelerate reaction rates, and make possi- these conditions, a higher [S] increases the fre-
ble reactions that would not normally occur at a use- quency with which molecules of S find the active
ful rate. However, cells must ensure that enzymatic site. However, after a point, increases in [S] no
reactions occur not at the fastest possible rate, but longer cause a proportional increase in V. The
at the appropriate rate. Thus, enzyme activity is reg- higher abundance of S molecules still increases
ulated within complex metabolic pathways. The the probability of a collision with E. However, if S
conditions that influence the rate of enzymatic reac- encounters E in the midst of a reaction cycle, the
tions are referred to as enzyme kinetics. enzyme is unable to bind S. Eventually, E is
The simplest way to influence an enzymatic re- saturated with S molecules and further increases
action is to change the concentration of substrates in [S] do not increase V beyond a maximal rate
61
Vmax
Vmax
Initial velocity (mmoles/min)
V
1
1/2 Vmax
1/2Vmax
Km
Km [S]
Substrate concentration (mM)
Figure 15 Homotropic enzymes and sigmoidal
Figure 14 The Michaelis-Menten rectangular kinetics Not all enzymes obey Michaelis-Menten
hyperbola Each point on the curve represents the initial kinetics. Homotropic enzymes show sigmoidal kinetics. The
velocity (V) calculated as shown in Figure 16. The maximal enzymes usually possess multiple active sites. When the
velocity (Vmax) is the velocity at which the curve reaches an enzyme binds one molecule of S, the changes in
asymptote. The Km is the [S] required to reach a velocity that conformation increase the ability to bind a second molecule
is one-half of the maximal velocity. of S. The slope of the linear range of the curve indicates the
degree of cooperativity. The slope of this region provides the
Hill coefficient.
(Vmax). When enzymes are at Vmax, each molecule
of enzyme has a characteristic number of catalytic the enzyme has high affinity for the substrate, and
cycles per unit time, known as the turnover num- little substrate is needed to drive the reaction at a
ber or kcat. high rate.
A high rate of enzymatic activity could be Not all enzymes demonstrate hyperbolic
achieved by a cell, in principle, in either of two Michaelis-Menten kinetics. For instance, ho-
ways. Some enzymes work very fast, and show a motropic enzymes show a sigmoidal relationship
high kcat. The cell does not need many molecules between V and [S] (Figure 15). Homotropic en-
of the enzyme because each molecule works zymes typically have multiple subunits that can
quickly. The fastest enzymes can undergo more each bind a substrate molecule. At low [S], each ac-
than 40,000,000 catalytic cycles each second. Alter- tive site has a low affinity for S. The enzyme does
natively, cells can make many copies of an enzyme not bind S very well and the reaction velocity is
with a low kcat. The relative importance of each slow. Once one subunit binds one molecule of S, it
strategy—faster enzymes versus more enzymes— undergoes a change in conformation that in turn al-
depends on the nature of the reaction and the de- ters the ability of other subunits to bind a substrate
sign of the enzyme. molecule. As a result, doubling of [S] more than
The relationship between [S] and V was first doubles V, a phenomenon called cooperativity. The
described mathematically by the biochemists degree of cooperativity is described by the Hill co-
Leonar Michaelis and Maud Menten as a rectan- efficient, which is the slope of relationship at the
gular hyperbola. The Michaelis-Menten equa- point of inflection.
tion is Enzyme kinetics are assessed under carefully
3S4
controlled experimental conditions that do not ap-
V VMAX proximate normal cellular conditions. Interpreting
3S4 Km the impact of enzyme kinetics in living cells is of-
The value for the Michaelis-Menten constant (Km) ten difficult. The conditions necessary to evaluate
is the concentration of substrate [S] required to ob- Vmax require [P] to be zero, which never occurs in
tain an initial velocity (V) that is half the maximal living cells. Thus, enzymes in cells almost never
velocity (Vmax). Km is an indicator of the affinity of could proceed at Vmax. As with other chemical re-
an enzyme for a substrate. A low Km means that actions, the rate and direction of the enzymatic re-
62
action depend on the difference between the mass

action ratio, which is calculated from the actual [S]
and [P], and the Keq value, which is the expected
[S] and [P] when the reaction reaches equilibrium.
In a near-equilibrium reaction, the mass action
Vmax
ratio is close to Keq; the forward and reverse direc-
tions continue at equal rates, with little net change
in [S] or [P]. Most enzyme reactions are far from
equilibrium in cells. If the mass action ratio is
lower than Keq, then the reaction will proceed in
the forward direction. When the mass action ratio
is higher than Keq, the reaction will tend to favor 0 0.1 0.2 0.3 0.4 0.5
the reverse direction. By altering the concentra- [KCI] (M)
tions of substrates and products, cells can regulate (a)
enzyme activities and metabolic pathways.
The physicochemical environment alters

enzyme kinetics
Every enzyme has a characteristic optimal activity
under a specific set of environmental conditions Vmax
(Figure 16). Enzyme kinetics are influenced by envi-
ronmental conditions, such as temperature, pH, salt
concentration, and hydrostatic pressure. While
these factors generally have little impact on your
metabolism, such environmental factors can influ-
ence the metabolic biochemistry of other species.
Some enzymes function optimally under condi- 0 10 20 30 40 50 60
tions that resemble normal cellular conditions. For Temperature (°C)
instance, mammalian enzymes often function opti- (b)
mally at normal body temperatures of 37–40°C.
Figure 16 Effects of salt and temperature on
However, the optimal conditions for many enzymes
enzyme kinetics Most enzymes function optimally under
bear little similarity to normal cellular conditions; physiologically-realistic conditions. (a) The activity of
the optimal temperature for some mammalian en- mammalian enzymes changes in response to the
zymes is well above normal body temperatures. concentration of the salt KCl. Maximal activity occurs at
Environmental conditions typically influence concentrations that approximate those found within the cell
enzyme kinetics through effects on weak bonds. (100–150 mM K). (b) Increasing temperature accelerates
First, changes in weak bonds can alter the three- enzymes. Beyond an optimal temperature, the enzyme
dimensional structure of the enzyme. For in- denatures and loses catalytic activity.
stance, warm temperatures could break bonds
that are necessary to form the active site. Second,
environmental conditions can alter the ionization
proper conformation, but flexible enough to incur
state of critical amino acids within the active site.
conformational changes during catalysis.
For instance, the amino acid histidine is important
Many of the studies assessing the effects of en-
in many active sites, and changes in pH can alter
vironmental conditions have focused on the effects
its protonation state and consequently substrate
of temperature on the enzyme lactate dehydroge-
affinity (Km). Any environmentally induced change
nase (LDH). This enzyme has an important role in
in Km, either an increase or a decrease, can be dis-
glucose metabolism, which we discuss in more de-
ruptive to a cell. Third, environmental conditions
tail later in this chapter. It catalyzes the following
can alter the ability of the enzyme to undergo
reversible reaction:
structural changes necessary for catalysis. En-
zymes must be rigid enough to maintain the Pyruvate NADH H Δ lactate NAD
63
Environmental conditions can change the Km petitive inhibitor depends on [S]. When [S] is low,
value of LDH for pyruvate and NADH. Lowering the inhibitor outcompetes S for the active site, re-
temperature increases the affinity of the enzyme ducing the reaction rate. At a very high [S], the in-
for its substrate pyruvate (Figure 17). When com- hibition by the competitor is greatly reduced.
paring the effects of temperature on Km in differ- Thus, a competitive inhibitor increases Km but
ent species, several patterns emerge. First, in doesn’t affect Vmax.
every species, the Km value decreases as tempera- Allosteric regulators are molecules that al-
ture decreases. Second, at any temperature, each ter enzyme kinetics by binding to the protein at lo-
species shows a very different Km value. For exam- cations far away from the active site. The allosteric
ple, when assayed at 15°C, Antarctic fish LDH has regulator alters the three-dimensional structure of
a high Km, LDH from temperate fish has an inter- the enzyme, inducing complex changes in enzyme
mediate Km, and desert lizard LDH has a low Km. kinetics. For example, an allosteric activator could
Third, when the LDH from each species is assayed increase the affinity of the enzyme for the sub-
at its normal body temperature, the resulting Km strate, as depicted in Figure 18b. Allosteric effec-
values fall within a narrow range, from 0.1 to 0.3 tors can activate or inhibit enzyme activity,
mM. Evolutionary variation in LDH structure is re- changing either Km or Vmax. Enzymes often possess
sponsible for the differences between species. multiple sites for different allosteric regulators.
These structural variations provide all the species Enzymes controlled by allosteric regulators are of-
with an enzyme that demonstrates similar kinetics ten larger and more complex than other enzymes.
under their natural conditions. This pattern, Typically, each metabolic pathway is regulated by
called conservation of Km, is common when com- one or more key allosteric enzymes.
paring enzyme kinetics of different animals. Enzymes can also be regulated by the covalent
modification of critical amino acid residues within
the protein. The most common type of covalent
Allosteric and covalent regulation control
modification is protein phosphorylation, where a
enzymatic rates
specific protein kinase transfers the phosphate
Molecules that do not participate directly in catal- group from ATP to an amino acid of the target en-
ysis can also alter enzyme kinetics. Competitive zyme. For instance, tyrosine kinase is a regulatory
inhibitors are molecules that can bind to the ac- enzyme that phosphorylates target proteins at
tive site, preventing substrate molecules from specific tyrosine residues. Another common class
binding (Figure 18a). The effectiveness of a com- of protein kinases is specific for threonine and ser-
ine residues. Protein phosphorylation is reversible.
Cells possess suites of protein phosphatases that
0.6
Temperate cleave phosphate groups from phosphorylated
0.5 fish Desert amino acid residues. Phosphorylation might stim-
lizard ulate an enzyme, as depicted in Figure 18c, or in-
0.4 Antarctic fish
Km (mM)
Polar fish
hibit it.
0.3
Conserved
range
0.2
Enzymes convert nutrients to reducing
0.1
energy
0
0 10 20 30 40 50 Enzymes transfer energy from nutrients to mole-
Temperature (°C)
cules that function as energy stores. These energy-
rich molecules are a type of energy currency,
Figure 17 Conservation of Km The Km of an enzyme acting as substrates and products for hundreds of
often changes with temperature. For a number of unrelated
different enzymes. Cells store chemical energy in
species, the Km of LDH for pyruvate (KmPYR) increases with an
two main forms: reducing energy and high-energy
increase in temperature; that is, at warmer temperatures LDH
molecules.
is less able to bind pyruvate. However, when you examine the
kinetic values that would occur at the actual body temperatures
Many enzymatic reactions capture energy in
for the animal, you find that the Km values are very similar the form of reducing equivalents: NAD and
across species. NADP. The enzymes that use reducing equivalents
(Source: Data from Hochachka and Somero, 2002) are called oxidoreductases and include enzymes
64
Vmax
– Inhibitor
Substrate Inhibitor
V
+ Inhibitor
Active
site
– Inhibitor + Inhibitor
[S]
Km Km
(a) Competitive inhibition (uninhibited)(inhibited)
Vmax
+ Activator
Substrate Substrate
bound with bound with – Activator
low affinity high affinity
V
Active
site Allosteric
site
Allosteric
regulator
– Activator + Activator
[S]
Km Km
(b) Allosteric activation (+ Activator) (No activator)
Vmax
Protein kinase
Phosphorylated
ATP O
ADP
Active
site OH O P O–
V
Pi
O
Vmax
Unphosphorylated
Protein phosphatase
Unphosphorylated Phosphorylated
(c) Covalent activation [S]
Figure 18 Enzyme regulation (a) Competitive In this figure, the allosteric regulator activates the enzyme by
inhibitors are able to bind to the active site of enzymes, increasing the affinity for the substrate, shown in the graph
thereby preventing the real substrate from binding. At low as a decrease in the Km. (c) Many enzymes are controlled by
[S], the inhibitor outcompetes the substrate. However, if [S] is phosphorylation-dephosphorylation. Protein kinases
increased to very high levels, the true substrate outcompetes phosphorylate the target enzyme, transferring a phosphate
the inhibitor, and thus these regulators have no effect on group from ATP to specific hydroxy groups. Protein
Vmax. (b) Allosteric enzymes are regulated by molecules that phosphatases remove the phosphate group. In this figure, the
bind at sites distant from the active site. The resulting enzyme is activated by phosphorylation, greatly increasing
structural change in the enzyme alters its kinetic properties. the Vmax.
65
with the common names dehydrogenase, reduc- NH2

tase, and oxidase. When an enzymatic reaction N
N
transfers an electron to NAD (or NADP), the re- O– O– O–
duced NADH (or NADPH) that is formed can be –O P O P O P O CH2 O N N
used to drive other reactions. In other words, en-
ergy can be stored by reducing a molecule and this O O O H H
H H
energy can be recovered, in part, by oxidizing the
reduced compound. OH OH
Consider the nonenzymatic and enzymatic re- ATP
actions for lactate oxidation. Without an enzyme,
lactate is oxidized to form pyruvate with the fol- COO–
lowing reaction:
O– CH2
Lactate → pyruvate 2H 2e H
–
G°′ 36 kJ/mol O P N C N
CH3
O +NH2
The negative standard free energy (G°′)
means that energy is liberated in this reaction,
Phosphocreatine
and without an enzyme the energy released would
be lost as heat. Cells possess the enzyme LDH, in-
troduced earlier in this chapter, which couples lac- O–
tate oxidation to NADH reduction. The NAD H NH3
–O
P N
reduction reaction has a positive G°′. H H H H
C N C C C C H
NAD 2e 2H → NADH H O H H H
H2N C
G°′ 62 kJ/mol
–O O
By coupling lactate oxidation to NAD reduc- Phosphoarginine
tion, the enzymatic reaction captures free energy
from lactate oxidation in the form of NADH.
O
Lactate NAD → NADH H pyruvate
C CH3
G°′ 26 kJ/mol
CoA S
Note that the enzymatic reaction for lactate
Acetyl CoA
oxidation has a positive G°′, which means the re-
verse direction of this reaction (lactate formation) Figure 19 High-energy molecules Cells
is normally favored. use several energy-rich molecules, such as ATP,
The most important reducing equivalent in en- phosphocreatine, phosphoarginine, and acetyl CoA, as
ergy metabolism is NADH. The reducing energy energy currency.
within the cell, or redox status, is best expressed
as [NADH]/[NAD]. This ratio is high when a cell is less reactions. ATP synthesis requires energy, and
rich in reducing energy, and low when cells are en- ATP breakdown liberates energy.
ergy poor. NAD is a reactant in many enzymes of
ADP3 HPO42 H → ATP4 H2O
energy metabolism, but other enzymes are al-
G°′ 30.5 kJ/mol
losterically regulated by NAD. Whether acting
through mass action effects or allosteric regula- ATP possesses two phosphodiester bonds
tion, enzymes sensitive to [NADH]/[NAD] allow (–P–O–P–). Some enzymes break the bond between
metabolic pathways to respond to the energy state. the second and third phosphate groups, forming
ADP. In some cases the inorganic phosphate (Pi) is
released as a product, but often the Pi is trans-
ATP is a carrier of free energy ferred to another molecule. Other enzymes target
Cells use many types of molecules to store energy the bond between the first and second phosphate
(Figure 19), but ATP is the most versatile of these groups, forming AMP and pyrophosphate (PPi).
high-energy molecules and participates in count- Because these energy exchange reactions involve
66
a breakdown of a phosphodiester bond, they are of- dine is transferred to ADP to form ATP. In verte-
ten called high-energy bonds. It is important to re- brates, creatine phosphokinase (CPK) catalyzes
alize that the energy is not stored in the bond per this reaction.
se, but is released when ATP hydrolysis occurs—a
Phosphocreatine ADP Δ ATP creatine
reaction with large, negative free energy.
The importance of utilizing a metabolite like Acetyl coenzyme A, or acetyl CoA, is another
ATP is, first, to avoid high concentrations of other important high-energy store. Energy is released in
metabolites; participation of ATP permits reac- reactions that hydrolyze its thioester bond
tions that otherwise would be thermodynamically (–O–S–). As we see later in this chapter, many
unfavorable. Second, ATP links major metabolic pathways of biosynthesis and energy metabolism
pathways that require cellular energy, such as en- intersect at acetyl CoA. Collectively, reducing en-
dergonic pathways of biosynthesis, with those that ergy and high-energy compounds provide the en-
generate energy, such as the exergonic process of ergetic support for many cellular processes.
carbohydrate catabolism.
The relative abundance of ATP reflects the en-
ergy status of a cell. The absolute concentration of Proteins
ATP is unimportant; what counts is the relative
Proteins play many important roles in cell struc-
proportion of the adenylate pool (ATP ADP
ture and function. Almost all enzymes are proteins
AMP) that exists in the energy-rich forms ATP and
(though many have nonprotein components). Pro-
ADP. The ATP status of the cell is best expressed
teins form the internal skeleton of a cell (cytoskele-
by the phosphorylation potential (Gp), the free
ton) as well the extracellular matrix needed to
energy associated with ATP hydrolysis (ATP →
organize cells into complex tissues. The diversity
ADP Pi):
in protein structure is afforded by the use of 20
3 ADP 4 3 Pi 4 amino acids that can be strung together in count-
¢Gp ¢G°¿ RT ln
3ATP 4 less combinations. The blueprint for all proteins in
a cell is in the form of DNA, which is transcribed
ATP is the most common form of energy cur- into RNA and translated to form the appropriate
rency, but the other nucleotides—GTP, TTP, and proteins at the right time.
CTP—have the same energetic value, although
only GTP is commonly used in energy metabolism.
Phosphorylated guanidine derivatives are im-
Proteins are polymers of amino acids
portant energy stores in many animals. Vertebrates Animals build proteins from combinations of 20
use phosphocreatine and invertebrates use phos- amino acids. As the name implies, amino acids
phoarginine, phosphoglycocyamine, phosphotauro- share the general structure of an amino group
cyamine, or phospholombricine. Phosphoguanidine (–NH2) and a carboxylic acid group (–COOH). They
compounds, each with a –P–N– bond, are useful en- are called
-amino acids because both the amino
ergy stores because they do not participate in and carboxyl groups are located on the first, or
,
many reactions within the cell. Consequently, cells carbon.
can accumulate very high concentrations of phos- Amino acids are distinguished from one an-
phoguanidines without affecting other pathways. other by their side groups (R). The R groups of
The concentration of ATP, in contrast, is kept low polar amino acids form hydrogen bonds with wa-
and relatively constant. Major changes in ATP con- ter. Some polar amino acids are uncharged at
centration would have kinetic consequences for physiological pH values (serine, threonine, cys-
countless enzymes that use ATP as a substrate or teine, tyrosine, asparagines, glutamine), while
product. For instance, the ATP concentration in others possess R groups with side chains that can
vertebrate muscle is typically about 5 mM, become charged. Acidic amino acids (aspartate,
whereas phosphocreatine concentrations might glutamate) are negatively charged at physiological
be 10–50 mM. Animal tissues use these high-energy pH when carboxyl groups become deprotonated
compounds when the need for ATP temporarily (–COOH → –COO H). Basic amino acids (argi-
outstrips the capacity to produce ATP. When ATP nine, lysine) take on a positive charge when amino
levels decline, the energy within phosphoguani- groups become protonated (–NH2 H → –NH3).
67
Many amino acids are nonpolar because their R protein folds onto itself to assume its secondary
groups are aliphatic chains (alanine, valine, structure. The information for proper folding is
leucine, isoleucine, methionine) or aromatic rings contained directly in the primary structure. The
(phenylalanine, tryptophan) that do not readily in- size, charge, and polarity of the side groups influ-
teract with water. The collection of amino acids, ence the interactions between amino acids in the
with their unique properties of side chain length, chain. Secondary structures arise when side groups
shape, charge, and polarity, provides cells with the of amino acids interact to form a structure that is
building blocks necessary to construct thousands more stable than the simple linear conformation.
of different proteins. The two most common protein secondary struc-
tural motifs are the
-helix and the -sheet (Figure
21). In the
-helix, the protein is twisted into a spi-
Proteins are folded into three- ral with 3.6 amino acids per turn and side chains
dimensional shapes extending outward. The structure is stabilized in
Amino acids are polymerized into linear chains by two ways. First, hydrogen bonds form between the
covalent peptide bonds that link the amino group CO of one amino acid and the N–H of the amino
(–NH3) of one amino acid to the carboxyl group acid four positions along the chain. Second, the
(–COOH) of another amino acid.
-helix structure is stabilized when opposing side
chains can interact. With the period of 3.6 amino
H O H O
acids, a side chain is exposed to the side chain of
| || | ||
the amino acid three or four positions away. For ex-
R1-N-H H-O-C-R2 → R1-N-C R2 H2O
ample, if two aromatic amino acids are three posi-
|
tions apart, when the protein twists into an
-helix
H
the structure will be stabilized by the hydrophobic
Two amino acids in a chain is a dipeptide. interactions between the side chains. Similarly,
Polypeptides are longer chains of amino acids. At negatively charged amino acids are often found
one end of the polymer, called the C terminus, the three residues away from positively charged amino
amino acid has an unbonded carboxyl group. At acids. Their electrostatic interactions stabilize the
the other end, the N terminus, the amino acid has protein. The other common type of secondary
an unbonded amino group. The linear sequence of structure, the -sheet, forms when linear regions of
amino acids in a protein is called the primary a protein align side by side and form hydrogen
structure. bonds. In this conformation, the side chains extend
Once the primary structure is established, above and below the face of the sheet.
proteins are organized into more complex three- Once a protein forms its secondary structure,
dimensional conformations (Figure 20). First, the the different regions fold together to create its
N
R
H
C
H
N
C
R
C
H
O
C
Primary structure Secondary structure Tertiary structure Quaternary structure
Figure 20 Protein structural levels The amino acid sequence of a protein is its
primary structure. This polypeptide can then be folded and organized into three-dimensional
conformations.
68
Disulfide bond Ionic bond
H H
C S S C O
β-Pleated sheet
H H C C C
H H H
O–+
H N C C
H H H
α-Helix
Folded
protein
Figure 21 Protein secondary structure: The ␣-

helix and ␤-sheet The most common secondary
structures in proteins are the
-helix and
-sheet. Weak Hydrophobic interaction Hydrogen bond
bonds stabilize both types of secondary structures. The
information that is used to fold the protein is contained within H H H
the primary sequence.
C C H H C
H H H
tertiary structure (Figure 22). If the protein folds N H O=C
in a way that allows two adjacent cysteine H H
residues to come into close proximity, their C C H

sulfhydryl groups (–SH) can form a covalent bond H C
(–S–S–) called a disulfide bond or bridge. Multiple H
H
H
weak bonds link various amino acids and side
chains to stabilize three-dimensional structure. Figure 22 Weak bonds and protein tertiary
Many proteins assume a globular structure when structure Both covalent bonds and weak bonds contribute to
hydrophobic interactions form between regions protein three-dimensional structures.
scattered throughout the protein. By pulling to-
gether hydrophobic regions, a hydrophobic core is
formed that stabilizes the structure of the protein. sequence to fold spontaneously, but others require
A protein achieves its quaternary structure the help of molecular chaperones. Each cell con-
when multiple subunits, or polypeptide chains, are tains different types of chaperones to ensure that
brought together. Proteins with two subunits are proteins are properly folded. They work by forcing
called dimers—a homodimer if the monomers the protein into a conformation that allows the ap-
are identical, otherwise a heterodimer. Proteins propriate weak bonds to form.
can be composed of even larger numbers of sub- Environmental conditions, such as tempera-
units, such as trimers (three subunits) and tetramers ture, can alter weak bonds and disrupt three-
(four subunits). dimensional protein structure. Increasing
temperature weakens the hydrogen bonds that
stabilize
-helices and -sheets. High temperature
Molecular chaperones help proteins fold can cause the protein to unfold, or denature. Once
Proteins can function properly only when they are denatured, a protein can no longer perform its
folded into the correct conformation. Many pro- proper function and may even damage cells.
teins can use the information within the primary Therefore, a partially denatured protein must be
69
HOCH2 HOCH2 refolded or destroyed before it can damage the cell.

6 6
5 O 5 O OH Molecular chaperones bind to denatured proteins,
4 1 4 1 folding them into the proper configuration. During
OH OH
HO 3 2 OH HO 3 2 heat stress, cells increase the levels of molecular
chaperones called heat shock proteins to cope
OH OH
with the increased number of denatured proteins.
α-D-Glucose (Glc) β-D-Glucose (Glc)
HOCH2
O OH
HOCH2 O OH Carbohydrates
HO
OH Carbohydrates share a preponderance of hydroxyl
OH CH2OH
(–OH), or alcohol, groups, and for this reason they
OH are often called polyols. For any animal, the diet is
OH
a vital source of the carbohydrates used to build
β-D-Galactose (Gal) β-D-Fructose (Fru)
and fuel cells. Glucose, the most common carbohy-
drate in animal diets, is central to cellular energy
HOCH2 HOCH2 metabolism and biosynthesis because of its meta-
O OH O OH bolic versatility. Cells can break glucose down for
OH H
energy, or store it for later consumption, or use it
OH H
HO HO to build other carbohydrates needed by the cell.
NH2 NH
C O Animals use monosaccharides for energy

β-D-Glucosamine (GlcN)
CH3
and biosynthesis
N-Acetyl-β-D-glucosamine (GlcNAc) Monosaccharides are small carbohydrates that
Figure 23 Common monosaccharides These have from three to seven carbons. The most com-
structural models of monosaccharides show how side mon monosaccharides are the six-carbon sugars
groups extend above and below the plane of the ring (hexoses) including glucose, fructose, and galac-
structures. The
and forms of glucose differ in the tose (Figure 23). Glucose and galactose, as well as
orientation of the hydroxy group on C-1. mannose, can be modified by the addition of acidic
groups, amino groups, and modified amino
groups. These sugar derivatives serve many pur-
poses in the cell, primarily as modi-
HOCH2 HOCH2 fications of other macromolecules,
HOCH2 O OH O including proteins, lipids, and nu-
1 O
cleic acids.
HO O 4
OH OH OH
O
HO
O HOCH 2
Many of the sugars that animals
1 β α 1
OH OH obtain in the diet are disaccharides,
OH OH two monosaccharides connected by
OH OH a covalent bond (Figure 24). In or-
Lactose (Gal (β1-4) Glc) Trehalose (Glc (α1-1α) Glc) der to use disaccharides, animals
first break them down into mono-
HOCH2 HOCH2 HOCH2 saccharides. Animals can also pro-
O HOCH2 O O O duce disaccharides such as lactose,
HO OH
1 α β 2 1 α 4
an important component of milk in
OH HO OH OH
HO
O
CH2OH O mammalian mammary secretions,
and trehalose, an energy store and
OH OH OH OH solute.
Sucrose (Fru (β2-1α) Glc) Maltose (Glc (1α-α4) Glc) The addition of carbohydrates
Figure 24 Common disaccharides Both trehalose and maltose are made from to other macromolecules is called
two glucose molecules but with bonds forming between different pairs of carbons. glycosylation. Glycosylated lipids
Sucrose and maltose are synthesized in plants; animals obtain them by eating the plants. (glycolipids) and proteins (glyco-
70
proteins) are common in the plasma membrane HOCH2 HOCH2 HOCH2 HOCH2
O O O O
of cells. A glycosylated macromolecule displays an ••• •••
OH OH OH OH
altered molecular profile, changing how it inter- O O O O O
acts with other macromolecules and reducing its OH OH OH OH
susceptibility to degradation. Amylose
Complex carbohydrates perform many ••• •••

functional and structural roles
Amylopectin
Complex carbohydrates, or polysaccharides, are
larger polymers of carbohydrates that serve in en-
•••
ergy storage and structure. Polysaccharides can
be composed of long chains of a single type of
•••
monosaccharide or combinations of two alternat-
ing monosaccharides. Common polysaccharides •••
important in metabolism and structure are shown ••• •••

in Figure 25. Starch is a general term for the glu-
Glycogen
cose polysaccharides used by plants and animals
(a) Glucose polymers
for energy storage. Plant starch, a mixture of amy-
lose and amylopectin, is an important dietary HOCH2 HOCH2 HOCH2
source of energy for many animals. Animal starch, O O O
or glycogen, is central to animal energy metabo- O
OH O
OH O O
OH
lism, acting as an internal energy store for most
animals and a nutrient for animals that eat other NH NH NH
animals. Amylose, amylopectin, and glycogen dif- C O C O C O

CH3
fer in the linkage between glucose molecules and CH3 CH3
the nature of the branching pattern. Cellulose, an-

other plant-derived glucose polymer, is essentially GlcNAc GlcNAc GlcNAc
indigestible in animals because of the nature of the Chitin
bonds between glucose units. Cellulose, in most HOCH2
O
animals, provides dietary fiber. However, some
O
animals, such as ruminants and termites, possess HOCH2 COO –
HO
OH H
O O O
gastrointestinal symbionts that can degrade cellu- NH
O
COO – OH
lose for energy. HO
O C O
O
Polysaccharides are also critical structural O NH OH CH3
OH
components of animal cells. Arthropods build C O
their exoskeletons with chitin, a polysaccharide of OH CH3
N-acetyl-glucosamine. Vertebrates secrete hyaluro-

nate, a polymer of N-acetyl-glucosamine and glu- GlcA GlcNAc GlcNAc GlcNAc
curonic acid, into the extracellular space, where Hyaluronate
its gel-like properties act as a spacer between cells (b) Glucose and amino sugar polymers
and tissues. Hyaluronate is a member of a class of
compounds called glycosaminoglycans that in- Figure 25 Polysaccharides (a) Plants and animals
clude chondroitin sulfate and keratan sulfate. use polymers of glucose as energy stores. Amylose and
amylopectin are the two polysaccharides that compose
These compounds are important components of
starch, an important dietary source of energy for animals.
animal tissues, such as cartilage.
Animals produce glycogen, which resembles the plant
In order to use glycogen as an energy store,
polysaccharides but with much greater branching.
animals control the balance between glycogen (b) Animals build many polysaccharides from combinations
synthesis (glycogenesis) and glycogen break- of monosaccharides and amino sugars, such as N-acetyl-
down (glycogenolysis). Glycogen phosphorylase glucosamine (GlcNAc). Chitin is a polymer of N-acetyl-
initiates glycogenolysis, releasing glucose in the glucosamine, whereas hyaluronate is a polymer of
form of glucose 1-phosphate. When glucose is N-acetyl-glucosamine and glucuronic acid (GlcA).
71
Glycogen synthase (inactive)
Protein Pyruvate
Protein kinase
phosphatase
Glycogen synthase (active) Pyruvate

CO2
Pyruvate carboxylase GTP

Glycogen Glycogen
(n glucose) (n+1 glucose) GDP
Oxaloacetate
NAD+ NADH CO2
Glycogen phosphorylase (active) ATP
Glycogen Glycogen PEPCK

phosphorylase phosphorylase ADP
Malate Phosphoenolpyruvate
kinase phosphatase
Glycogen phosphorylase (inactive) Malate

NAD+
Figure 26 Control of glycogen synthase and
glycogen phosphorylase Under conditions in which NADH
glycogen breakdown is desirable, both glycogen synthase and
Oxaloacetate
glycogen phosphorylase are phosphorylated by protein CO2
kinases. Phosphorylation inhibits glycogen synthase but
stimulates glycogen phosphorylase. Similarly, PEPCK GTP
dephosphorylation of these two enzymes by protein
GDP
phosphatases favors glycogen synthesis.
Phosphoenolpyruvate
abundant, glycogen synthase is activated and glu-
cose 1-phosphate is used to increase the size of the 2-Phosphoglycerate
glycogen particle. Protein kinases and protein
phosphatases regulate both glycogen synthase 3-Phosphoglycerate
and glycogen phosphorylase (Figure 26).
ATP
ADP
Gluconeogenesis builds glucose from 1,3-Bisphosphoglycerate
noncarbohydrate precursors NADH
Glucose is essential for energy metabolism and NAD+
biosynthesis. When dietary glucose is inadequate
or when glycogen stores are compromised, ani-
Glyceraldehyde 3-phosphate Dihydroxyacetone phosphate
mals can produce glucose from noncarbohydrate
precursors via gluconeogenesis. The gluco-
neogenic pathway (Figure 27) using mitochondrial Fructose 1,6-bisphosphate
pyruvate as a starting point has the following over- FBPase
Pi
all reaction:
Fructose 6-phosphate
2pyruvate 4ATP 2GTP 2NADH 4H2O →
glucose 4ADP 2GDP 6Pi 2NAD 2H Pi
Glucose 6-phosphate
Figure 27 Gluconeogenesis Cells convert pyruvate Glucose 1-phosphate

to glucose and glycogen using the enzymes of
UTP
gluconeogenesis. The exact route of phosphoenolpyruvate
Glucose
synthesis depends upon tissue and species. Some species UDP
use a mitochondrial PEPCK to produce phosphoenolpyruvate. Glycogen
72
Gluconeogenesis begins in the mitochondria, Glucose

where pyruvate carboxylase converts pyruvate to ATP
Hexokinase
oxaloacetate, the substrate for PEP carboxykinase
ADP
(PEPCK). In species with a mitochondrial PEPCK,
Glucose 6-phosphate Glycogen
PEP is transported to the cytoplasm; if PEPCK is
cytoplasmic, the mitochondria convert oxaloac- Phosphoglucose isomerase
etate to malate, export it, and then resynthesize
oxaloacetate within the cytoplasm. A series of re-
actions produces glucose 6-phosphate, which can ATP
Phosphofructokinase
be used to produce glycogen, or in some tissues ADP
converted to glucose by glucose 6-phosphatase.
Fructose bisphosphate
Because gluconeogenesis requires a great deal of
energy, cells stimulate gluconeogenesis only when Aldolase
they have excess energy available. The metabolic

Glyceraldehyde Dihydroxyacetone
indicators of energy status, such as acetyl CoA and 3-phosphate phosphate
adenylates (AMP, ADP, and ATP), regulate the glu-
coneogenic rate. The pathway is controlled mainly
Triosephosphate isomerase
by availability of gluconeogenic substrates and al-
losteric regulation of pyruvate carboxylase and
Glyceraldehyde 3-phosphate 2 NAD+
dehydrogenase
fructose 1,6-bisphosphatase (FBPase). 2 NADH
1,3-Bisphosphoglycerate (×2)
Glycolysis is a low-efficiency, high-velocity 2 ADP
pathway Phosphoglycerokinase
2 ATP
Glycolysis is the pathway that breaks down glucose 3-Phosphoglycerate (×2)
obtained from the blood and glucose 6-phosphate
derived from processing of the glucose 1-phosphate Phosphoglycerate mutase
liberated from stored glycogen. This pathway is a

2-Phosphoglycerate (×2)
vital source of ATP because it can proceed in the ab-
sence of oxygen (anoxia) and can produce ATP very Enolase
H2O
rapidly (albeit for brief periods).
Phosphoenol pyruvate (×2)
Although glycolysis is usually discussed from
the perspective of glucose or glycogen breakdown, 2 ADP
Pyruvate kinase
other carbohydrates derived from the diet are also 2 ATP
processed into hexoses that can enter glycolysis.
Disaccharides are first broken down into mono- Pyruvate (×2)
saccharides: trehalose into two glucose, lactose Figure 28 Glycolysis Glycolysis is a series of
into glucose and galactose, sucrose into glucose cytoplasmic enzymes that breaks down glucose or glycogen
and fructose. The glycolytic pathway (Figure 28) to produce ATP. Because ATP is required by hexokinase,
using glucose as initial substrate has the following glycolysis from glycogen produces more ATP (three ATP per
overall reaction: glucosyl) than it does from glucose (two ATP per glucose).
The other important products of glycolysis are pyruvate and
Glucose 2ADP 2NAD →
NADH. The three irreversible reactions are highlighted.
2ATP 2pyruvate 2NADH 2H
When glucose is carried into the cell, the enzyme Seven of the ten glycolytic reactions are freely re-
hexokinase rapidly phosphorylates it, using a mole- versible, and catalyzed by the enzymes shared with
cule of ATP. Since glucose 6-phosphate is not the gluconeogenic pathway. The three irreversible
readily transported across the cell membrane, glycolytic reactions—hexokinase, phosphofructoki-
phosphorylation of glucose traps glucose within the nase (PFK), and pyruvate kinase (PK)—are impor-
cell. The next steps in glycolysis are a series of enzy- tant sites of regulation for the pathway, acting via
matic reactions that convert the glucose backbone mass action effects, allosteric regulation, and cova-
to fructose, which is then hydrolyzed to form two lent modification. During periods of high energy de-
trioses that are ultimately converted to pyruvate. mand, much of the ATP is broken down to ADP and
73
AMP, affecting the mass action ratios for all three pyruvate dehydrogenase (PDH) produces acetyl
regulatory enzymes. Both ADP and AMP are power- CoA, which is further oxidized to produce CO2. The
ful activators of PFK enzymatic activity, whereas reducing energy (4 NADH and 1 FADH2) and nu-
ATP inhibits PFK, as well as PK. When cells do not cleotides (1 GTP) allow mitochondria to produce
need energy, glycolysis is inhibited at PFK and PK. the equivalent of 15 ATP from pyruvate. Since the
With PFK inhibited, glucose 6-phosphate is diverted cytoplasmic production of pyruvate produces only
into glycogen synthesis. Thus, the fate of the glucose 1 ATP per pyruvate, considerably more energy is
6-phosphate—glycolysis or glycogen synthesis—is produced by glucose oxidation (glucose → CO2)
linked to energy status through regulation of PFK. than by glycolysis (glucose → pyruvate).
This is an example of negative feedback regulation, Mitochondria also dispose of the cytoplasmic
where an increase in the concentration of products NADH produced in glycolysis. Although they cannot
inhibits the pathway. oxidize NADH directly, mitochondria use two
In addition to the 2 mol of ATP per glucose, gly- redox shuttles to obtain the reducing energy of cy-
colysis produces 2 mol of pyruvate and NADH. Gly- toplasmic NADH: the
-glycerophosphate shuttle
colysis can continue only if the cell can remove the and the malate-aspartate shuttle (Figure 29). In the
pyruvate and NADH produced. The fate of these
-glycerophosphate shuttle, cytoplasmic NADH is
products depends on two factors: the metabolic de- first oxidized by the enzyme
-glycerophosphate
mands of the cell and the availability of oxygen. dehydrogenase (
-GPDH), embedded within the
mitochondrial inner membrane. Oxidation of gly-
colytic NADH in the
-glycerophosphate shuttle
Mitochondria oxidize glycolytic pyruvate generates two ATP. The malate-aspartate shuttle
and NADH under aerobic conditions uses pairs of enzymes that are located in both the
When energy is required and oxygen abundant, cytoplasm and the mitochondria. First, cytoplasmic
pyrvuate produced in glycolysis enters the mito- malate dehydrogenase oxidizes NADH. This trans-
chondria for further oxidation. First, the enzyme fers the reducing energy of NADH to malate, which
AspAT NADH
Glycolysis Oxaloacetate
Glucose Pyruvate
6 1
MDH NAD+
2-Oxoglutarate Glutamate
NAD+ NADH + H+ Aspartate Malate
G3PDH
Inner membrane
5 2
G3P DHAP
G3PDH
Malate
Cytosol FAD+ FADH2 Aspartate 2-Oxoglutarate Glutamate
NAD+
Inner membrane Q 3
– 4
Oxaloacetate
Matrix AspAT NADH
(a) α Glycerophosphate shuttle (b) Malate-aspartate shuttle
Figure 29 Redox shuttles (a) Glycolytic NADH can mitochondria with complete cycling of the reactants. The
be oxidized by the combined actions of cytoplasmic and enzymes malate dehydrogenase (MDH) and aspartate
mitochondrial forms of glycerol 3-phosphate dehydrogenase. aminotransferase (AspAT) are located in both the cytoplasm
The complete
-glycerophosphate shuttle leads to transfer of and mitochondria. This cycle also requires specific
the reducing power of NADH to mitochondrial FADH2. (b) The transporters capable of carrying metabolites across the
malate-aspartate shuttle, shown as a series of reactions mitochondrial membrane.
from 1 to 6, results in net transfer of NADH into the
74
enters the mitochondria and is oxidized by malate demands of specific tissues. For example, a turtle
dehydrogenase. The remainder of the cycle ensures can depress its metabolic rate at the onset of a dive.
that the cytoplasm is provided with adequate ox- Second, animals can extend hypoxic survival by
aloacetate and the mitochondrial oxaloacetate is restoring high levels of glycogen. For some bivalve
moved. The enzyme aspartate aminotransferase molluscs, for example, almost half their dry weight
converts oxaloacetate to aspartate in the mitochon- is glycogen, providing many days of anoxia toler-
dria. Aspartate is exported to the cytoplasm where ance. Third, some anoxia-tolerant organisms alter
another aspartate aminotransferase regenerates the nature of glycolysis to produce an alternative
oxaloacetate. The other substrates and products in end product that is less toxic than lactate. Some
the aspartate aminotransferase reaction, glutamate molluscs produce strombine, alanopine, or oc-
and 2-oxoglutarate, are required in the transport of topine. Some species of fish can convert lactate to
malate and aspartate. ethanol, which is then excreted into the water. This
additional reaction spares them the toxicity of lac-
Terminal dehydrogenases oxidize NADH tate, but in the process they lose a valuable source
under anaerobic conditions of energy. Bivalve molluscs and some endoparasites
Since mitochondria require oxygen to process also produce alternate end products, but gain extra
pyruvate and NADH, the nature of the end prod- energy along the way. Phosphoenolpyruvate (PEP)
ucts of glycolysis depends on the availability of can be diverted from glycolysis to produce succinate
oxygen. Environmental hypoxia arises when ex- (4 ATP/glucose) or propionate (6 ATP/glucose).
ternal oxygen levels fall below critical levels for The various alternative pathways and anaerobic
prolonged periods. Intertidal bivalves may close end products are summarized in Figure 30. Col-
their shells during tidal cycles, inducing hours of Glucose
hypoxia, whereas parasites of the gastrointestinal
tract live perpetually under hypoxia. Functional
CO2 NADH NADH
anoxia can arise when tissue oxygen demands NADH
outstrip oxygen delivery from the blood. For ex- Pyruvate
ample, muscle can become hypoxic during intense

X
exercise. Diving animals gradually deplete their NADH
onboard oxygen stores, causing short-term hy-
Ethanol Lactate
poxia in some tissues. In each of these situations,
animals depend on glycolysis for energy and must Oxaloacetate Tauropine (x=taurine)
be able to oxidize NADH to allow glycolysis to con- Nopaline (proline)
NADH Alanopine (alanine)
tinue. One of the most common pathways for Strombine (glycine)
NAD regeneration is through the activity of LDH, Lysopine (lysine)
Octopine (arginine)
an enzyme we introduced earlier in this chapter. Malate

Pyruvate NADH H Δ lactate NAD
This reaction regenerates NAD and disposes of
pyruvate, permitting glycolysis to continue. For Fumarate
many species, lactate production is a good indica-

tion of glycolytic flux. Once produced in the LDH
reaction, lactate can either be retained in the tis-
Succinate
sue or exported from the cell into extracellular
fluid. Although lactate is slightly toxic, it can be tol-
erated for short periods. When the anoxia bout
ends, lactate is metabolized, and is often used as a Propionate
substrate to regenerate glucose and glycogen.
Figure 30 Anaerobic end products of glycolysis
The most hypoxia-tolerant and anoxia-tolerant Animals collectively have many different ways to oxidize
animals use three general mechanisms to extend NADH when oxygen is limiting. Many animals and tissues rely
survival. One is to reduce their metabolic demands on lactate dehydrogenase, but other pathways occur in
to extend the life of their energy stores by entering hypoxia-tolerant animals. Some anaerobic end products can
some form of dormancy or reducing the metabolic lead to production of extra ATP.
75
lectively, these variations of glycolysis allow ani- Medium chain fatty acids (MCFAs) and long chain
mals to succeed in anoxic environments that are fatty acids (LCFAs) are common in energy stores
toxic to other species. and as part of phospholipids that make up cell
membranes. Fatty acids also differ in the number
and position of double bonds between carbon
Lipids atoms. Saturated fatty acids have no double bonds
and are linear in structure. The introduction of a
Lipids are a class of hydrophobic organic mole-
double bond into a linear fatty acid causes a bend
cules including fatty acids, triglycerides, phospho-
in the chain, which has important consequences
lipids, steroids, and steroid derivatives. They have
for membrane structure. Monounsaturated fatty
many roles in animal cells, acting as substrates for
acids have one double bond. Polyunsaturated fatty
energy production, building blocks for mem-
acids, or PUFAs, possess multiple double bonds.
branes, and signaling molecules.
Fatty acid nomenclature considers both the
chain length and the number of bonds. Palmitic
Fatty acids are long aliphatic chains acid is denoted as 16:0, meaning it is 16 carbons
produced from acetyl CoA long and has no double bonds. There are two
Fatty acids are long chains of carbon atoms naming systems to denote fatty acids, which differ
(aliphatic) ending with a carboxyl group (Figure in how they identify the location of the first double
31). They can vary in chain length from two car- bond. In the delta () system, a number corre-
bons, as with acetate, to more than 30 carbons. sponds to location of the double bond relative to
The shortest fatty acids are often called volatile the carboxyl carbon; in the omega (ω) system, the
fatty acids, or VFAs, because they readily evapo- number refers to the distance from the methyl end
rate from solution. VFAs are produced by rumi- of the fatty acid. Thus, the 18-carbon fatty acid
nants with the bacterial fermentation of cellulose. oleic acid can be either 18:1 9 or 18:1 ω9. Linoleic
acid is denoted as either 18:2 9,12 or 18:2 ω6.
Animals can produce many fatty acids using
2 4 6 8 10 12 14 16 18
O C C C C C C C C C the enzyme fatty acid synthase, which cyclically
C C C C C C C C C
adds two-carbon units to the fatty acid. Though
1 3 5 7 9 11 13 15 17 fatty acids grow by adding acetyl groups, malonyl
HO
CoA, a three-carbon activated fatty acid is the ac-
18:0 - Stearic acid (saturated) tual substrate for the enzyme fatty acid synthase.
C Malonyl CoA is produced by acetyl CoA carboxy-
C lase. Using the reducing energy of NADPH, fatty
C C
C C
O C C C C C acid synthase repeatedly adds acetyl CoA groups
C
C C C C C C to the fatty acid. After seven cycles, when the fatty
HO
acid has grown to 16 carbons, palmitate has been
produced and is released by the enzyme. The
18:1 (Δ9) - Oleic acid (monounsaturated) overall reaction for palmitate synthesis is
C
Acetyl CoA 7malonyl CoA 7NADPH
C 7H → palmitate 7NADP
C C
C C C C C C Though palmitate is the product of fatty acid
O C
C
C synthase, accessory enzymes process much of it to
C C C C C
produce other fatty acids. These enzymes elongate
HO
the carbon chain and introduce double bonds to
18:2 (Δ9,12) - Linoleic acid (polyunsaturated) produce the other important fatty acids, such as
oleic acid. Many animals can produce all of the
Figure 31 Fatty acids Saturated fats such as stearic
acid (18:0) are linear in structure. Addition of a double bond, fatty acids needed for growth, but some animals
as shown with the monounsaturated fatty acid oleic acid are incapable of producing specific fatty acids and
(18:1), introduces a bend in the structure. The second double must obtain these in the diet. For example, hu-
bond shown in the polyunsaturated acid linoleic acid (18:2) mans have a dietary requirement for linoleic acid
causes further disruption of the linear structure. (18:2 ω6) and linolenic acid (18:3 ω3).
76
Fatty acids are oxidized in mitochondrial H H H

O
-oxidation C C C C
Fatty acids are an important fuel for many tissues, O–
H H H
such as the mammalian heart, which typically de- Fatty acid
rives more than 70% of its energy from fatty acid
oxidation. The fatty acid oxidation pathway occurs ATP
Activation Fatty acyl CoA synthase
primarily in the mitochondria and results in the CoASH
production of acetyl CoA. Depending on the condi- AMP+PPi
tions, this acetyl CoA can be oxidized by mitochon-
H H H
dria or be diverted to other pathways. Fatty acids O
can have many structures, differing in chain length, C C C C
branching patterns, and desaturation. These varia- S-CoA
H H H
tions require side reactions to convert the fatty Fatty acyl CoA
acids to forms that can enter -oxidation. We will
focus on the pathway for oxidation of palmitate, but Oxidation Fatty acyl CoA dehydrogenase FAD
FADH2
along the way we will identify some of the alternate
pathways used to process other fatty acids. H H H
O
Because the actual substrate for -oxidation is C C C C
fatty acyl CoA, cells must first convert fatty acids to S-CoA
their CoA esters using a fatty acyl CoA synthase. H
Enoyl CoA
Short and medium chain fatty acids are able to en-
ter the mitochondria directly, where they are acti- H2O
Hydration Enoyl CoA hydratase
vated by a mitochondrial fatty acyl CoA synthase.
Palmitate, which cannot cross into mitochondria,
H OH H
is oxidized by the mitochondria by a multistep O
process involving activation and transport. The C C C C
fatty acid is converted to fatty acyl CoA. Next, the S-CoA
H H H
enzyme carnitine palmitoyl transferase-1, or CPT-1, β-Hydroxyacyl CoA
replaces the CoA with carnitine, forming fatty acyl NAD+
carnitine, which is carried into the mitochondria, Oxidation β-hydroxyacyl dehydrogenase
where another enzyme, CPT-2, converts it back to NADH +H+
fatty acyl CoA. This elaborate transport scheme
H O H
provides an extra level of control over long chain O
fatty acid oxidation. By regulating the activity of C C C C
CPT-1, cells control how much fatty acid can enter H H
S-CoA
the mitochondria for catabolism. β-Ketoacyl CoA
Once inside the mitochondria, fatty acids enter
CoASH
the -oxidation pathway (Figure 32). This is a Thiolysis Thiolase
cyclical pathway that sequentially cuts pairs of
carbons off the end of the fatty acid in the form of H H
O O
acetyl CoA. The shortened fatty acid returns to the
C C + HC C
pathway, and the cycle is repeated until the entire
S-CoA S-CoA
fatty acid is broken down to acetyl CoA. With each H H
trip through the pathway, reducing equivalents are Fatty acyl CoA Acetyl CoA
produced at two enzymatic steps: fatty acyl CoA de- Figure 32 Fatty acid oxidation Fatty acids are
hydrogenase produces FADH2, and -hydroxyacyl activated in the cytoplasm to form fatty acyl CoA. Once
CoA dehydrogenase produces NADH. About 30% of transported into mitochondria, fatty acyl CoA enters the
the energy liberated from fatty acids is derived from -oxidation pathway. Oxidation, hydration, oxidation, and
the reducing equivalents produced in -oxidation. thiolysis produce acetyl CoA, reducing equivalents, and a fatty
The remaining 70% derives from oxidation of acetyl acyl CoA shortened by two carbons. The shortened fatty acyl
CoA in the TCA cycle. CoA reenters the -oxidation pathway and the cycle repeats
until the fatty acid is reduced to acetyl CoA units.
77
Ketogenesis Ketolysis
tivated into the CoA ester, then hy-
drolyzed by thiolase to form two
2 Acetyl CoA 2 Acetyl CoA acetyl CoA molecules.
Ketone bodies are a useful alter-
Thiolase CoASH CoASH Thiolase native to fatty acids for many ani-
Acetoacetyl CoA Acetoacetyl CoA mals. Although some energy is lost in
GTP
Acetyl CoA the complete cycle of ketogenesis and
HMG CoA
synthase Succinate ketolysis, for some tissues, particu-
CoASH
β-Ketoacyl larly under starvation conditions, ke-
HMG-CoA Succinyl
CoA CoA tone bodies are the only metabolic
synthase transferase
HMG CoA energy source available. Chon-
lyase Acetyl CoA drichthians (sharks and their rela-
Succinyl CoA
Acetoacetate Acetoacetate tives) in fact appear biochemically
NADH + H+ NADH + H+ predisposed to using ketone bodies
β-HBDH β-HBDH as their “lipid” fuel. Unlike in other
NAD+ NAD+
vertebrates, their muscles are unable
β-Hydroxybutyrate β-Hydroxybutyrate
to use fatty acids directly, instead re-
lying on ketone bodies as a fuel for
Figure 33 Ketone metabolism Acetyl CoA can be converted to the ketone
bodies acetoacetate and -hydroxybutyrate. This reaction normally occurs in specific energy.
ketogenic tissues, such as liver. Ketone bodies are released through the blood for
uptake by ketolytic tissues, such as brain. Acetyl CoA is resynthesized at the cost of
Triglyceride is the major form
one GTP to regenerate the substrate succinyl CoA.
of lipid storage
Most fatty acids in animal cells are es-
Fatty acids can be converted to ketone terified to a glycerol backbone. A monoacylglyceride
bodies has a single fatty acid esterified to glycerol, typically
Fatty acids are valuable sources of energy, but un- at the first position of the glycerol molecule. Diacyl-
der some conditions they must first be processed glyceride has fatty acids esterified to the first and
into ketone bodies: acetone, acetoacetate, and second position of glycerol. Triglyceride has three
-hydroxybutyrate (Figure 33). Ketone bodies fatty acids esterified to the glycerol backbone (Fig-
provide a fuel for tissues that cannot use fatty ure 34). Each of these terms—monoacylglycerides,
acids directly. The mammalian brain usually re- diacylglycerides, and triglycerides—refers to a class
lies on glucose oxidation for energy, but after an of molecules. For example, hundreds of chemically
extended period of food deprivation, glucose lev- distinct triglyceride molecules can be constructed by
els may decline, forcing tissues to rely more on using different fatty acids in each of the three posi-
lipid stores. Since the brain cannot use fatty acids tions on the glycerol backbone.
directly, the liver converts the fatty acids to ketone
bodies, which can be transported into the brain H H H
and oxidized.
H C C C H Glycerol
The first step in ketone body synthesis, or ke-
togenesis, is the production of acetoacetyl CoA O O O
from two molecules of acetyl CoA, catalyzed by thi-
C O C O C O
olase. This is the same enzyme used in the final step
of -oxidation, but in ketogenesis it operates in the CH2 CH2 CH2
reverse direction. After condensation with another Fatty acids

CH2 CH2 CH2
acetyl CoA and subsequent hydrolysis, acetoacetate
•••
•••
•••
is formed. Acetoacetate can then be converted to CH3 CH3 CH3

-hydroxybutyrate by the enzyme -hydroxybu-
tyrate dehydrogenase ( -HBDH), or it can break Figure 34 Triglycerides Triglycerides are composed
down spontaneously to form acetone. In the target of three fatty acids esterified to a glycerol backbone. Fatty
tissues, ketolysis reconverts -hydroxybutyrate acids can vary in chain length and number
and acetoacetate to acetyl CoA. Acetoacetate is ac- of double bonds.
78
Triglycerides are vital energy stores for ani- Dihydroxyacetone

mals, and can be found in high concentrations in phosphate Glycerol
lipid storage tissues in the form of lipid droplets. In

NADH+H+ ATP
insects, a tissue called the fat body is the main site
of lipid storage. Many other invertebrates, such as
NAD+ ADP
molluscs and crustaceans, store lipid in a large he-
patopancreas. Vertebrates store triglyceride in CoASH Glycerol–3–P
CoA
liver, muscle, and adipose tissue, such as blubber.
OH
OH OH Pi
Adipocytes, the cells within adipose tissue, store
Fatty acid
Fatty acid
triglyceride when an animal is well fed, then release
CoASH
lipids when the animal needs extra fuel.
Triglyceride synthesis, or lipogenesis, is a
CoASH
multistep process overlapping with phospholipid
synthesis (Figure 35). Each fatty acid is activated
into its CoA ester by fatty acyl CoA synthase. Start- Pi
ing with glycerol 3-phosphate, the fatty acids are
added sequentially to carbon 1, then carbon 2,
forming a phosphatide. After removal of the phos-
phate group, diacylglycerol is formed. Addition of a Phosphatidic Phospholipid
acid synthesis
third fatty acid completes the triglyceride molecule.
Triglyceride breakdown, or lipolysis, requires
enzymes called lipases that attack the triglyceride
molecule, breaking the bond between the fatty acid
OH
and the glycerol backbone. Hormone-sensitive li-
pase liberates fatty acids from triglycerides and di-
acylglycerides. Another lipase, monocyglyceride
lipase, completes the breakdown of the triglyceride Diacylglycerol
by releasing the last fatty acid from the glycerol
backbone. The liberated fatty acids are either used CoASH
directly within the cell or transferred to the circula-
tion for uptake by other tissues that use them for
energy metabolism.
The balance between triglyceride synthesis
and degradation is carefully controlled within an-
imals. Lipolysis does not directly generate energy,
but lipogenesis requires energy. As with other Figure 35 Triglyceride synthesis Glycerol
pathways we have discussed, if both synthesis and 3-phosphate, produced from glycolysis (dihydroxyacetone
phosphate) or glycerol, is the acceptor for two sequential
degradation occurred simultaneously, cells would
additions of activated fatty acids (fatty acyl CoA). The
waste energy.
formation of triglyceride requires dephosphorylation and
addition of another fatty acid group to the third and last
Phospholipids predominate in biological position on the glycerol backbone.
membranes
In addition to their role in energy metabolism, fatty group, such as serine, choline, ethanolamine, and
acids are vital components of the phospholipids inositol. The physical properties of a phosphoglyc-
used to produce biological membranes. Animal eride are determined by the properties of both the
cells produce two classes of phospholipids: phos- fatty acids (chain length, saturation) and the polar
phoglycerides and sphingolipids (Figure 36). head group.
Phosphoglycerides are constructed from Although sphingolipids are chemically very
phosphatides, an intermediate in triglyceride syn- different from phosphoglycerides, they have simi-
thesis. In phospholgylceride synthesis, the phos- lar three-dimensional shapes. The backbone of a
phate group links the phosphatide to a polar head sphingolipid is sphingosine. With its long aliphatic
79
Choline
+ makes a specific combination of sphingolipids,
providing a kind of cellular signature that other
cells can recognize. During development, when
cells move throughout the body to begin the
Phosphate
process of tissue formation, sphingolipid signa-
–
tures provide migrating cells with landmarks.
When the migrating cells find the correct sphin-
Glycerol golipid signature, they cease migration and differ-
entiate to form tissues.
Phospholipids are broken down by phospho-
lipases, many of which are important in cell
Fatty acid
Fatty acid
signaling cascades. Each type of phospholipase at-

tacks a specific region of a phospholipid molecule.
Phospholipase A (PLA) breaks the ester bonds that
connect the fatty acids to the glycerol backbone.
PLA1 releases the fatty acid from the first carbon
(a) Phosphoglycerides of glycerol, whereas PLA2 releases the fatty acid
from the second position. Phospholipases B and C
break different phosphodiester bonds between the
Choline
+ polar head group and the glycerol backbone.
–
When PLB attacks phosphatidyl inositol, inositol
Phosphate
and phosphatide are produced. When PLC attacks
the same phospholipid, inositol phosphate and di-
acylglyceride are released. It is an important en-
Sphingosine
zyme in signal transduction pathways of many
cells.
Fatty acid
Steroids share a multiple ring structure

Steroids are a collection of lipid molecules that
share a basic aromatic structure of four hydrocar-
bon rings. The steroid cholesterol is found in
many cellular membranes and is part of the
lipoprotein complexes that transport lipids
(b) Sphingolipids through the blood. It is also a precursor for syn-
Figure 36 Phospholipids Phospholipids, including thesis of the vertebrate steroid hormones. Al-
(a) phosphoglycerides and (b) sphingolipids, share a similar though invertebrates don’t possess steroid
three-dimensional structure. They are built on different hormones, some use a steroid-like hormone,
backbones: glycerol for phosphoglycerides and sphingosine ecdysone, to control maturation and development.
for sphingolipids. The pathways of steroid synthesis involve
nonsteroid intermediates (Figure 37). Steroid syn-
chain, its structure is similar to monoacylglycerol. thesis begins when acetate is used to produce
Ceramide is formed when a fatty acid is esterified mevalonate, the precursor for activated isoprene.
to sphingosine, creating a structure that resem- Activated isoprene is the precursor for many fa-
bles diacylglycerol. Many different types of sphin- miliar molecules, such as carotenoids and vita-
golipid can be constructed by attaching different mins A, E, and K. Ubiquinone, a type of quinone,
polar head groups to ceramide. When phospho- is an important component in mitochondrial en-
choline is attached to ceramide, sphingomyelin is ergy production. Activated isoprene is also used to
formed. Carbohydrates can be attached to ce- produce isoprenoids that act as hormones, includ-
ramide to form neutral glycolipids and ganglio- ing insect juvenile hormone and pheromones.
sides. Sphingolipids are most often found on the Further along the pathway of cholesterol synthesis
extracellular side of the cell membrane. Each cell
80
is squalene, a steroid used by sharks to aid in Acetate

buoyancy. Cholesterol is the precursor for many
steroid hormones.
Vitamin K Mevalonate Vitamin A
Mitochondrial Metabolism
Ubiquinone Activated isoprene Carotenoids
Mitochondria process metabolites generated in
the cytoplasm, breaking them down to capture
their chemical energy in the form of ATP. The main Isoprenoids Squalene Vitamin E
point of entry for mitochondrial energy-producing
pathways is acetyl CoA, which as you’ve learned
earlier is produced in many pathways (Figure 38). Vitamin D Cholesterol Bile acids
Acetyl CoA enters the cyclical tricarboxylic acid
cycle (TCA cycle) and is oxidized to form reduc-
ing equivalents (NADH, FADH2), which provide the Pregnenolone
fuel for mitochondrial ATP production.
Corticosterone Progesterone Testosterone

The TCA cycle uses acetyl CoA to generate
reducing equivalents
Aldosterone Cortisol Estradiol
Once acetyl CoA is produced within mitochondria,
its fate depends on intracellular conditions. When Figure 37 Steroid biosynthesis This simplified pathway
cells need energy, acetyl CoA enters the TCA cycle, of steroid synthesis illustrates the many intermediates that are
where its oxidation ultimately leads to ATP pro- used by cells.
duction. The TCA cycle (Figure 39) consists of
eight enzymes that collectively catalyze the follow- enzymes, and the catalytic activity of enzymes.
ing reaction: Tissues that use a lot of energy, such as heart and
brain, have high levels of the TCA enzymes. In
Acetyl CoA ! 3NAD! ! GDP ! Pi ! FAD ’
many tissues, the flux through the TCA cycle is af-
2CO2 ! 3NADH ! FADH2 ! GTP
fected by the levels of acetyl CoA and oxaloacetate,
The four dehydrogenases in the TCA cycle pro- as well as other intermediates in the cycle. When
duce reducing equivalents: NADH is produced by tissues have abundant energy, they typically use
isocitrate dehydrogenase, 2-oxoglutarate dehy- acetyl CoA and intermediates as biosynthetic sub-
drogenase, and malate dehydrogenase; FADH2 is strates. Acetyl CoA is an important substrate in
produced by succinate dehydrogenase. Most of the fatty acid synthesis, and oxaloacetate is a sub-
ATP produced through acetyl CoA oxidation comes strate for glucose synthesis. When biosynthetic re-
from the subsequent oxidation of NADH and actions deplete these substrates, the rate of the
FADH2. The TCA cycle also produces one molecule TCA cycle declines. Allosteric effectors also regu-
of GTP, which is energetically equivalent to ATP. late the TCA cycle. Calcium, frequently elevated
This reaction, catalyzed by succinyl CoA synthase,
is an example of substrate-level phosphoryla-
Dietary sucrose Glucose Dietary starch
tion. The TCA cycle is not really an isolated path-
Glycogen
way so much as a collection of enzymes acting on
a pool of metabolites exchanged with other path-
ways. When intermediates are removed for other Lactate Pyruvate Amino acids
reactions, cells use anaplerotic pathways to re-
Fatty acids Amino acids
generate the intermediates. Ketone bodies
Cells control the rate of the TCA cycle in three
ways: by regulating the concentrations of reac-
Acetyl CoA
tants (substrates and products), the levels of the
Figure 38 Acetyl CoA production from diverse
metabolites
81
Acetyl CoA pass electrons directly to ubiquinone.

For example, the TCA cycle enzyme
Citrate synthase
succinate dehydrogenase is actually
Oxaloacetate Citrate complex II of the ETS. An FAD group
within its structure becomes reduced
Malate
dehydrogenase NADH Aconitase during oxidation of succinate, form-
ing FADH2. The enzyme in turn
passes the electrons from FADH2 to
Malate Isocitrate ubiquinone. Once reduced, ubiquin-
one transfers its electrons to com-
plex III, which in turn transfers
NADH
Fumarase Isocitrate electrons to cytochrome c. Complex
dehydrogenase IV, or cytochrome c oxidase, ac-
CO2
cepts electrons from cytochrome c
and passes them on to molecular
Fumarate 2-Oxoglutarate oxygen. Complete reduction of oxy-
FADH2 NADH gen (O2) requires four electrons
Succinate 2 -Oxoglutarate
CO2 from cytochrome c and consumes
dehydrogenase dehydrogenase
four protons to produce two water
GTP
Succinate Succinyl CoA molecules.
Complexes I, III, and IV are also
Succinyl CoA proton pumps. When these com-
synthase
plexes transfer energy to the next
Figure 39 Tricarboxylic acid cycle The enzymes of the TCA cycle oxidize carrier, enough free energy remains
acetyl CoA to release its energy in the form of reducing equivalents (3 NADH, 1 FADH2) to pump protons out of the mito-
and 1 GTP. chondrial matrix. Fewer protons
are pumped in the oxidation of
during periods of high metabolic demand, stimu- FADH2 because these enzymes pass their electrons
lates isocitrate dehydrogenase and 2-oxoglutarate directly to ubiquinone, bypassing the proton-
dehydrogenase, increasing the rate of NADH pro- pumping complex I. The proton gradient formed
duction to help the cell meet its energy demands. by the ETS has both electrical and chemical com-
ponents: a pH gradient (pH) and a membrane po-
tential (Ψ). This proton motive force is potential
The ETS generates a proton gradient, heat, energy that can be used to drive other processes,
and reactive oxygen species such as ATP synthesis.
Mitochondria use reducing equivalents as the sub- The ETS converts much of the energy liber-
strate for oxidative phosphorylation, a complex ated from NADH oxidation to the proton motive
pathway that combines oxidation by the electron force. Some energy is “lost” in the formation of two
transport system (ETS) with phosphorylation by-products: heat and reactive oxygen species
(Figure 40). The ETS builds an electrochemical (ROS). Conditions that increase electron flow and
gradient that can be used to drive ATP synthesis oxygen consumption also increase heat produc-
and energy-dependent transport processes. tion. ROS production is an inevitable consequence
Found within the inner mitochondrial membrane, of electron movement throught the ETS. Usually
the ETS consists of four multisubunit proteins more than 99% of the electrons that enter the ETS
(complexes I, II, III, and IV) and two electron car- make the journey all the way to the end of the
riers (ubiquinone, cytochrome c). chain, forming water. However, a few are stolen
Although electrons can enter the ETS in several from the ETS by molecular oxygen to form super-
ways, each pathway converges on the first mobile oxide (O2), a potent ROS that can attack chemical
carrier, ubiquinone. The NADH produced in the bonds, damaging macromolecules such as lipids,
TCA cycle passes electrons to complex I, which in proteins, and DNA. Cells possess vigorous antiox-
turn reduces ubiquinone. Several FADH2-linked en- idant defense mechanisms to inactivate superox-
zymes found in the inner mitochondrial membrane ide before it can cause damage. The enzyme
82
Electron transport system Phosphorylation
Intermembrane
H+ H+ H+ space
H+
Cyt
Electron C
Complex Complex Complex Complex

I Q III IV V
Mitochondrial
inner membrane
Complex II
NADH FAD FADH2 O2

+ H+
H+ H + H+
ADP
Succinate H 2O
NAD+ Fumarate
+ Pi
Mitochondrial
H+ matrix
ATP
Figure 40 Oxidative phosphorylation Complex I (Q). Electron transfer continues through complex III,
collects electrons from NADH produced by various cytochrome c, and finally complex IV, cytochrome oxidase.
mitochondrial dehydrogenases. Complex II, or succinate During electron transport, complexes I, III, and IV also pump
dehydrogenase, transfers electrons from succinate to FAD. protons out of the mitochondrial matrix, creating the proton
Both complex I and II, as well as other FAD-link motive force (p). The mitochondrial F1FO ATPase (complex V)
dehydrogenases not shown, transfer electrons to ubiquinone uses p to fuel ATP synthesis.
superoxide dismutase, or SOD, consumes super- ylation; the two processes are functionally coupled
oxide to produce hydrogen peroxide (H2O2), which through a mutual dependence on p.
is less toxic than superoxide. Other antioxidant en- The rate of ATP synthesis by the F1FO ATPase
zymes, such as catalase and glutathione peroxi- depends on the magnitude of p and the availabil-
dase, consume H2O2, preventing it from causing ity of the substrates ADP and inorganic phosphate
cellular damage. (Pi). When cells are rapidly hydrolyzing ATP, [ADP]
and [Pi] increase, accelerating the rate of the F1FO
ATPase reaction. To understand how this process
The F1FO ATPase uses the proton motive is regulated, consider what happens in a muscle
force to generate ATP that goes from rest to exercise. At rest, the rate of
To this point we have discussed how mitochondria ATP breakdown is slow and [ATP] builds up while
build p but not how it is used to produce ATP. Mi- [ADP] and [Pi] decline. The ETS builds p to its
tochondria possess an ATP synthase, usually maximum because the ATPase, the major drain on
called the F1FO ATPase, that uses the energy con- the gradient, is inhibited. With little flux through
tained in p to drive the phosphorylation of ADP. the ETS, the rate of respiration is low. This is the
(Although it normally functions in the direction of biochemical reason why you breathe less when
ATP synthesis, the F1FO ATPase is reversible and resting. When muscle activity begins, ATP is hy-
able to break down ATP under some conditions.) drolyzed and the concentrations of ADP and Pi in-
The F1FO ATPase possesses a proton-pumping re- crease. With the stimulation of the ATP synthase,
gion and a catalytic region. When protons pass p is depleted and ETS accelerates to replenish
through the enzyme, which spans the mitochon- the gradient. We increase our oxygen consump-
drial inner membrane, the energy is used to catalyze tion during exercise because of this linkage be-
the synthesis of ATP. Oxidative phosphorylation is tween ATP synthesis and oxidation.
the combination of oxidation by the ETS and phos- The functional linkage between oxidation and
phorylation by F1FO ATPase. Note that there is no phosphorylation depends on the integrity of the
physical linkage between oxidation and phosphor- inner mitochondrial membrane. All membranes
83
are somewhat permeable to protons, but the inner Myofibril

mitochondrial membrane is relatively resistant to
proton leak. If the protons pumped out of the mi- ATP ADP + Pi
tochondria by the ETS were to leak back into the
mitochondria, p would be dissipated, causing CPK
two effects on oxidative phosphorylation. First, Creatine Phosphocreatine
the ETS would continue at a high rate, pumping
protons and consuming oxygen in a futile effort to
Creatine Phosphocreatine
rebuild p. Second, the reduction in p would pre- Outer
CPK membrane
vent the mitochondria from producing ATP. Mito-
chondria that show high rates of respiration with
no ATP production are considered uncoupled. ATP ADP + Pi
While this state is disastrous for energy produc-
tion, it is an important mechanism to produce Inner
heat. Some mammals have specific proteins that membrane
ADP
facilitate the movement of protons across the in-
ner membrane. These uncoupling proteins are im- ATP
portant in mammals that experience cold stress,
such as newborns and hibernators. Mitochondrion
Figure 41 Phosphocreatine shuttle Phosphocreatine

Creatine phosphokinase enhances energy is produced by the mitochondrial enzyme creatine
stores and transfer phosphokinase (CPK) and diffuses to the myofibrils, where
another CPK enzyme regenerates the ATP.
Some of the energy stored first as ATP is used to
produce other high-energy phosphate compounds
of equivalent energy, such as phosphocreatine. A shuttle improves the efficiency of energy transfer
vertebrate muscle, for example, may have 5–10 two ways. First, creatine and phosphocreatine are
times more phosphocreatine than ATP, serving as smaller molecules than the adenylates and have
an energy store. When the muscle begins to work higher diffusion coefficients. Second, the absolute
at high intensity, ATP is consumed to support mus- concentrations of creatine and phosphocreatine
cle activity. The resulting decrease in [ATP] and in- are much greater than those of the adenylates, al-
crease in [ADP] drive the creatine phosphokinase lowing much steeper intracellular gradients to
(CPK) reaction in the direction of ATP production, form, which accelerates the rates of diffusion.
at the expense of phosphocreatine. As muscle ac-
tivity continues, the phosphocreatine pool is grad-
ually depleted, allowing muscles to preserve ATP
at normal levels for longer periods. Whereas the
Integration of Pathways of Energy
existing pool of ATP is sufficient for only a few sec-
Metabolism
onds of activity, the large phosphocreatine pool al- The metabolic traits exhibited by whole animals
lows muscle to maintain ATP levels and sustain can be traced back to the cellular pathways of en-
contractions for a much longer duration. ergy metabolism. Put simply, in order to remain in
In addition to bolstering energy stores, phos- energetic balance, cells must produce ATP at rates
phocreatine is a component of the phosphocrea- that match the ATP demand. Consider the situa-
tine shuttle, a pathway that improves the efficiency tion in a mammalian heart cell. We know from
of energy transfer within the cell (Figure 41). The rates of oxygen consumption that the heart con-
cycle begins with ATP produced by the mitochon- sumes ATP at a rate of about 30 µmol/min/g. Since
dria. CPK on the outer mitochondrial membrane the concentration of ATP doesn’t change during
uses this ATP to phosphorylate creatine. The normal activity, the heart cell must also produce
phosphocreatine diffuses from the mitochondria ATP at the same rate (30 µmol/min/g). Since the
to the myofibrils where another CPK uses the concentration of ATP is only about 5 µmol/g, at a
phosphocreatine to regenerate ATP. This CPK metabolic rate of 30 µmol/min/g, the heart turns
over the entire ATP pool several times per minute.
84
At this turnover rate, a cell that produces ATP at Oxygen and ATP control the balance
a rate only 10% less than the rate of demand between glycolysis and OXPHOS
would be depleted of ATP within two minutes. At
Glycolysis produces 2 mol of ATP for every mol of
the cellular level, the balance between energy-
glucose, but glucose oxidation yields 36 mol of ATP
consuming pathways and energy-producing path-
per mol of glucose. Despite the differences in en-
ways is orchestrated by the diverse regulators of
ergy yield, glycolysis and oxidative metabolism
metabolism, such as adenylates, redox balance,
both play important roles in energy metabolism.
Ca2, and carbon supply. These regulators “in-
Glycolysis, in addition to being able to operate
form” the cell of energy needs, and the metabolic
without oxygen, can produce ATP at much greater
pathways respond accordingly. What is interesting
rates than can oxidative metabolism. The condi-
about multicellular animals is that the needs of the
tions that allow such high rates also require the
cell are often superceded by the needs of the whole
pathway to be somewhat inefficient. In contrast,
organism. A liver cell, for example, not only re-
oxidative metabolism is very efficient in conserv-
sponds to its own metabolic needs but produces
ing chemical energy, but to do so, it is necessarily
energy substrates for the entire animal. When glu-
slow. Think of glycolysis as a high-performance
cose levels are low, the liver increases the rates of
sports car—useful to get somewhere fast but not
gluconeogenesis and glycogenolysis, releasing glu-
the best car for gas mileage. Oxidative metabo-
cose to the blood for use in other tissues. This al-
lism, by contrast, is the fuel-efficient compact car.
truistic response is imposed on the liver cell by
Like some suburban families, the cell maintains
hormones that affect the catalytic properties of the
both types of engines in working order, to be called
enzymes of intermediary metabolism, largely
upon for different needs.
through covalent modification, such as phosphor-
ylation.
The sum of the cellular metabolic properties
Physical properties of fuels influence fuel
yields the whole animal metabolic patterns. Vari-
selection
ations in animal metabolic rate are central to Each of the major metabolic fuels displays physical
many problems in animal physiology. About properties that influence how the fuel is stored and
allometric scaling of metabolic rate: large animals used. Carbohydrate is stored as large granules of
have lower mass-specific metabolic rates than glycogen, coated with water molecules that make
small animals. Animals control metabolic rate to up its hydration shell. Glycogen particles can be so
survive challenging conditions, such as environ- large that they interfere with cellular processes.
mental hypoxia, hypothermia, and dehydration. Some tissues, such as the mantle of bivalve mol-
In the accompanying feature, we describe the luscs, can safely accumulate high levels of glycogen,
ways physiologists measure whole animal meta- but if glycogen reached this high level in a muscle it
bolic rate in the lab and in the field (see Box 2, would prevent the muscle from contracting nor-
Methods and Model Systems: Metabolic Rate). mally. Although glycogen is readily mobilized, its
Metabolic strategies in animals address the physical properties prevent most cells from storing
constant fluctuations in nutrient availability, en- high levels. In contrast, lipid is stored at much
ergy demand, and environmental conditions. En- higher levels in the form of anhydrous, amorphous
suring the correct flow of energy requires droplets of triglyceride. These physical differences,
exquisite control of the pathways of intermediary coupled with the energy content of a given mass of
metabolism. Opposing pathways must be recipro- stored fuel, affect fuel selection. Cells can obtain
cally regulated to avoid a futile cycle: simultane- about 10 times more ATP from lipid than from the
ous synthesis and degradation of a metabolite. same mass of hydrated glycogen particles. Given
Similarly, the various alternatives must be utilized the advantage of lipid as an energy store, you might
in a way that takes into consideration the advan- wonder why animals use glycogen at all. Recall that
tages and disadvantages of each class of fuel. glycogen can be mobilized much faster than lipid,
These choices are also influenced by long-term and plays a vital role under conditions in which en-
and short-term metabolic priorities of the cells ergy is required very quickly, as in the “fight-or-
and organisms. flight” response. Most cells use a combination of
lipid and carbohydrate fuels to balance the advan-
tages and disadvantages of each fuel.
85

Metabolic Rate
If metabolism is literally the sum of all resting metabolic rate (RMR) must ensure that the an-
chemical reactions, then what exactly is meant by imal is unstressed and inactive at a neutral ambient
metabolic rate and how is it measured? Metabolic rate is temperature and has digested its most recent meal.
the overall flux through the pathways of energy produc- While this approach yields important information about
tion, which matches the rate of energy consumption. In the physiological hardwiring of an animal, it may not be
the presence of oxygen, the pathways that lead to produc- the best estimate of the animal’s metabolic rate under
tion of ATP consume carbon fuels and oxygen (O2), and normal conditions. Ecological physiologists are often
produce heat, carbon dioxide (CO2), and water. Many more interested in long-term metabolic rate of free-
physiological questions revolve around changes in meta- ranging animals in the natural setting. One of the most
bolic rate, and many approaches have been developed to common approaches to measuring field metabolic rate
measure the substrates and products of metabolism. is the doubly labeled water method. Most water in the
Direct calorimetry assesses metabolic rate in terms of body is composed of the most common isotopes of hy-
heat production, measured in energy units (joules). For drogen (1H) and oxygen (16O). To initiate a doubly labeled
purely pragmatic reasons (direct calorimetry requires water experiment, the animal of interest is captured and
expensive, specialized equipment), this is the least com- injected small volumes of water composed of less com-
mon way to measure metabolic rate. A more common ap- mon isotopes of hydrogen (e.g., 2H) and oxygen (18O).
proach to measuring metabolic rate is indirect Over time, the labeled hydrogen is lost from the body
calorimetry, in which the researcher measures the rate primarily as water, through evaporation, respiration,
of O2 consumption or CO2 production. To infer a metabolic and excretion. Likewise, labeled oxygen is also lost in
rate from these measurements, it is important to recog- water, but some is exchanged with the O in CO2. Thus,
nize where O2 is consumed (largely in the electron trans- the difference between the loss of labeled oxygen and
port system) and where CO2 is produced (primarily in the labeled hydrogen reflects the rate of CO2 production.
TCA cycle). The quantitative relationship between these This method works very well in air-breathing animals,
three estimates of metabolic rate—heat production, O2 but in water breathers, the rates of water flux are much
consumption, and CO2 production—depends on many too great to detect the impact of CO2 production on iso-
factors. You learned earlier in this chapter that the ratio tope ratios.
of CO2 produced/O2 consumed reflects the metabolic fuel.
References
Likewise, the oxycaloric relationships (O2 consumed/
q Hulbert, A. J., and P. L. Else. 2004. Basal metabolic rate: History,
joules released) depend on the nature of the fuel. composition, regulation, and usefulness. Physiological and Bio-
Each of these approaches for measuring metabolic chemical Zoology 77: 869–876.
rate requires that the researcher hold an animal under q Nagy, K. A. 2005. Field metabolic rate and body size. Journal of
controlled conditions and ensure that it remains in a Experimental Biology 208: 1621–1625.
constant, stable condition. A researcher interested in
The main way the cells regulate the balance phatase (PDHP). ATP, NADH, and acetyl CoA each
between fatty acids and carbohydrates is through activate PDHK, causing PDH to be converted to its
the mitochondrial enzyme pyruvate dehydroge- inactive, phosphorylated form. The activity of
nase (PDH). This enzyme is regulated allosterically PDHP, in contrast, is governed primarily by Ca2.
by ATP, acetyl CoA, and NADH. When cells have High [Ca2] stimulates PDHP, converting PDH to its
fatty acids available, their oxidation increases con- active dephosphorylated form.
centrations of ATP, NADH, and acetyl CoA. These
metabolites inhibit PDH, sparing pyruvate for glu-
coneogenesis. When energy stores are depleted, Fuel selection can be calculated from the
the concentrations of NADH, ATP, and acetyl CoA respiratory quotient
tend to decrease, which lessens the inhibition of Each pathway for oxidation of fuels demonstrates
PDH. These same metabolites also influence the characteristic relationships between the amount of
phosphorylation state of PDH by regulating the ac- (1) ATP produced, (2) oxygen consumed, and (3) CO2
tivities of PDH kinase (PDHK) and PDH phos- generated. The reason these parameters differ
86
among fuels can be traced back to the pathways of Energetic intermediates regulate the
degradation. Ratios of different combinations of balance between anabolism and
these three parameters provide important informa- catabolism
tion about fuel selection. The differences in the ra-
A cell activates pathways of energy production
tio of ATP produced to oxygen consumed (the ATP/O
when it needs energy, but when energy is abun-
ratio) can be traced to the reliance on FAD-linked
dant it stimulates anabolic pathways, storing nu-
enzymes. Each time an NADH molecule is produced
trients or producing building blocks for cell growth
in the mitochondria, oxidative phosphorylation can
or cell division. How do cells actually sense the
produce 3 molecules of ATP and consume 1 atom of
need for energy and regulate the transition be-
oxygen (ATP/O 3). When a molecule of FADH2 is
tween catabolism and anabolism? Many of the
produced, only 2 molecules of ATP can be generated
pathways we have discussed are sensitive to the
while consuming the same 1 atom of oxygen (ATP/
cellular indices of energetic status, primarily
O 2). Carbohydrate oxidation uses predominantly
acetyl CoA, adenylates, and NADH. Changes in the
NADH-linked enzymes, whereas lipid oxidation re-
concentration of these products reflect energy sta-
lies more heavily on FAD-linked enzymes. Because
tus and cause compensatory changes in metabolic
of this difference, carbohydrate yields more ATP for
pathways. When cells are “energy-rich,” the con-
a given volume of oxygen. This difference has an ef-
centrations of acetyl CoA, NADH, and ATP are rel-
fect on the fuel preference of at least some animals
atively high and the concentrations of CoA, NAD,
that live at low oxygen levels. For example, the
ADP, and AMP are low. Consider how these
heart of most humans uses lipid as a major fuel. In
metabolites stimulate gluconeogenesis while in-
contrast, humans that have adapted to high alti-
hibiting glycolysis (Figure 42). By matching the
tude, such as the natives of the high Andes, rely
more heavily on glucose oxidation. Of course, in Glucose
more extreme hypoxia and anoxia, animals have lit-
tle choice but to rely on glycolysis.
Differences in the ratio of CO2 produced to O2
consumed, known as the respiratory quotient
(RQ), arise from the pathways of oxidation. Glu- –AMP
+ADP
cose has six carbons, and oxidizing it completely +AMP PFK FBPase
to 6 CO2 yields 2 NADH in the cytoplasm, 2 NADH – ATP
via PDH, 6 NADH via the TCA cycle, and 2 FADH2
Fructose 1,6-biphosphate
via succinate dehydrogenase. The 12 reducing
Glycolysis Gluconeogenesis
equivalents consume 12 atoms of oxygen, or 6
molecules of O2. Thus, carbohydrate oxidation
yields an RQ of 1 (6 mol of CO2 to 6 mol of O2). In
contrast, oxidation of fatty acids generates an RQ
of about 0.7, although the exact number depends Phosphoenol pyruvate
on the specific fatty acid. Consider the pathway of
palmitate oxidation. As a 16-carbon fatty acid, it
–ATP
generates 16 mol of CO2 per mol of palmitate. –Acetyl CoA PK Oxaloacetate
Seven cycles of -oxidation are required to break PC +Acetyl CoA
palmitate into 8 molecules of acetyl CoA, yielding Pyruvate
7 FADH2 and 7 NADH. Oxidation of the 8 acetyl
CoA in the TCA cycle yields 24 NADH and 8 PDHa PDHb –ATP
FADH2. Oxidation of the 46 reducing equivalents –Acetyl CoA
–NADH
consumes 23 mol of O2, giving an RQ of 0.7 (16 mol
+NADH
of CO2 to 23 mol of O2). Because of these charac- +Acetyl CoA
teristic relationships between RQ and fuel oxida- +ATP Acetyl CoA
tion, measurement of CO2 production and O2 Figure 42 Reciprocal regulation of glucose
consumption of whole animals can provide impor- metabolism High-energy compounds, such as ATP,
tant insight into the pathways that are being used acetyl CoA, and NADH, inhibit glycolysis and stimulate
to support energy metabolism. gluconeogenesis at key regulatory enzymes.
87
rates of ATP synthesis with rates of ATP utiliza- themselves from the environment, giving them con-
tion, cells are able to defend ATP concentrations trol over intracellular conditions. Second, mem-
within a narrow range. branes help cells organize intracellular pathways
Animals also use other metabolites to recipro- into discrete subcellular compartments, including
cally regulate opposing pathways. When meta- organelles. Separation of processes also requires
bolic conditions induce cells to commit to fatty acid specific mechanisms to transfer molecules across
synthesis, the increases in the levels of malonyl the membranes. Many complex physiological prop-
CoA block fatty acid oxidation by inhibiting CPT-1. erties and responses depend on cellular transport
Cells further separate anabolism and catabolism and transfers between subcellular compartments.
using tissue specializations. The liver has the en- Ultimately, the cellular properties that determine
zymes for ketogenesis but cannot break down ke- physiological function are controlled through regu-
tone bodies. Muscles have the enzymes for ketolysis lation of gene expression.
but cannot synthesize ketone bodies. In fact, the
control of energy metabolism in complex animals
reflects a division of labor such that some tissues
Membrane Structure
become servile to others. Liver and adipose tissue
perform important functions for whole animal Cellular membranes are composed of phospho-
metabolic balance, giving lower priority to their lipids, other lipids, and diverse proteins. The
own cellular and metabolic needs. fluid mosaic model, shown in Figure 43, illus-
trates the structural features of biological mem-
branes. Each of the two layers is a sheet of lipid
molecules arranged side by side. The surfaces of
2 CO N CEP T C HE C K the lipid bilayer are composed of the polar head
8. Compare the four types of macromolecules. groups of phospholipids, and the internal hy-
Discuss how variation in structure arises in drophobic core is composed of long fatty acid
each class. chains of the phospholipids attached through van
9. Distinguish between the following types of der Waals forces.
reactions: anabolic, catabolic, amphibolic,
anaplerotic.
10. How is oxidation coupled to phosphorylation in The lipid profile affects membrane
mitochondrial oxidative phosphorylation? properties
11. Compare the pathways of glucose metabolism Animals produce specialized membranes with
(synthesis and degradation) under (a) high unique molecular signatures by varying the struc-
versus low energy conditions and (b) normal
versus low oxygen conditions.
tures and proportions of the different types of lipid.
Much of the variation can be attributed to the profile
12. Under what conditions is it more advantageous
to use carbohydrate rather than lipid as a of phosphoglycerides, the most abundant of which
metabolic fuel? are phosphatidylcholine (PC), phosphatidylserine
(PS), and phosphatidylethanolamine (PE). Recall
from earlier in this chapter that each of these phos-
pholipids is really a class of molecules with con-
Cell Physiology stituent fatty acids that differ in chain length and
In the opening essay, we discussed how the evo- saturation. Although phosphoglycerides are the
lutionary origins of animals required a new rela- most abundant molecules in the bilayer, membranes
tionship between cells to foster multicellular also possess other lipids, including sphingolipids,
relationships. Cellular membranes1 perform two glycolipids, and cholesterol, as well as many pro-
main roles that are central to multicellularity and teins. Glycolipids resemble phospholipids, but with
cellular function. First, they allow cells to isolate complex carbohydrate modifications that impart a
negative charge to the polar head group. Nerve cells
possess high concentrations of sphingolipids and
1
Cellular membranes refer to all of the membranes within
glycolipids because they alter the electrical proper-
a cell, including the plasma membrane (or cell membrane)
that surrounds the cell and the membranes that form the ties of the membrane. Glycolipids are also important
organelles. in communication between cells.
88
The unusual ability of cholesterol

Sugar residues to increase fluidity while decreas-
of glycoprotein
ing permeability provides animals
Glycoprotein with an important mechanism for
controlling membrane properties.
Phospholipid
bilayer
Lipid membranes are
heterogeneous
Channel
protein While the fluid mosaic model illus-
trates the general relationships be-
tween lipid and protein variation in
Peripheral membrane proteins, it underem-
proteins Integral Cholesterol
phasizes the spatial variation seen
proteins
in membrane lipids (Figure 45).
Figure 43 Fluid mosaic model Membranes are composed of lipids The inner and outer layers of the
such as phospholipids, cholesterol, and glycolipids. Proteins can be embedded in phospholipid bilayer typically pos-
the lipid bilayer. Each of the elements moves laterally within the membrane,
sess different types of lipids. PE
giving it a functional fluidity.
and PS are found almost exclu-
sively in the inner leaflet, whereas
Cholesterol has an unusual role in mem- PC is concentrated in the outer leaflet. Glycolipids
branes. Although it is absent from some mem- are found only in the outer leaflet of the mem-
branes, such as mitochondrial membranes, brane. Membranes also possess discrete regions
cholesterol can compose almost half the lipid com- that are enriched in cholesterol and glycolipids.
ponent of other membranes. Cholesterol influ- These lipid rafts serve two important functions.
ences membrane properties in complex ways Their molecular composition causes a slight thick-
because of the way it integrates into the lipid bi- ening of the lipid bilayer, which recruits phospho-
layer (Figure 44). One end of the molecule inter- lipids with longer chain fatty acids and proteins
acts with phospholipids near the polar head with relatively long transmembrane domains. Be-
groups, filling gaps between phospholipids to re- cause of the distinct molecular composition of lipid
duce the permeability to low-molecular-weight rafts, they can act as microcompartments within
solutes. Cholesterol also disrupts the interactions the cell, providing an additional way to spatially
between fatty acids, enhancing membrane fluidity. organize pathways.
H3C CH2
CH CH2 Environmental stress can alter membrane
CH2
CH3 fluidity
CH2 CH
CH3 CH3 An essential component of the fluid mosaic model

is the ability of the constituents to move through-
out the membrane. Phospholipids and proteins
Cholesterol can rotate in position as well as move laterally
HO
through the membrane. Membrane fluidity de-
pends on the properties of the membrane lipids,
which are influenced by the physical environment.
Cells regulate the fluidity of the membrane by con-
trolling the nature of lipids to achieve the appro-
priate degree of molecular movement. Low
temperature, for example, can strengthen the van
Figure 44 Unusual membrane properties of der Waals forces between membrane lipids, re-
cholesterol Cholesterol strengthens the interactions stricting molecular movement within the mem-
between phospholipid polar head groups while disrupting the brane (Figure 46). Since this can adversely affect
interactions between fatty acid tails. membrane function, many animals actively
89
Extracellular fluid
Membrane proteins have
important structural and regu-
Cholesterol latory roles within cells. They
contribute to structural support
Glycolipids
by linking the intracellular cy-
toskeleton to the extracellular
matrix. Many of the intrinsic
membrane proteins are recep-
tors that are part of complex
signaling pathways. Because
membranes are physical barri-
Cytoplasm Lipid raft
ers to the free movement of
Figure 45 Membrane heterogeneity Cellular membranes are many vital organic and inor-
heterogeneous in composition. Most cells maintain distinct profiles in inner and outer ganic solutes, cells use integral
monolayers, sometimes exchanging phospholipids between layers. Lipid rafts are proteins to transport molecules
regions of the plasma membrane that accumulate cholesterol and glycolipids, across membranes.
thickening the membrane. These thicker regions preferentially recruit proteins with
longer transmembrane domains.
remodel their membranes to compensate for the Transport Across Cellular

effects of the physical environment. By altering the Membranes
membrane lipid profile, they can keep membrane
fluidity constant. This pattern of membrane regu- Many cellular processes depend on the ability to
lation, is called homeoviscous adaptation. move molecules across membranes. A cell must be
able to bring nutrients across its plasma mem-
brane and expel end products. Hormones synthe-
Membranes possess integral and sized within the cell must be processed and
peripheral proteins packaged for secretion. All animal cells must be
Protein is an important constituent of most cellu- able to move specific ions across the plasma mem-
lar membranes, in some cases making up more brane to control their ionic and osmotic proper-
than half the mass of the membrane. Integral ties. Specific integral membrane proteins mediate
membrane proteins are tightly bound to the mem- these transport processes. The kinetic properties
brane, either embedded in the bilayer or spanning of a transporter are similar to those of enzymes,
the entire membrane. Peripheral membrane with an affinity constant (Km) and a maximal veloc-
proteins have a weaker association with the lipid ity (Jmax). The three main classes of membrane
bilayer, typically binding to integral membrane pro- transport are passive diffusion, facilitated diffu-
teins or glycolipids. The different relationships be- sion, and active transport. These classes of trans-
tween the bilayer and membrane proteins are port are distinguished by the direction of
shown in Figure 47. transport, the nature of the carriers, and the role
of energy in the process (Figure 48).
Lipid-soluble molecules cross membranes

by passive diffusion
Cold Although membranes are barriers to the move-
ment of many molecules, some molecules cross
Warm membranes without a transporter. The ability of a
molecule to freely cross a biological membrane de-
pends on its hydrophobicity. Many molecules,
Liquid crystalline Gel such as steroid hormones, are freely soluble in
Figure 46 Temperature and membrane fluidity lipid. When these molecules encounter a cell
Temperature alters the fluidity of membranes by changing membrane, they dissolve into the lipid bilayer and
the interactions between phospholipids. escape to the other side. Both influx and efflux oc-
90
cur simultaneously, but the net

movement (influx minus efflux) de- Peripheral
pends on the concentration gradi- protein
ent. The net movement of molecules P
P Glycolipid
is from high concentration to low anchor
concentration. The steeper the con-
centration gradient, the greater the
rate of movement across the mem-
brane. This type of transport is β-barrel
called passive diffusion. No spe- Single Multiple

pass pass Peripheral
cific transporters are required, and protein
α-helix α-helix
no energy, beyond the concentration
gradient itself, is required. Figure 47 Integral membrane proteins Membrane proteins can
demonstrate many different types of relationships with membranes. Each membrane
protein has within its structure hydrophobic regions that interact favorably with the
Membrane proteins can bilayer. Depending on the protein, these regions can be
-helices or -barrels.
facilitate the diffusion of Transmembrane proteins span the entire bilayer, exposing regions to both sides of the
impermeant molecules membrane. Often these exposed regions possess modifications, such as the
Hydrophilic molecules cross mem- carbohydrate chains of glycoproteins. Peripheral membrane proteins are not
branes by other pathways that involve embedded within the membrane but associate with exposed regions of integral
membrane proteins.
specific transport proteins. If the con-
centration gradient is favourable, the Outside of cell
molecule may cross the membrane
by facilitated diffusion. As with Lipid-soluble
solute
passive diffusion, no energy beyond
that of the concentration gradient is Concentration
gradient
required to drive transport, but with
facilitated diffusion a protein is re-
quired to carry the molecule across
Energy
the membrane. Three main types of
proteins carry out facilitated diffu-
sion: ion channels, porins, and per-
meases (see Figure 49). Passive Channel Permease Active
diffusion transport
Ion channels are membrane
Facilitated diffusion
proteins that form pores through Inside of cell
which only specific ions may pass,
and only when the channel is open. Figure 48 Modes of membrane transport The mechanisms of transport
The channels are specific to one or across cellular membranes depend on the lipid solubility of the solute as well as the
sometimes two ions. Ca2 channels, direction and magnitude of the concentration gradient. Passive diffusion needs no
for instance, possess a structure that carrier, as lipid-soluble solutes move freely across the membrane. Facilitated
diffusion carries impermeant solutes across the membrane on protein carriers,
allows the free movement of Ca2,
including channels (either ion channels or porins) and permeases. Solutes can also be
but does not allow other cations
2 transported by active transport, which can move molecules against a concentration
such as Mg , K , or Na to cross at gradient.
appreciable rates. The specificity of
transport is due to a structural component of the IP3, is present. Voltage-gated channels are
channel known as the selectivity filter. The chan- opened or closed in response to membrane poten-
nel can be opened in response to cellular condi- tial. For example, K channels in muscle and neu-
tions. Ligand-gated channels are opened when rons open when the membrane depolarizes.
specific regulatory molecules are present. One im- Mechanogated channels are regulated through
portant ligand-gated channel is the Ca2 channel interactions with the subcellular proteins that
sensitive to inositol triphosphate (IP3); this channel make up the cytoskeleton. Changes in cell shape,
induces the release of Ca2 stores when its ligand, such as cell swelling, alter the arrangement of the
91
Δψ Δψ
(a) Voltage-gated (b) Ligand-gated (c) Mechanogated
Figure 49 Carriers involved in facilitated diffusion Channels are proteins that

mediate facilitated diffusion of ions and other metabolites. Channels typically exist in either a
closed or an open conformation. They are opened by specific triggers, including specific ligands,
voltage conditions, or physical associations with structural elements.
cytoskeleton. Upon sensing the changes in the tration. In contrast, cells use active transport to
cytoskeleton, mechanogated channels may open move molecules across membranes against con-
or close. centration gradients. Two main forms of active
Porins are large channels that function in transport are distinguished by the source of the en-
similar ways to ion channels but permit the pas- ergy that drives the process. In primary active
sage of much larger molecules. Mitochondria have transport, the carrier protein uses an exergonic re-
a porin in the outer membrane that facilitates the action to provide the energy to transport a molecule.
transfer of low-molecular-weight molecules from The other form of active transport, called secondary
the cytoplasm to the mitochondria. Aquaporins active transport, couples the movement of one
are water channels in the plasma membranes; molecule to the movement of a second molecule.
each aquaporin molecule can transport 3 billion The most common primary active transporters
water molecules per second. Some aquaporins, use the hydrolysis of ATP to provide the necessary
called aquaglyceroporins, are also capable of energy. Three general classes of ATP-dependent
transporting nonwater molecules, such as glycerol transporters, or ATPases, mediate primary active
and possibly urea. Aquaporins may also be in- transport: P-type ATPases, F-type (or V-type) AT-
volved in transport of gases across membranes. Pases, and ABC transporters. P-type ATPases use
The third type of protein that facilitates diffu- ATP hydrolysis to pump specific ions across mem-
sion is a permease. Rather than creating a pore for branes. For example, animal cells have a Na/K
a molecule, a permease functions more like an en- ATPase in the cell membrane that extrudes Na
zyme. It binds the substrate and then undergoes a from the cell in exchange for K. Many tissues have
conformation change that causes the carrier to re- Ca2 ATPases to transport Ca2 across membranes.
lease the substrate to the other side. Several tissues F-type and V-type ATPases are structurally re-
possess glucose permease, a transporter that allows lated ATPases that pump H across membranes
glucose to enter cells, passing from high concentra- using the energy of ATP hydrolysis. The mitochon-
tion to low concentration. Unlike porins and ion drial F-type ATPase operates in reverse, using H
channels, permeases can become saturated with movements down electrochemical gradients to
substrate at high concentration, such that the trans- provide the energy for ATP synthesis. The V-type
port process depends on how quickly the permease ATPases allow cells and organelles to extrude pro-
can carry its substrate across the membrane. tons to acidify a compartment, such as the lumen
of the lysosome or the inside of the stomach.
The ABC transporters carry large organic mol-
Active transporters use energy to pump ecules across the cell membrane. Cells often use
molecules against gradients ABC transporters to export toxins from the cell.
In passive and facilitated diffusion, molecules can The multidrug resistance protein, an important
move only from high concentration to low concen- ABC transporter, is often linked to types of cancers
92
that become resistant to chemotherapy. Some can- ganisms. Electrical signaling is not, however, a
cerous cells survive chemotherapy by transporting unique property of nerve and muscle cells. Several
the toxic drug out of the cell before the chemother- other types of cells use electrical signals, including
apeutic agent can kill it. fertilized eggs and hormone-secreting cells.
Secondary active transport uses the energy
held in the electrochemical gradient of one mole-
The interior of the membrane is
cule to provide the energy to drive another mole-
electronegative at rest
cule against its gradient. If the molecules move in
opposite directions, the carrier is called an Membrane potential can be measured using a mi-
antiport, or exchanger. For example, red blood croelectrode. Microelectrodes consist of a thin
cells use a Cl/HCO3 exchanger (also called band 3) recording electrode encased in a very fine-tipped
to drive the transport of these ions across the mem- glass pipette that can be inserted through the cell
brane. The direction of ion movement by this car- membrane into the cell. The microelectrode is
rier depends on the relative gradients of the two connected via a voltmeter to a reference electrode
ions. Alternatively, a symport, or cotransporter, that is immersed in the solution outside the cell.
is used to move molecules in the same direction. The voltmeter measures the voltage drop across
For example, intestinal cells use a Na-glucose co- the circuit caused by the membrane potential (Vm).
transporter to import glucose against its concentra- In most animal cells, the membrane potential is
tion gradient, driven by a greater inward Na between 5 and 100 mV. By convention, the
electrochemical gradient. membrane potential is expressed relative to the
All of these transport processes influence chem- voltage outside the cell. Thus, the negative value
ical gradients across membranes, but only a subset for Vm means that the interior of the cell mem-
of transporters affect the electrical gradient. Carri- brane is more electronegative than the exterior of
ers that transport uncharged molecules, such as the the cell membrane.
glucose permease, are termed electroneutral car-
riers. Similarly, carriers such as the Cl/HCO3 ex-
changer that exchange two ions of the same charge Ionic concentration gradients and
are also electroneutral. In contrast, the carriers that permeability establish membrane
transfer a charge across the membrane are called potential
electrogenic carriers. When we discuss Na/K Only two factors are required to establish a poten-
ATPase throughout this text, keep in mind that it is tial difference across a membrane: a concentration
an electrogenic carrier because it exchanges 3 Na gradient for an ion and a membrane that is perme-
for 2 K ions. able to that ion. Consider a situation where two so-
lutions are separated by a membrane that is
impermeable to ions (Figure 50). Assume that the
interior of the cell contains 100 mM KCl and 10 mM
Membrane Potential NaCl, and the extracellular fluid contains 100 mM
All animal cells maintain a voltage difference NaCl and 10 mM KCl. The concentration gradient
across their cell membranes, as well as some or- for K (100 mM inside the cell and 10 mM outside
ganelle membranes, such as the mitochondrial the cell) favors outward movement, whereas the
membrane. This voltage difference represents a concentration gradient for Na (100 mM outside
source of potential energy that cells can harness to and 10 mM inside the cell) favors inward move-
move molecules across membranes. The voltage ment. There is no gradient for the movement of Cl
difference is termed the resting membrane poten- (because the concentration of Cl is 110 mM both
tial difference, or the membrane potential, for inside and outside the cell). The solutions on either
short. In addition to using the membrane potential side of the membrane are also electroneutral, with
as a source of energy, excitable cells use changes equal numbers of anions and cations.
in membrane potential as communication To create a membrane potential, we insert
signals. This property is particularly important channels that allow the passage of K, but no other
for nerve and muscle cells, and thus the ion. The concentration gradient will cause K to
membrane potential is critical for allowing move out of the cell along the concentration gradi-
the coordinated movements of cells and or- ent, creating a local region of electronegativity on
93
K+ ion
Cl– ion Na+ ion
Inside cell: 100 mM KCl, 10 mM NaCl

Outside cell: 10 mM KCl, 100 mM NaCl
Concentration
gradient
Electrical
Inside cell Outside cell gradient
– + –
– + + – – – + –
+ – – – + +
– + –
– – + + + – +
+ + + – + –
+ – + – + +
– + – – – + + –
– – + – – + + –
+ + – – + – –
– – +
– – – + + + – + –
+ – + + +
+ + + – + – +– ++ + +
– – – – –
+ – +
– – – + + – ++ –
– –
+ + – – + – + + –
– + + + + +
+ + +
+ + – – – + – – + +
– – –
1 No permeability to any ion 2 K+ channels open, 3 Outward concentration

K+ exits cell gradient eventually equals
inward electrical gradient
Figure 50 Potassium movements and membrane potential
the inner face of the membrane (where K left) where R is the gas constant, T is the temperature
and a local region of electropositivity on the outer (Kelvin), z is the valence of the ion, F is the Fara-
face of the membrane (where K appeared). This day constant (23,062 cal/V-mol), and [X] is the mo-
excess negative charge at the inside face of the lar concentration of the ion. In our example,
membrane generates an electrical force that tends [K]outside 10 mM and [K]inside 100 mM, result-
to draw positive charges back into the cell. As ing in EK 60 mV. In other words, the force driv-
more K leaves the cell, the electrical force gradu- ing the outward movement of K resulting from its
ally increases to a level that exactly balances the 10-fold concentration gradient can be exactly bal-
driving force from the K concentration gradient. anced by a 60 mV excess of negative charge inside
Potassium ions continue to move across the mem- the membrane (a membrane potential of 60 mV).
brane, but their inward and outward fluxes ex- The equilibrium potential for a particular ion
actly balance each other. The potential difference is often termed its reversal potential, because
across the membrane under these equilibrium the direction of ion movement across the mem-
conditions is termed the equilibrium potential brane changes when the voltage difference across
for that ion (Eion). Because only a single ion can the membrane exceeds this level. In the case of
move across the membrane in this hypothetical our hypothetical example, net K flux was down
example, the equilibrium potential is equivalent to its concentration gradient from the inside to the
the resting membrane potential (Eion Vm). outside of the cell until the membrane potential
For a given concentration gradient, it is possi- difference reached 60 mV. If the membrane po-
ble to calculate the equilibrium potential for an ion tential were to become even more negative, the
using the Nernst equation, net movement of K would be from the outside of
the cell back to the inside—against its concentra-
RT 3X4 outside tion gradient. Note that the actual number of ions
Eion
3X4 inside
ln
zF that need to move across the membrane before
94
reaching the equilibrium potential is actually very and permeabilities of all of the relevant ions (see
small (less than 1/100,000 of the total K ions Box 3, Mathematical Underpinnings: The Gold-
within a typical cell), and does not result in a man Equation). The Goldman equation essentially
measurable change in the overall K concentra- represents the sum of the equilibrium potentials
tion either inside or outside the cell. for all of the relevant ions, with a weighting factor
It is important to emphasize that the membrane that takes into account the relative permeabilities
potential is the result of extremely small differences of the ions. The influence of each ion over the
in the number of charged molecules immediately overall membrane potential is thus proportional to
adjacent to the membrane—a difference that is too its permeability. For example, resting neurons are
small to detectably affect the overall ion concentra- more permeable to K than to the other ions, and
tion of the cytoplasm or extracellular fluid. The lo- as a result, K plays the major role in setting the
calization of the charge difference immediately resting membrane potential of neurons.
adjacent to the membrane arises because the cell
membrane acts as a capacitor. A capacitor is a de-
The Na/K ATPase establishes
vice containing two electrically conductive materi-
concentration gradients
als separated by an insulator, a very thin layer of
a nonconducting material. Electrical charges can Active pumping of Na and K ions by the electro-
interact with each other across the insulator if the genic Na/KATPase is responsible for establish-
layer is sufficiently thin. In a cell, the cytoplasm ing the concentration gradients for these ions
and the extracellular fluid are conducting materi- across the cell membrane. Ultimately it is these
als, whereas the lipid bilayer of the cell membrane concentration gradients (along with the selective
is the insulator. The excess positive charge along permeability of the membrane) that establish the
the outside of the membrane attracts the excess membrane potential. The Na/KATPase is also
negative charge along the intracellular face of the responsible for maintaining the resting membrane
membrane. These electrical interactions can only potential. Although most membranes are only
occur across very small distances, and do not af- sparingly permeable to Na at rest, a small
fect ions in the bulk phase of the cytoplasm or ex- amount of Na does leak into the cell down its
tracellular fluid. Thus, the membrane potential electrochemical gradient, while K leaks out.
occurs only in the area immediately adjacent to Without appropriate compensation, these ion
the membrane. movements would result in the dissipation of the
Na and K concentration gradients that are
needed to establish the membrane potential. Cells
Potassium plays the major role in use the Na/K ATPase to compensate for the leak-
establishing membrane potential age of Na and K ions. If you poison the Na/K
In our hypothetical example neither Na nor Cl ATPase with a drug called ouabain, the membrane
affected the membrane potential because there potential difference of the cell slowly decays over
was no concentration gradient for Cl and because the course of a few hours, eventually reaching a
the membrane was not permeable to either of value of 0 mV.
these ions. Of course, the situation in real cells is
not so simple, since there are several ions that dif-
fer in concentration between the inside and the Changes in membrane permeability alter
outside of the cell, and real membranes have vary- membrane potential
ing degrees of permeability to multiple ions. For Because ion permeability is a major factor in-
most cells, the primary ions that affect the mem- volved in establishing the resting membrane po-
brane potential are K, Na, and Cl because they tential, changes in ion permeability cause changes
can move across membranes and there are differ- in membrane potential. Excitable cells such as
ences in their intracellular and extracellular con- neurons and muscle cells alter the permeability of
centrations. A modification of the Nernst equation, their membranes to generate changes in mem-
the Goldman-Hodgkin-Katz Constant Field equa- brane potentials. We can use the Nernst equation
tion (usually referred to as the Goldman to predict the nature of the ion movements follow-
equation) can be used to calculate the resting ing changes in membrane permeabilities. For ex-
membrane potential based on the concentrations ample, in mammalian neurons the concentration
95

The Goldman Equation
The Goldman-Hodgkin-Katz Constant The two terms for K permeability also cancel out,
Field equation (often simply referred to as the leaving an equation that is equivalent to the Nernst
Goldman equation or GHK), allows the estimation of the equation for potassium (with the exception of the va-
membrane potential based on the concentrations, valence term, z, which is neglected because potassium
lences, and relative permeabilities of a series of ions. has a valance of 1). Notice, however, that if we do the
Since most plasma membranes under resting condi- same exercise assuming that the membrane is perme-
tions have appreciable permeability only to postassium, able only to chloride, we end up with an equation that is
sodium, and chloride, the Goldman equation can be similar to the Nernst equation, except that it neglects
written as follows: the valence and has the intracellular concentration in
RT PK 3K 4 o PNa 3 Na 4 o PCl 3 Cl 4 i
the numerator and the extracellular concentration in
Em the denominator, rather than the other way around. Re-
PK 3 K 4 i PNa 3 Na 4 i PCl 3 Cl 4 o
ln
F call that one of the rules of logarithms is that ln x ln
where Pion is the permeability of the membrane to that (1/x). By inverting the ratio of the concentrations of chlo-
ion and [ion]o and [ion]i represent the extracellular and ride, the Goldman equation takes into account the fact
intracellular concentrations, repectively, of a given ion. that chloride has a valence of 1.
From the Goldman equation, the impact of ion per- In addition to providing an estimate of the resting
meability on the membrane potential is clear. Any ion membrane potential, the Goldman equation allows the
with a low permeability has little effect on the mem- estimation of the membrane potential during electrical
brane potential, even if there is a large concentration signaling. For example, when a large number of Na
gradient across the membrane for that ion. Notice that channels open within the membrane (as is the case dur-
if the permeability of the membrane for an ion is zero, ing signaling in nerve cells), the permeability of the
then the term for that ion drops out of the equation. For membrane to Na increases greatly. In the case of neu-
example, consider the case of a membrane that is im- ral signaling, this increase in Na permeability is so
permeable to Na and Cl. In this case, the Goldman large that PNa becomes much greater than PK and PCl.
equation simplifies to Under these conditions, the Goldman equation is domi-
nated by the term for Na, and the membrane potential
RT PK 3 K 4 o

approaches the equilibrium potential for Na as calcu-
Em
PK 3 K 4 i
ln
F lated by the Nernst equation.
of Na is typically about 10-fold greater outside movement until the membrane potential reaches
the cell, so ENa 58 mV. In contrast, K concen- the equilibrium potential for K of 90 mV. The
tration outside the cell is only about 1/40 of that loss of positive charges from the interior of the cell
inside the cell, so EK 90 mV. The resting mem- results in a hyperpolarization. Many cells use cy-
brane potential of neurons is typically about 70 cles of depolarization, hyperpolarization, and re-
mV. If the Na permeability of the membrane in- polarization as communication signals.
creases (as a result of the opening of Na chan-
nels), Na will enter the cell, because both the
electrical and concentration gradients favor in-
Subcellular Organization
ward Na movement until the membrane poten- Eukaryotes rely on complex intracellular organi-
tial reaches the equilibrium potential for Na of zation to orchestrate the many processes required
58 mV. The resulting inward Na movement for life. Central to the diversity in physiological
causes a reduction in the membrane potential function is the ability of individual cells to perform
termed a depolarization (Figure 51). In contrast, specific roles for the tissue and animal. We gain a
if the K permeability of the membrane increases clearer understanding of complex physiological
(as a result of the opening of K channels) K will systems by studying the role of the various cellular
move out of the cell, because both its concentra- compartments that contribute to the process.
tion and electrical gradients favor outward K
96
Experimentally, it is easier to measure the relative cannot be more negative than 75 mV or more positive
permeability of ions, rather than the absolute perme- than 55 mV because there are no chemical gradients
ability. Hence, the Goldman equation is often rewritten large enough to produce larger membrane potential dif-
after dividing each term by PK. ferences. At rest, the membrane does not quite reach
the equilibrium potential for K because of the compet-
RT 3K 4 o PNa>PK 3 Na 4 o PCl>PK 3Cl 4 i ing effects of Na, but because Na permeability is rel-
Em
3 K 4 i PNa>PK 3 Na 4 i PCl>PK 3Cl 4 o
ln
F atively low its influence is small, and the membrane
potential is close to the K equilibrium potential. Note
For a cell such as a squid giant axon, the following val- that the squid giant axon also has appreciable perme-
ues can be used to calculate the membrane potential: ability to Cl (about half that of K). In fact, some cell
[K]i 400 mM and [K]o 20 mM membranes (e.g., in muscle cells) are more permeable
to Cl than they are to K. However, even in this case, K
[Na]i 50 mM and [Na]o 440 mM
plays the major role in establishing the membrane po-
[Cl]i 51 mM and [Cl]o 560 mM tential. The Na/K ATPase actively pumps Na and K
PNa / PK 0.04 ions to establish their concentration gradients. The K
PCl / PK 0.45 concentration gradient sets the resting membrane po-
tential difference, and Cl ions passively distribute
Substituting these values into the Goldman equation themselves across the membrane in response. Thus, in
predicts the membrane potential of this squid giant the case of Cl ions, the intracellular and extracellular
axon to be 60 mV at rest, which is a good approxima- Cl levels are a consequence rather than a cause of the
tion of the measured resting membrane potential. resting membrane potential.
Returning to the Nernst equation, we can also calcu-
late the equilibrium potentials for each of these ions.
Using the concentrations relevant to the squid giant
axon, the equilibrium potential is 75 mV for K, 55 Reference
mV for Na, and 60 mV for Cl. These equilibrium po- q Hodgkin, A. L., and A. F. Huxley. 1952. A quantitative description
tentials establish the “boundary conditions” for the of membrane current and its application to conduction and exci-
membrane potential. That is, the membrane potential tation in the nerve. Journal of Physiology 117: 500–544.
Mitochondria are the powerhouse of the cell of any biological membrane in animals. Mitochon-
Mitochondria are complex organelles, possessing dria organize the inner membrane into layers, or
intricate networks of membranes (Figure 52). The lamellae, that are tightly folded. In some tissues, as
innermost compartment is the mitochondrial ma- much as 70 m2 of mitochondrial inner membrane
trix, delimited by the inner mitochondrial mem- can be folded into a 1-cm3 volume of mitochondria.
brane. The outer mitochondrial membrane Mitochondrial structure varies greatly among
surrounds the organelle and creates another com- cell types. Many cells, such as liver, contain hun-
partment called the intermembrane space. Each of dreds of individual oblong mitochondria scattered
these compartments has its own complement of throughout the cell. These individual mitochon-
enzymes and performs different functions for the dria are rapidly transported throughout the cell.
mitochondria and the cell. The matrix houses the Some cells organize their mitochondria into net-
enzymes and metabolites of the TCA cycle. The in- works of interconnected organelles called the
ner mitochondrial membrane, which is often mitochondrial reticulum, which is constantly re-
highly convoluted, holds the enzymes of oxidative modeled by enzymes that mediate its fission and
phosphorylation and all the transporters neces- fusion.
sary to move metabolites in and out of the mito- Earlier in this chapter you learned that mito-
chondria. About 80% of the mass of the inner chondria possess the enzymes of oxidative phos-
membrane is protein, the highest protein content phorylation, and make most of the ATP a cell
97
Na+ channel Na+ K+ channel

K+
Open Open
Na+ K+
channels channels
+50 +50 +50
0 0 0
mV
mV
mV
Hyperpolarization
–50 –50 –50
Depolarization
–100 –100 –100

Time (msec) Time (msec) Time (msec)
Figure 51 Hyperpolarization and depolarization The gradients of Na and K

across the cell membrane largely determine the resting membrane potential. When specific ion
channels open, the movement of ions changes the membrane potential. If K moves out of the
cell, the magnitude of the membrane potential increases (hyperpolarization). If Na moves into
the cell, the magnitude of the membrane potential decreases (depolarization).
requires. Cells frequently respond to changes in It has an important role in maintaining cell struc-
energy demand by altering their levels of mito- ture, acting as a frame upon which the cell mem-
chondria, using both biosynthetic and degradative brane is mounted. It gives the cell its characteristic
pathways. Most of the genes required for synthe- external shape and also supports and organizes in-
sis of mitochondrial proteins are located in the nu- tracellular membranes. Organelle networks such as
cleus. Mitochondrial biogenesis requires that each the endoplasmic reticulum and Golgi apparatus are
of these genes be expressed in unison to produce mounted on the cytoskeleton. The cytoskeleton is
the hundreds of proteins needed for new mito- dynamic in structure, under constant reorganiza-
chondria or an extension of the mitochondrial tion. Apart from its structural roles, the cytoskeleton
reticulum. Mitochondrial biogenesis also requires is an important participant in many cellular
replication of mitochondrial DNA (mtDNA) and processes, including signal transduction.
synthesis of additional mitochondrial membranes. The cytoskeleton is constructed from three
Degradative pathways control the levels of mito- types of fibers: microfilaments, microtubules,
chondria and mitochondrial proteins. Damaged and intermediate filaments. These proteins are
mitochondrial fragments are engulfed by au- long strings of monomers connected end-to-end
tophagosomes and degraded in lysosomes. Cells to form a polymer. Microtubules are large, stiff
that fail to destroy defective mitochondria suffer tubes composed of the protein tubulin. Micro-
energy shortfalls and eventually cell death. filaments are small, flexible chains of actin. Inter-
mediate filaments, so named because they are
intermediate in size, are composed of many types
The cytoskeleton controls cell shape and of monomers. Most cells possess each of these cy-
directs intracellular movement toskeletal elements, but many cells are richer in
The cytoskeleton is a network of protein-based one particular type. For example, the tails of sperm
fibers that extends throughout the cell (Figure 53). are largely microtubules, muscles are largely actin
98
Mitochondrial reticulum
Myofibril
Microtubules
(green)
Nucleus
Outer Inner membrane Mitochondrial Microfilaments

membrane cross-section (red)
Matrix
(a)
Contact site
Figure 52 Mitochondrial structure Mitochondria are

found in almost every cell type, but with many different
appearances. Muscle mitochondria exist as a network
extending throughout the muscle myofibrils. In cross-section
they appear as individual organelles, but three-dimensional Nucleus
reconstructions show the reticulum structure. Inside the
mitochondria the highly folded inner membrane can be seen.
Intermediate
polymers, and skin is rich in the intermediate fila- filaments
ment keratin.
Other proteins work in conjunction with the
cytoskeleton to conduct many types of movement.
These proteins, called motor proteins, are
mechanoenzymes that use the energy of ATP hy-
drolysis to walk along the cytoskeleton. Myosin is
the motor protein that walks along actin polymers;
kinesin and dynein move on microtubules. (b)
Figure 53 Three protein fibers of the
The endoplasmic reticulum and Golgi cytoskeleton Panel (a) shows microtubules (green) and
microfilaments (red). Panel (b) shows intermediate filaments.
apparatus mediate vesicular traffic
Cells have layers of membranous organelles extend-
ing around the nucleus to the periphery of the cell help form the vesicle, but they also have an impor-
(Figure 54). The first layer, the endoplasmic retic- tant influence on where the vesicle is sent.
ulum (ER), is the gateway to the other compart- Cells are often illustrated in ways that suggest
ments. Proteins are made in the ER, folded, and that vesicles drift freely throughout the cyto-
then sent to their final destinations in the plasma plasm. In reality, vesicles are carried throughout
membrane, the Golgi apparatus, lysosomes, and en- the cell by motor proteins moving on cytoskeletal
dosomes. The vehicle that carries proteins between tracks. For example, vesicles coated with COP-I
compartments is a vesicle, a small membrane- may be carried toward the Golgi apparatus,
bound organelle. Some vesicles are surrounded by whereas vesicles coated with COP-II may be sent
a shell of coat proteins, such as clathrin, coat pro- to the ER. Coat proteins and other vesicle mem-
tein complex I (COP-I), and COP-II. These proteins brane proteins influence which motor protein is
99
Damaged mitochondrion Cytoplasm Extracellular fluid

Autophagosome Lysosome
Phagocytosis
Autophagy
Late endosome
Plasma
membrane
Pinocytosis
Early
endosome
Membrane
protein
cycling
Secretory
vesicle
Endoplasmic Golgi
Storage
reticulum network
vesicle
Figure 54 Intracellular traffic Vesicles move throughout the cell, transferring

membranes and vesicle contents between compartments.
bound. If a vesicle binds myosin it will be carried Conversely, when a secretory vesicle fuses to the
on microfilaments, but if it binds dynein it will be plasma membrane, its internal contents are ex-
carried on microtubules. Protein kinases and pelled but the vesicle membrane, both lipid and
protein phosphatases regulate vesicular traffic by integral proteins, disperses into the plasma mem-
altering the cytoskeleton, motor proteins, or vesi- brane. Cells control the numbers and types of pro-
cle proteins. These processes ensure that vesicles teins in the plasma membrane through endocytosis
and their contents are sent to the correct location and exocytosis. Vesicles rich in transporters fuse to
at the correct time. the plasma membrane to increase transport capac-
Many types of intracellular sorting pathways ity. Conversely, regions of the plasma membrane
use the ER-Golgi network. Most cells produce pro- are extracted during vesicle formation to remove
teins, and sometimes other molecules, for release transporters for storage or degradation. Vesicles in
from the cell. This process, called exocytosis, be- transit can be directed to other compartments to
gins in the ER. Proteins are made here and pack- assist in processing their contents. Endosomes act
aged into vesicles that move through the Golgi as clearinghouses for vesicles, collecting them and
apparatus, ultimately fusing to the plasma mem- then redistributing their contents and membrane
brane to release the vesicle contents to the extracel- proteins into new vesicles that are sent to their cor-
lular space. In the reverse pathway, endocytosis, rect locations. They send damaged proteins and
vesicles form at the plasma membrane, engulfing foreign materials to lysosomes for proteolytic
liquid droplets (pinocytosis) or large particles degradation. Once vesicles reach their destination,
(phagocytosis). The same pathways of endocytosis another series of proteins mediate the fusion of
and exocytosis regulate the proteins found in the vesicles with target membranes.
plasma membrane, such as membrane trans- The pathways of intracellular sorting allow
porters and channels. When transporters are no animal cells to control many of the processes we
longer needed, they can be removed from the mem- have considered throughout this chapter, includ-
brane and stored in vesicles until needed again. ing secretion, ingestion, and membrane transport.
100
Another function of these pathways, Proteins and glycoproteins

specifically the secretory pathway, is
to build and maintain a fibrous net- Simple structures Complexes
work outside the cells: the extracel- Carbohydrate Collagen monomes Cross links
lular matrix. Collagen
Collagen
fibril
Elastin
The extracellular matrix Elastin
fiber
mediates interactions between
cells Collagen
Fibronectin
Cells are organized into a three-
dimensional tissue by a network of Heparin
fibers called the extracellular ma-
GAGs and proteoglycans
trix. The proteins used to build the
matrix are synthesized by the ER, Simple structures Complexes
packaged into vesicles, and sent out
Hyaluronan
of the cell using the secretory path-
way. During transit through the Golgi Hyaluronan
apparatus, suites of enzymes modify Aggrecan
the proteins, adding branched chains Core protein Keratan sulfate aggregate
of sugars. As you learned earlier in
Aggrecan
this chapter, glycosylation alters the
properties of the proteins in many
Chondroitin sulfate Aggrecan
ways. In the extracellular matrix, wa-
ter binds to the hydrophilic sugars to Figure 55 Extracellular matrix components The extracellular matrix is
create a gel-like coating that fills the composed of combinations of proteins and glycoproteins, glycosaminoglycans (GAGs)
space between cells. and proteoglycans. Many of the individual molecules, shown in the left column, can be
Extracellular matrix macromol- combined into more complex macromolecules, shown on the right. The protein
ecules can be proteins, simple gly- components are shown in green and the GAG components in blue.
coproteins, glycosaminoglycans, or
combinations of both, known as proteoglycans lently attached to proteins to form proteoglycans.
(Figure 55). Collagen is a long, stiff fiber formed Cartilage is composed primarily of aggrecan, a
as a triple helix of three separate collagen glyco- proteoglycan that incorporates more than 100 gly-
protein monomers. Elastin is a small protein that cosaminoglycans into its structure. Many proteo-
is linked together into an intricate web. When the glycans link the different extracellular matrix
network is stretched it acts like a rubber band, proteins together to form a network.
providing the tissue with elasticity. Many extracel- The extracellular matrix can be simple in
lular matrix components are linked together by structure and composed of only a few proteins, or
the glycoprotein fibronectin. Each fibronectin mol- it can be organized into an extensive network. The
ecule binds other fibronectins as well as different extracellular matrix is more than just the cement
matrix components to form a fibrous network. that connects cells together. Many specialized
Hyaluronan is a glycosaminoglycan composed structures such as the insect exoskeleton, verte-
of thousands of repeats of the disaccharide glu- brate skeleton, and molluscan shells are modified
curonic acid-N-acetylglucosamine. With its hydra- extracellular matrices secreted by specific cells.
tion shell, it forms a noncompressible gel that acts For example, bone and cartilage are tissues
as a cushion between cells. Hyaluronan fills the formed from the extracellular matrix of os-
spaces between joints of land animals, easing teoblasts and chondroblasts, respectively. The
movement. Other glycosaminoglycans, such as basal lamina (Figure 56), or basement mem-
2 brane, is a type of extracellular matrix found in
chondroitin sulfate and keratan sulfate, are cova-
many tissues, where it acts as a solid support that
2
Keratan is a GAG of the extracellular matrix, whereas keratin helps anchor cells. It is designed and maintained
is an intermediate filament protein of the cytoskeleton. primarily by specialized cells called fibroblasts.
101
Epithelial cell
Connective tissue:
Collagen
Blood vessel Plasma

membrane Collagen Proteoglycans Membrane
Hyaluronan
protein
Macrophage
Fibroblast
Figure 56 Basal lamina In many tissues, fibroblasts produce a thick layer of

extracellular matrix called the basal lamina. Some cells use the basal lamina as a foundation,
but other cells and blood vessels use it as a porous frame.
Cells use various strategies to modulate both trix metalloproteinases to break down the extra-
the matrix properties and their relationship with cellular matrix of the local cells to allow the blood
the matrix. First, most types of extracellular ma- vessels to penetrate into new regions of the tissue.
trix components can be made many ways. For in-
stance, mammals have 20 different collagen
genes, so in principle a collagen trimer can be con-
structed 8000 (203) ways. Even though most of
Physiological Genetics
these possible variants are never constructed, it il-
and Genomics
lustrates the potential for variation in one of the The nature of physiological diversity, whether in
many components of the extracellular matrix. Sec- the response of an individual or in the variations
ond, variations occur in the type and position of arising over evolutionary time, resides in the
carbohydrate groups of simple glycoproteins and genes: how they differ between species and how
proteoglycans. Each variation influences the phys- they are regulated in individual cells. Homeostatic
ical properties of the extracellular matrix protein. regulation depends on the ability of the cell to put
By controlling which proteins are made and how the right protein in the proper place at the proper
they are modified by glycosylation, cells determine time with the appropriate activity. Cells have many
which building blocks are available to build the ex- mechanisms to control the rates of synthesis of
tracellular matrix. Cells control which proteins are specific proteins. RNA polymerases read the
released to the extracellular space using the secre- genes, producing mRNA in the process of trans-
tory pathway discussed in the previous section. cription. Once RNA is made, it is used as a tem-
Secreting the extracellular matrix components plate to produce protein in the process of
from the cell is really only one step in building a tis- translation. Cells can control the levels of both
sue. The cells also produce integral membrane RNA and protein using mechanisms that target
proteins called matrix receptors to connect them to rates of synthesis and degradation.
the extracellular matrix. Integrins are an impor-
tant class of plasma membrane receptors that bind
the cytoskeleton on the inside of cells and bind the
Nucleic acids are polymers of nucleotides
extracellular matrix on the outside of cells. A cell The two types of nucleic acids, deoxyribonucleic
changes its association with the extracellular ma- acid (DNA) and ribonucleic acid (RNA), are struc-
trix by changing the types of integrins in its mem- turally similar but perform different functions
brane, mediated by endocytosis and exocytosis. within the cell. DNA is the genetic blueprint for
Cells can also break down the extracellular building cells. RNA reads the information encoded
matrix by secreting proteases called matrix metal- by the DNA and interprets it to make proteins.
loproteinases. By controlling both the production Cells produce three main forms of RNA: transfer
of the matrix and its degradation, cells can regu- RNA (tRNA), ribosomal RNA (rRNA), and messen-
late their ability to move throughout a tissue. For ger RNA (mRNA). Certain molecules of RNA com-
example, when blood vessels grow, they use ma- plex with proteins to form riboproteins.
102
Both RNA and DNA are polymers of nu- Double-stranded DNA twists into an
-helix
cleotides. All nucleotides are composed of a ni- with two topological features: a minor groove and
trogenous base attached to a sugar linked to a a major groove. The two strands of DNA appear as
phosphate. RNA and DNA differ in the type of ridges, separated by a trough. These contours be-
sugar in the nucleotide: ribonucloetides contain tween two strands compose the minor groove. The
ribose whereas deoxyribonucleotides possess major groove results from the twisting pattern of
deoxyribose. Both RNA and DNA are synthesized the
-helix. Every 10 base pairs, a distance of
from combinations of four types of nucleotides about 3.6 nm, the helix completes a full turn,
that differ in the nature of their nitrogenous bases. forming the major groove that resembles a saddle.
Three of the four nitrogenous bases, the pyrimidine Variations in nucleotide sequence cause subtle re-
cytosine and the purines adenine and guanine, are gional alterations in the shape of DNA and the
found in nucleotides of both RNA and DNA. The topology of the major and minor grooves. This
fourth nitrogenous base is another pyrimidine: structural variation is information that is used by
uracil in RNA and thymine in DNA. The ribonu- the DNA-binding proteins to attach to the correct
cleotides are ATP, UTP, CTP, and GTP. The deoxyri- location to regulate expression of specific genes.
bonucleotides are dATP, dTTP, dCTP, and dGTP. In The DNA in animal cells is highly compressed
many cases, the nucleotide sequence in DNA and into tight structures with the aid of DNA-binding
RNA is represented using one-letter codes. Thus, A proteins called histones. If you were to unwind
refers to the residue derived from the nucleotide the DNA in a single mammalian cell, the strands
ATP (in RNA) or dATP (in DNA), C is CTP/dCTP, G is would stretch several meters. The long strands of
GTP/dGTP, T is dTTP, and U is UTP. DNA wrap twice around the barrel-shaped his-
Nucleic acids form from long polymers of nu- tones until a structure resembling a strand of
cleotides linked by phosphodiester bonds that form pearls is formed. These strands are then twisted
between the phosphate of one nucleotide and the and folded into highly compressed arrangements,
sugar of the adjacent nucleotide. The end of the poly- which has two main advantages to cells. First, it al-
mer that terminates with a phosphate group is lows the cell to fit large amounts of DNA into the
deemed the 5-prime end (5′); the other end termi- small volume. Second, coating DNA with histones
nates with a sugar and is the 3′ end. The nucleic acid helps reduce the damage caused by radiation and
has a polarity, conferred by its 5′ and 3′ ends, that is chemicals. However, in this compressed configura-
an important consideration when discussing the bio- tion DNA is biochemically inert; it cannot function
chemical processes involved in nucleic acid function. as a template for RNA synthesis (transcription)
DNA is a double-stranded
-helix
packaged into chromosomes
DNA usually exists within cells as a 3′ 5′
5′
double-stranded polymer (Figure 3′
C Nucleotide Minor
57) in which hydrogen bonds connect G
groove
the two strands. Each specific nu- Phosphate
A T
cleotide can form hydrogen bonds
Sugar
with only one other nucleotide. Three G C (deoxyribose) Major
hydrogen bonds form between G and groove
C, whereas two hydrogen bonds form T A Sugar-

between A and T. When one strand of Hydrogen phosphate
3′ bonds backbone
DNA encounters another comple- 5′
mentary strand, hydrogen bonds 3′ 5′
form between the strands, creating a (a) Schematic model (b) Ribbon diagram (c) Space-filling model
double-stranded molecule. The two Figure 57 DNA structure Each strand of DNA binds to another,
strands anneal in an antiparallel complementary strand. Hydrogen bonds form between specific base pairs. Two bonds
arrangement, with the 5′ end of one form between A and T. Three bonds form between C and G. The double-stranded DNA
strand associated with the 3′ end of is twisted into an
-helix, forming a minor groove between strands. The major groove
the other strand. reflects the period of the twisting of the helix.
103
or DNA synthesis (replication). Cells must use tionship between the size of the genome and the
histone-modifying enzymes to release histones complexity of the animal. For example, both the
from DNA, thereby regulating gene expression. largest and the smallest vertebrate genomes are
found in fish. The pufferfish genome is only about
DNA is organized into genomes 0.3% the size of the lungfish genome. There is also
no relationship between the number of chromo-
The entire collection of DNA within a cell is called somes and the complexity of the animal. Humans
the genome. Within the nucleus, the genome is di- possess 46 chromosomes. Some deer have only 6,
vided into separate segments of DNA called whereas carp may have more than 100.
chromosomes. Within chromosomes are the
genes, which possess the DNA sequences that are
used to produce all the different types of RNA, in- Transcriptional control acts at gene
cluding the mRNA that encodes proteins. Each regulatory regions
gene also possesses regions of DNA called promot- The rate of synthesis for many proteins is propor-
ers that determine when the gene is expressed. tional to the levels of mRNA. Historically, mRNA
Many genes are divided into multiple sections on
the same chromosome. The sections that encode Mammals
RNA are known as exons, and the interspersed
Birds
DNA sections are called introns (Figure 58).
In most animals, genes account for less than Reptiles
half of the genome. The majority of the genome is Frogs
a mixture of different types of random and repeti- Salamanders
tious DNA, much of which serves no known func-
Lungfish
tion and is often called junk DNA.
Across the animal kingdom, genome size Teleosts
ranges more than 6000-fold (Figure 59). The small- Chondrichthians
est genome is found in one of the simplest animals; Agnathans
placozoans, a relative of sponges, have only about Nonvertebrate
chordates
0.02 pg of DNA per cell. The largest genome in an-
imals, about 133 pg/cell, belongs to the African Crustaceans
marbled lungfish. Surprisingly, there is little rela- Insects
Arachnids
Telomeres
Myriapods
Centromere Molluscs
Annelids
Echinoderms
Tardigrades
(a) Chromosome Flatworms
Rotifers
Introns
Nematodes
Cnidarians
Sponges
Promoter
Exons 10–2 10–1 1 10 102 103
Genome size (pg)
Gene Figure 59 Genome sizes in the animal
(b) Gene
kingdom The genome size in animals can vary widely,
Figure 58 Chromosomes and genes Chromosomes and there is no relationship between genome size and
possess structural regions, such as centromeres and telomeres, complexity. Bar lengths reflect the range in the sizes of
in addition to noncoding regions and genes. genomes measured in picograms (pg).
104
levels were measured using northern blots, but re- Cells can regulate the rate of mRNA synthesis
cent advances in genomics and engineering have by altering the conformation of the gene and
led to the development of techniques for assessing changing the ability of the transcriptional machin-
complex changes in the levels of mRNA for thou- ery to assemble. Sometimes gene expression is in-
sands of genes simultaneously. duced by stimulation of the enzymes that remodel
At any point in time, most of the genome of a chromatin. These enzymes work by altering the
cell is wrapped around histones and rolled into nu- structure of the histones that organize DNA into
cleosomes (Figure 60). Under these conditions the nucleosomes. Histones can be modified by acety-
genes are quiescent, unable to bind the transcrip- lation, methylation, and phosphorylation. For ex-
tional machinery. When the gene product is re- ample, when a histone acetyl transferase (HAT)
quired, the chromatin must be remodeled to allow adds an acetyl group to a critical lysine in a his-
transcriptional activators access to the regulatory tone, this induces a change in structure that per-
regions of the gene. Transcriptional regulators, mits remodeling of chromatin to favor gene
both DNA-binding proteins and coactivators, asso- expression. The gene can be silenced by a histone
ciate with each other to form regulatory complexes deacetylase (HDAC) that removes the acetyl group.
on the promoter. The transcription initiation com- Once the regulatory regions within the gene
plex assembles near a specific region of the pro- are exposed, the transcriptional machinery is
moter designated as the transcription start site, able to assemble. Transcription factors may bind
typically a sequence of TATA (the TATA-box). Once to sites close to, or distant from, the transcrip-
the complex assembles, the process of mRNA syn- tional start site. Some transcription factors intro-
thesis can begin. duce bends into the DNA that bring critical
regions of the gene in close proximity. Other tran-
scription factors bind coactivators, which serve
as docking sites for other proteins. Eventually,
the general transcription factors are assembled,
Nucleosome
the RNA polymerase is recruited, and the process
of transcription can begin. The entire process de-
pends critically on the interactions between
dozens of proteins. Consequently, cells can fine-
Histone tune the process by regulating the ability of dif-
Histone remodeling
ferent proteins to interact, typically by changes in
Histone protein phosphorylation. The phosphorylation
state can affect the transfer of a transcription fac-
tor between the cytoplasm and the nucleus. It can
also alter the ability of transcriptional regulators
Transcriptional
regulators bind to interact with DNA or other proteins, both stim-
ulatory and inhibitory proteins. Since each gene
is regulated by dozens of transcription factors,
Activator
the combinations of regulatory conditions are
Coactivator
General
endless.
transcription The primary mRNA transcript possesses se-
TATA
factors quences that will eventually code for the protein
(exons) as well as other sequences that are inter-
Transcription
start site RNA polymerase spersed between exons (introns). It must first be
processed in a way that removes introns and
Figure 60 Transcriptional regulation Quiescent
splices together exons. Next, the spliced RNA must
DNA is tightly wrapped around histones. Remodeling of
be polyadenylated; long strings of 200 or more
chromatin gives DNA-binding proteins access to gene
control regions. The general transcription factors allow RNA ATP residues are added to the 3′ end of the tran-
polymerase II to bind to initiate transcription. Other DNA script to produce the poly A tail that is character-
regulatory proteins, such as the activators and coactivators istic of mRNA. Once these post-transcriptional
shown here, increase the likelihood that the transcriptional modifications are completed, the mature mRNA is
machinery will assemble. exported to the cytoplasm.
105
RNA degradation influences RNA levels called a codon. The 5′ end of the mRNA recruits
proteins called initiation factors, in combination
Controlling transcription is one important mecha-
with a methionine tRNA (tRNAMET) and a ribo-
nism for cells to alter RNA levels; another is to vary
some. The complex moves down the mRNA chain
the rate of RNA degradation. RNA is degraded by
until it reaches the sequence AUG, which is the
nucleases called RNases. An RNase can attack the
start codon. Another amino acyl tRNA is recruited,
end of the RNA (exonucleases) or internal sites
and the ribosome catalyzes the formation of a
(endonucleases), preventing the mRNA from act-
peptide bond between the amino acids to begin
ing as a template for protein synthesis.
the process of elongation. In most circumstances,
Cells have ways to preferentially degrade or
proteins called elongation factors enter the ribo-
protect individual mRNAs. A long poly A tail pro-
some and accelerate the catalytic cycle. In a typi-
tects an mRNA from degradation. Soon after re-
cal animal cell, each individual ribosome can add
lease into the cytoplasm, exonucleases nibble off
an amino acid to the chain at a rate of one to two
the ends of the poly A tail. The mRNA can still be
per second. The process continues until the ribo-
translated into protein at this point. Once the
somal complex reaches a stop codon, a nucleotide
exonucleases shorten the tail to about 30 bases,
sequence that is incapable of binding any amino
the RNA is attacked by an endonuclease, causing
acyl tRNA. At any point in time, a single mRNA
enough damage to prevent the protein from being
may be translated by many ribosomes bound all
translated.
along the mRNA.
Other processes accelerate the rate of mRNA
Cells can control the rate of translation using
degradation. Some mRNAs are unstable, existing
nonspecific mechanisms that affect all translation
in the cytoplasm for only a few minutes before be-
within the cell, as well as specific mechanisms that
coming degraded. These unstable mRNAs have
influence only a subset of mRNAs. Many of the ini-
long stretches of A and U bases within their 3′ un-
tiation factors and elongation factors are regulated
translated regions (3′ UTR). These AU-rich regions
through protein phosphorylation. In addition,
recruit proteins that accelerate mRNA degrada-
each of these factors can bind inhibitory proteins.
tion. The ability to accelerate RNA degradation is
Such mechanisms allow cells to mount global
essential in many cells, particularly those that pro-
changes in translation rates. Many types of mRNA
duce regulatory proteins. Once a signaling protein
possess sequences that act to regulate their trans-
is no longer needed, the RNase machinery can
lation. For example, sequences in the 3′ UTR and
rapidly degrade the mRNA to prevent it from be-
5′ UTR bind proteins that alter the ability of the
ing translated.
mRNA to be translated.
Cells can also reduce the rate of RNA degrada-
tion. Stabilizing proteins can bind to specific re-
gions in the poly A tail or other regions of the Cells rapidly reduce protein levels through
mRNA to prevent RNase attack. This allows the protein degradation
cell to maintain a pool of preformed mRNA avail-
Once proteins are synthesized, they remain in the
able for immediate use if cellular conditions de-
cell until they are degraded. Just as cells use
mand the gene product.
degradation to control mRNA levels, they use pro-
tein degradation to control protein levels. Some
proteins are removed only when they sustain
Global changes in translation control many enough damage to become dysfunctional. The
pathways structural changes in damaged proteins recruit
Once an mRNA arrives in the cytoplasm, the enzymes that mark the protein for degradation.
process of translation can begin with the assis- These enzymes transfer a small protein called
tance of ribosomes and amino acyl tRNAs. Ribo- ubiquitin to the damaged protein. Once the
somes, complexes of rRNA and proteins, catalyze ubiquitination machinery has attached a ubiquitin
the formation of peptide bonds between amino chain to the damaged protein, the protein is
acids in the growing protein. The amino acids are bound by a multiprotein complex called the
provided in the form of amino acyl tRNA. Each proteasome. Proteolytic enzymes within the pro-
amino acid uses a specific tRNA that can bind to a teasome degrade the ubiquitin-tagged proteins to
specific set of three nucleotides on the mRNA amino acids.
106
Earlier we discussed how some types of mRNA Primary transcript E1 E2 E3 E4 E5 E6

are preferentially degraded. Many of these unsta- E1 E2 E3 E4 E5 E6 E1 E3 E4 E5 E6
ble mRNAs encode proteins that are also subject to E1 E3 E5
Intron
accelerated degradation. Proteins such as cell cy-
cle regulators and transcription factors can be
ubiquitinated even in the absence of structural
damage. Characteristic amino acid sequences
within the proteins recruit the ubiquitination ma-
(a) Alternate splicing
chinery. Often the recognition sequences can be
phosphorylated, altering their ability to be sub-
jected to rapid degradation. LDH-A
Collectively, cells use these regulatory LDH-a
processes to control the levels of mRNA and pro-
tein. They enable cells to modify cellular proper-
ties in response to changing environmental and
physiological conditions. Cells are also able to
modulate their physiological response by altering
the types of proteins they express. Animals, partic-
1 1
ularly vertebrates, can draw upon isoforms of pro-
teins with subtly different properties that provide (b) Allelic variation
cells with alternative strategies to meet environ-

mental and physiological challenges.
LDH-A
LDH-B
Protein variants arise through gene
duplications and rearrangements
Protein isoforms provide a cell with flexibility in
structure and function. A suite of proteins can be
created with distinct properties. Isoforms can be
produced through multiple mechanisms involving (c) Gene families
single genes, different alleles, or different genes Figure 61 Origins of protein variants Cells are
(Figure 61). able to produce protein isoforms in many different ways.
Variations in protein structure can arise when Cells can splice exons in different combinations to create
the primary mRNA from a gene is connected to- distinct proteins. Often the same gene can occur in different
gether using different combinations of exons, a sequences within a population. Some individuals can have
process known as alternative splicing. For ex- two different versions of the same gene (A or a) on
ample, more than 40 different isoforms of fi- chromosomes inherited from each parent. Gene duplications
can lead to extra gene copies in different loci. These genes
bronectin can result from a single gene. Each
can diverge to encode different enzymes (A and B).
isoform of fibronectin binds different combina-
tions of extracellular matrix molecules.
Within any population of animals, there is
some variation in the exact sequence of specific or catalytic properties of allozymes may be subtly
genes. As a consequence, a diploid individual may different. Often different allozymes predominate
possess two different versions of the same gene, in two populations of animals. For example, if a
one arising from the mother and one from the fa- specific allozyme functions better in the cold, that
ther. These different forms of the same gene are gene might occur at a higher frequency in popula-
alleles. If the gene encodes an enzyme, the iso- tions of animals exposed to the cold.
forms are also called allozymes. Often the differ- Other types of isoforms are encoded by sepa-
ences in allozyme structure have little effect on rate genes that arose from ancestral gene dupli-
function. Because they are functionally neutral, cations. Figure 62 shows some of the ways that
natural selection does not remove them from the genes can become duplicated. During the
population. However, in some cases the regulatory process of meiosis, long stretches of DNA may be
107
will be endowed with extra copies of the dupli-

cated genes. These extra copies could kill the cell
or, if neutral or beneficial, get transmitted to the
next generation.
Another way that genes can become dupli-
cated is through mobile elements. Many organ-
isms possess genes that are capable of jumping
from one chromosome to another. In most cases,
the mobile element encodes a transposase, the en-
(a) Homologous recombination zyme required to cut the DNA from one strand and
(equal crossover)
insert it into another. Occasionally, other genes be-
come trapped in the mobile elements. When the
mobile elements move, the other genes are carried
along, endowing the recipient chromosome with
the extra copy.
Genetic recombination does not always lead to
production of extra copies of entire genes. In some
cases, fragments of genes are moved from one
gene and inserted into a completely different gene.
A protein may possess domains within its struc-
(b) Unequal crossover ture that resemble regions of otherwise unrelated
proteins. For instance, hundreds of different pro-
teins can bind ATP using a protein structure called
an ATP-binding cassette. This structure, which
appears in all living organisms, probably arose
only once, or a few times, billions of years ago. Its
appearance in so many different genes and in all
taxa is likely due to genetic recombination events
that moved this region from one gene to another.
(c) Mobile elements Ancient genome duplications contribute

to physiological diversity
Figure 62 Gene duplications Gene recombination
can provide cells with extra copies of genes. In contrast to Gene duplications provide organisms with extra
equal crossover, (a) where homologous regions of copies of redundant DNA that can accumulate mu-
chromosomes are exchanged, unequal crossover (b) provides tations and diverge to endow the organisms with
one chromosome with extra genetic material. (c) Cells also novel capacities. The key to achieving the oppor-
possess many different kinds of mobile elements that can tunity for specialization is obtaining the raw mate-
move or duplicate genes between chromosomes. rial: a nonlethal extra copy of a gene. At several
points in the evolution of animals, whole genomes
transferred from one chromosome to another. In were duplicated. Many of the duplicated genes
most cases, two chromosomes exchange homolo- were eventually lost, but many were retained and
gous regions and no gain or loss of genes occurs. diverged to form gene families. Many of the
This process of shuffling gene combinations is anatomical and functional specializations of verte-
one of the advantages of sexual reproduction. Oc- brates are a result of these genomic duplications.
casionally, the machinery of homologous recom- Often, if a particular gene is found in a single
bination misidentifies homologous regions. copy in an invertebrate, there are four isoforms in
Unequal crossover results, and one chromosome vertebrates. This “rule-of-four” reflects ancestral
donates an end to another chromosome. The genome duplications; each single gene locus was
progeny derived from the gamete that lost the duplicated, giving two copies of all genes, then
chromosomal region would not likely survive. reduplicated, giving four copies of all genes. The
However, the progeny from the recipient gamete individual genes within the duplicated genomes
108
underwent mutation, selection, and drift to diverged in structure, they have not yet become dif-
verge into distantly related genes. After a period of ferent in function.
divergence, some individual genes duplicated Over many generations, the duplicated genes
again. The newly duplicated genes were more can follow many fates. The duplicated gene might
closely related to each other than to their distant incur mutations in the promoter or coding region
ancestors, creating gene clusters. When did these that prevent it from being transcribed, rendering
genome duplications occur? A possible answer it a pseudogene. In some cases, one copy of the
comes from phylogenetic analyses of a family of gene mutates and diverges, resulting in a protein
genes involved in development, the Hox family. with distinct properties. In other cases, both
The first genome duplication probably occurred copies mutate and diverge, resulting in a pair of
just before the jawless vertebrates, or agnathans, proteins with overlapping functions.
diverged from the vertebrate lineage. The second These genetic processes, originating early in
duplication coincided with the development of animal evolution and operating at the level of indi-
jaws. The primitive chordates such as amphioxus vidual cells, provide animals with physiological
have a single cluster of Hox genes, the agnathan flexibility. The integration of different cell types
lamprey has two or sometimes three clusters, and into complex physiological systems is an impor-
the more recent jawed vertebrates, from sharks to tant reason why animals have radiated into so
humans, possess at least four clusters of Hox many diverse species over the course of evolution.
genes. In each case, genome duplications coin-
cided with important revolutions in morphological
and physiological complexity. 2 C O NC E P T C H E CK
These original genome duplications in the ver-
13. Compare the categories of membrane transport
tebrate lineage probably occurred more than 300 in terms of energy requirements and direction of
million years ago. Many modern animals have ex- transport in relation to chemical gradients.
perienced relatively recent genome duplications, 14. Discuss the composition of biological
including many examples of frogs and fish that membranes. What are the unique properties of
gained an extra set of chromosomes to become each type of lipid?
tetraploids. In some cases, tetraploid populations 15. How can cells alter the fluidity of membranes,
exist within diploid species; not nearly enough and why is this capacity important to cellular
time has passed within the tetraploid lineage for function?
the duplicated genes to diverge. The common 16. Summarize the roles of the different subcellular
compartments within a cell, and discuss how
carp, however, became tetraploid about 15 million
they influence physiological function.
years ago. Its closest relative, the grass carp, has
17. Discuss the origins of genetic variation. How
half the number of chromosomes. Many genes that
does genetic variation provide physiological
are in single copy in other vertebrates are found in flexibility?
pairs in common carp. While the pairs have di-
Summary
Chemistry k Cells can also store energy in the form of elec-
k All biological systems depend on kinetic and po- trochemical gradients. Gravitational energy and
tential energy. elastic storage energy are used in locomotion.
k Food webs are essentially transfers of chemical k Covalent bonds, which arise when two atoms
energy between organisms. share electrons, are strong in comparison to
weak bonds, including hydrogen bonds, van der
k Molecules possess thermal energy, which is re-
Waals forces, and hydrophobic interactions.
flected in molecular movement, and many
metabolic processes in cells are mechanisms for k Weak bonds control the three-dimensional struc-
capturing and transferring this energy. ture of macromolecules. They form and break in
response to modest changes in temperature.
109
k Solute concentration imposes osmotic chal- branes. Steroids and their precursors fulfill
lenges. Organisms must modulate their biologi- many roles within cells, and steroid hormones
cal solutions to regulate the ionization of water are particularly important in cell signaling.
into H and OH.
k Cells oxidize fatty acids for energy using the mi-
k Changes in proton concentration, or pH, alter tochondrial -oxidation pathway, which gener-
many molecular properties. As a result, animals ates reducing equivalents and acetyl CoA. The
have many physiological mechanisms to regu- rate of -oxidation is governed by the availabil-
late pH, including pH buffers. ity of fatty acids and the rate of transport into
the mitochondria using the carnitine shuttle.
Biochemistry
k Enzymes are organic catalysts, usually pro- k Fatty acids can be synthesized by the enzyme
teins, that speed reactions by reducing the acti- fatty acid synthase, for use in biosynthesis or
vation energy barrier. energy storage. When energy is needed, lipases
can break down triglycerides to release the
k Enzyme reaction velocity (V) and substrate fatty acids.
affinity (Km) depend on the physicochemical en-
vironment, such as the temperature, ion com- k Under some conditions, such as starvation, fatty
position, and pH of the solution. acids can be converted to ketone bodies for use
in tissues that cannot use fatty acids directly.
k Cells control reaction rates by changing the con-
centration of reactants, the levels or activities of k Most oxidative fuels can be converted to acetyl
enzymes, or the concentration of substrates and CoA within mitochondria. When acetyl CoA en-
products. ters the tricarboxylic acid cycle, acetyl CoA is
oxidized to produce reducing equivalents,
k Competitive inhibitors compete for the enzyme NADH and FADH2.
active site. Allosteric regulators bind at loca-
tions distant from the active site, altering en- k Oxidation of reducing equivalents by the elec-
zyme kinetics. Many enzyme and nonenzyme tron transport system generates a proton gradi-
proteins are regulated by covalent modification. ent, heat, and reactive oxygen species.
For example, protein kinases use ATP to attach
k The mitochondria F1FO ATPase, or ATP syn-
phosphate groups to specific amino acid
thase, uses the proton motive force to generate
residues, and protein phosphatases remove
ATP. Phosphorylation is coupled to oxidation
phosphate groups.
through a shared dependence on the proton
k Cells use combinations of enzymes and enzy- motive force.
matic regulation to construct and maintain
k Under some circumstances, mitochondria can
complex metabolic pathways.
become uncoupled, leading to the production of
k Proteins, carbohydrates, and lipids have impor- heat instead of ATP.
tant roles in structure and metabolism. Animals
k The balance between biosynthesis and catabo-
store excess carbohydrate as glycogen. Glucose
lism is regulated by energetic intermediates
can be produced from noncarbohydrate precur-
such as ATP, NADH, and acetyl CoA. Without
sors using gluconeogenesis. Glucose can be bro-
this regulation, the two processes could occur
ken down to pyruvate (glycolysis) or further
simultaneously, leading to loss of energy in fu-
oxidized to CO2.
tile cycles.
k Most animals use lactate dehydrogenase to bal-
k Metabolic regulation also determines which fu-
ance redox and dispose of pyruvate. Anoxia-
els are oxidized under which conditions.
tolerant animals can use other pathways for
oxidizing NADH in the absence of oxygen, some
Cell Physiology
of which provide additional ATP.
k Membranes allow cells to create permeability
k Phospholipids, including phosphoglycerides barriers that help them to define environments.
and sphingolipids, are used to make cell mem- Membranes are heterogeneous combinations of
110
phospholipids, cholesterol, and numerous inte- are the most important component of the rest-
gral and peripheral proteins. ing membrane potential. Changes in membrane
permeability alter the membrane potential in
k The nature of the lipid membrane influences
ways that cells use to communicate.
fluidity, an important determinant of protein
function. k Many aspects of animal physiology can be
traced back to cellular processes.
k While some hydrophobic molecules can cross
membranes by passive diffusion, membrane k The basic structure of cells—including the mito-
proteins are required for transport of most chondria, cytoskeleton, extracellular matrix,
molecules. and secretory networks—can be regulated and
remodeled to serve many purposes.
k Some transporters, such as ion channels, facili-
tate the diffusion of impermeant molecules k The ability to follow developmental programs,
down concentration gradients by creating pores. or respond to physiological and environmental
challenges, resides in the genes. Physiological
k Active transporters use energy to pump mole-
change begins in many cases with the ways
cules against gradients.
cells control genes.
k The electrochemical gradients that exist across
k Cells and tissues are remodeled using processes
cellular membranes are produced by active
from transcriptional control to post-translational
transporters and used to drive diverse physio-
regulation.
logical processes.
k Evolutionary processes, including gene and
k The interior of the plasma membrane is elec-
genome duplications, provide the raw material
tronegative, with a membrane potential be-
for achieving physiological diversity.
tween 5 and 100 mV. Potassium gradients
Review Questions
1. How does the density of water change in rela- 3. What metabolic conditions can affect the val-
tion to temperature? How do these properties ues of the respiratory quotient?
affect animals that live in marine and fresh- 4. What metabolic conditions affect the rela-
water environments? tionship between ATP produced and oxygen
2. If the enzymatic reaction A B Δ C D is consumed?
near equilibrium, then the mass action ratio is 5. Trace the path of a protein hormone, such as
close to the equilibrium constant. What hap- insulin, from its gene in the nucleus to secre-
pens to the mass action ratio if you add more tion out of the cell.
enzyme? What happens when you add more
6. Discuss the mechanism by which cells can use
of A? What do you need to know to predict
transporters to change their osmotic and ionic
what would happen if temperature changed?
properties.
Synthesis Questions
1. A type of protein comes in six different forms. pyruvate is often close to the Km value for LDH.
Each form can dimerize with the other. How Why might this be advantageous, in terms of
many unique homodimers and heterodimers kinetic regulation?
can be formed from these six proteins? 3. Describe, in chemical terms, how antacids work.
2. Many animals maintain metabolites at con- 4. Why do your hands get wrinkled if you spend
centrations near the Km value for metabolic too much time in the bathtub? Would the same
enzymes. For example, the concentration of
111
thing happen when you swim in the ocean? 6. Other physiological processes require changes
Describe these environments using the termi- in the activities of proteins. While this can
nology of osmolarity and tonicity. arise through changes in the levels of pro-
5. Many physiological processes require a teins, it can also change through regulation of
change in the levels of proteins, such as mem- protein function. Discuss the various ways
brane transporters. Discuss the processes that that cells can alter the activity of enzymes or
cells can use to change the protein levels. Dis- transporters.
cuss how the subcellular compartment influ- 7. Discuss the ways in which a cell is able to al-
ences this pathway. ter its interactions with other cells.
Quantitative Questions
1. What is the proton concentration of a solution 3. What rate of oxygen consumption would you ex-
at pH 7.4? At what temperature would this so- pect in a tissue with a metabolic rate of 30 µmol
lution be neutral? ATP/ min?
2. Calculate the basis for an RQ 1 for carbohy-
drate oxidation. Why does palmitate oxidation
give an RQ 0.7?
For Further Reading

See the Additional References section at the end This book looks at how animals and other
of the chapter for more references related to the organisms alter macromolecules in relation to
topics in this chapter. environmental stress.
Hochachka, P. W., and G. N. Somero. 2002.
Chemistry Biochemical adaptation. Oxford: Oxford
These texts provide good overviews of the University Press.
chemical and physical underpinnings of cell
biology and biochemistry. These two books present differing views of the
history of the discovery of the structure of DNA.
Becker, W. M., L. J. Kleinsmith, and J. Hardin.
2003. The world of the cell, 5th ed. San Sayre, A. 1975. Rosalind Franklin & DNA. New
Francisco: Benjamin Cummings. York: Norton, 1975.
Lehninger, A. L., D. L. Nelson, and M. M. Cox. Watson, J. 2001. The double helix: A personal
1999. Principles of biochemistry, 3rd ed. New account of the discovery of the structure of
York: Worth. DNA. New York: Touchstone Books.
Biochemistry
This text is a good primer for understanding the
factors that affect protein structure. This book, written by two pioneers in
comparative biochemistry, explores the metabolic
Branden, C., and J. Tooze. 1991. Introduction basis of biological diversity. Although the focus is
to protein structure. New York: Garland on animals, they also consider other organisms
Science. that exemplify biochemical strategies for survival
in adverse environments.
These publications provide good background on
the interactions between energy, chemical bonds, Hochachka, P. W., and G. N. Somero. 2002.
and water. Biochemical adaptation. Oxford: Oxford
University Press.
Bryant, R. G. 1996. The dynamics of water-protein
interactions. Annual Review of Biophysics and Arthur Kornberg’s autobiography gives his
Biomolecular Structure 25: 29–53. perspective on the history of the study of
Thornton, R. M. 1998. The chemistry of life. metabolic biochemistry.
Menlo Park, CA: Benjamin Cummings. Kornberg, A. 1991. For the love of enzymes: The
Westof, E. 1993. Water and biological odyssey of a biochemist. Cambridge, MA:
macromolecules. Boca Raton, FL: CRC Press. Harvard University Press.
112
Lehninger is one of the standard undergraduate Ohno’s early book outlines his perspective on the
textbooks in biochemistry, with particularly good importance of gene duplication in the evolution of
sections on metabolism and metabolic regulation. biological diversity. More recently, in a series of
Nelson, D. L., and M. M. Cox. 2000. Lehninger papers, a number of authors bring the field up-to-
principles of biochemistry. New York: Worth. date, incorporating recent evidence of the role of
genome duplications in origins of gene families
Cell Physiology and cellular diversity.
These two textbooks cover the breadth of cell and Ohno, S. 1970. Evolution by gene duplication.
molecular biology, with excellent illustrations. Heidelberg: Springer Verlag.
The strength of Alberts is its comprehensive Various authors. 1999. Gene duplication in
nature, while Becker is very readable. development and evolution. Seminars in Cell
Alberts, B., A. Johnson, J. Lewis, M. Raff, and Developmental Biology 10: 515–563.
K. Roberts, and P. Walter. 2002. Molecular
biology of the cell. New York: Garland Science. An excellent overview of transport and
Becker, W. M., L. J. Kleinsmith, and J. Hardin. transporters.
2002. The world of the cell. San Francisco: Stein, W. D. 1990. Channels, carriers and pumps:
Benjamin Cummings. An introduction to membrane transport. San
Diego: Academic Press.
This comprehensive review of the ATP synthase
does an excellent job of explaining how the The original book by Sir D’Arcy Wentworth
enzyme works in the context of structural models Thompson, written in 1917, was one of the first
of its function. to examine how physiology was influenced by
Boyer, P. D. 1997. The ATP synthase—A splendid mathematics and physics.
molecular machine. Annual Review of Thompson, D. W. 1961. On growth and form.
Biochemistry 66: 717–749. Abridged edition edited by J. T. Bonner.
Cambridge: Cambridge University Press.
This book discusses the nature of evolutionary
and physiological variation from the perspective
of cell and developmental biology.
Gerhart, J., and M. Kirschner. 1997. Cells,
embryos and evolution. New York: Blackwell
Science.
Benison, S. A., A. C. Barger, and E. L. Wolfe. 1987. Walter B. Madigan, M. T., and B. L. Marrs. 1997. Extremophiles.
Cannon: The life and times of a young scientist. Scientific American 276: 82–87.
Cambridge, MA: Harvard University Press. Maloney, P. C., and T. H. Wilson. 1985. The evolution of ion
Dyson, F. J. 1954. What is heat? Scientific American 191: pumps. BioScience 35: 43–48.
58–63. Mitic, L. L., and J. M. Anderson. 1998. Molecular architecture
Gibbs, A. G. 1998. The role of lipid physical properties in of tight junctions. Annual Review of Physiology 60:
lipid barriers. American Zoologist 38: 268–279. 121–142.
Golding, G. B., and A. M. Dean. 1998. The structural basis of Palmer, T. 1995. Understanding enzymes, 4th ed. London:
molecular adaptation. Molecular Biology and Evolution Prentice Hall/Ellis Horwood.
15: 355–369. Pennycuick, C. J. 1992. Newton rules biology: A physical
Hastings, J. W. 1996. Chemistries and colors of approach to biological problems. New York: Oxford
bioluminescent reactions: A review. Gene 173: 5–11. University Press.
King, J., C. Haase-Pettingell, and D. Gossard. 2002. Protein Powers, D. A., and P. M. Schulte. 1998. Evolutionary
folding and misfolding. American Scientist 90: 445–453. adaptations of gene structure and expression in natural
Kinne, R. K. H., ed. 1990. Basic principles in transport. populations in relation to a changing environment: A
Basel, Switzerland: Karger. multidisciplinary approach to address the million-year
Logue, J. A., A. L. DeVries, E. Fodor, and A. R. Cossins. 2000. saga of a small fish. Journal of Experimental Zoology 282:
Lipid compositional correlates of temperature-adaptive 71–94.
interspecific differences in membrane physical structure.
Journal of Experimental Biology 203: 2105–2115.
113
Credits
20 Getty Images, Scott Sady/Getty Images.
21 Photo Researchers, Inc., Eye of Science/Photo
Researchers, Inc.
28 Photo Researchers, Inc., Stephen Dalton/Photo
Researchers, Inc.
75 (a) Dr. Alexey Khodjakov/Photo Researchers, Inc. (b)
Riccardo
Cassiani-Ingoni/Photo Researchers, Inc.
114
115
Cell Signaling and Endocrine Regulation
At every level of organization, life depends on communica- into the environment, but its concentration remains low.
tion. Animals send signals to each other in the form of When many bacteria are present within a small area, how-
sounds, scents, and visual cues. Within an animal, organs, ever, the environmental concentration of autoinducer rises.
tissues, and cells communicate with each other using At high concentrations, the autoinducer binds to a specific
chemical and electrical signals. Even within a single cell receptor with the bacterial cell, causing the receptor to
there is constant communication of information among or- change shape and act as a transcription factor that induces
ganelles. Two of the most familiar types of cellular com- the transcription of the genes involved in light production.
munication in animals involve the nervous system and the Thus, when the bacteria are present at high densities, the
endocrine system. Although the nervous and endocrine light-producing genes are induced and the bacteria glow in
systems may appear to be quite different, they are part of the dark.
a continuum of cellular communication systems that share V. fischeri seldom reach high enough densities to glow
many important similarities. when they are free-living, but these bacteria are also found
In all organisms, cellular communication systems in- in a mutualistic relationship with a species of squid—
volve sending and receiving a signal, often in the form of a Euprymna scolopes shown in the photograph above. The bac-
chemical. We can see the fundamentals of these mecha- teria colonize specialized light organs on the underside of
nisms even in prokaryotes. For example, the marine bac- the squid. The squid’s light organs provide an ideal home for
terium Vibrio fischeri is capable of producing light, but does the bacteria, allowing them to grow to very high density and
so only when the bacteria are present at high density. When produce light. This light, which glows from the underside of
the bacteria are at low densities, they produce a chemical the squid, allows the predatory squid to blend in with the
called an autoinducer that diffuses across the membrane light descending through the water from the surface, mak-
116
The brightly colored rumps of female Hamadryas baboons are the
Aggregation of individual amoeboid cells of Dictyostelium discoideum result of chemical signaling.
into a colony is activated by chemical signals.
entiates to form a complex structure consisting of a stalk

ing them invisible from below. Thus, the glowing bacteria act and a fruiting body. The fruiting body produces spores that
as camouflage that helps the squid to catch their prey. The are capable of surviving extremely harsh conditions. The
complex mutualistic relationship between the bacteria and spores can also break away from the fruiting body to be car-
the squid depends on cellular signaling among the bacteria ried by the wind to other locations. Once conditions improve,
via the autoinducer, and between the bacteria and the squid the spores germinate into individual amoeboid cells, start-
because squid reared in the laboratory in the absence of the ing the cycle over again.
bacteria do not develop a complete light organ. These two examples of cellular signaling, in a prokaryote
Another example of cellular signaling can be found in and a unicellular eukaryote, illustrate the fundamental fea-
unicellular eukaryotes such as Dictyostelium discoideum, a tures of cellular communication in all living things: the pro-
species of cellular slime mold. Much of the time slime duction of a signal in one cell, the transport of that signal to a
molds function as individual, independent, amoeboid cells. target cell, and the transduction of that signal into a response
These cells move through their environment phagocytosing in the target cell.
other cells for food. But when conditions are poor, slime The complexity of animal physiology and behavior re-
mold cells begin to secrete a signaling molecule called quires an enormous diversity in signaling mechanisms.
cyclic adenosine monophosphate (cAMP). When a slime Nowhere is this diversity more obvious than in the endocrine
mold cell encounters environmental cAMP, the cAMP binds system. In most animals, the endocrine system is involved in
to a receptor on the surface of the slime mold cell, causing controlling and regulating almost every physiological
the receptor to undergo a conformational change. The con- process including growth, development, metabolism, and
formational change of the receptor activates two different ion and water balance. The endocrine system’s role in repro-
intracellular signaling pathways. The first signaling pathway duction and development is one of the most obvious mani-
activates an enzyme called adenylate cyclase, which cat- festations of cellular signaling. For example, when female
alyzes the production of cAMP in the recipient cell, causing Hamadryas baboons are ready to mate, a variety of en-
cAMP secretion. The second signaling pathway causes the docrine signals cause the development of a characteristic
recipient cell to release intracellular calcium, which acts on patch of red, swollen skin around their genitals. These
the proteins of the cytoskeleton to induce amoeboid move- swellings act as a visual signal to attract males, helping to
ments. Together, these two intracellular responses cause promote reproduction. Thus, the endocrine system is re-
an amoeboid slime mold cell that encounters environmen- sponsible for inducing a very large and obvious change in the
tal cAMP to move up the cAMP gradient toward the signal- phenotype of these females. In insects, the endocrine sys-
ing individual, and to add to the secreted cAMP in the tem controls the metamorphosis from larva to butterfly.
environment. As more and more cells respond to the sig- Despite their diversity and complexity, however, the mecha-
nal and begin to aggregate into a small area, the cAMP sig- nisms of endocrine signaling in animals share many fea-
nal intensifies, attracting even more amoeboid cells, and tures in common with the signaling systems of unicellular
increasing the size of the aggregation of cells. Eventually, organisms. In this chapter, you will see the critical role of
the group of cells forms a migratory blob termed a pseudo- these cellular communication mechanisms in allowing ani-
plasmodium. The pseudoplasmodium moves through its mals to perform their complex functions.2
environment until it finds a suitable spot, and then differ-
117
Overview into its environment. The chemical messenger

then travels through the extracellular fluids until it
Everything that an animal does involves commu- reaches the target cell. At the target cell, the chem-
nication among cells. Moving, digesting food, and ical messenger binds to a receptor, changing the
even reading this text all require the coordinated shape of the receptor and activating signal trans-
action of thousands of individual cells engaging in duction pathways that cause a response within
constant communication. Communication between the target cell. Interactions between chemical
cells occurs when a signaling cell sends a signal to messengers, receptors, and signal transduction
a target cell, usually in the form of a chemical mechanisms allow cells to communicate with each
messenger. Figure 1 summarizes the principal other.
types of cell signaling in animals. Adjacent cells Chemical messengers can travel from a signal-
can communicate directly through aqueous pores ing cell to nearby target cells by diffusion in a
in the membrane called gap junctions, but the ma- process called paracrine communication. These
jority of cells have no direct contact with each messengers can even affect the signaling cell, in a
other. Thus, most cell signaling is indirect, and be- process called autocrine communication. But the
gins when one cell releases a chemical messenger rate of diffusion is limited by distance, and thus
Signaling cell Signaling cell Signaling cell

Response
Chemical
messenger Signaling
Signal cell
transduction
Circulatory
Gap system
junction
Chemical Electrical
messenger signal
Receptor
Receptor
Receptor
Chemical Chemical
messenger messenger
Signal Signal (neurotransmitter)
transduction transduction
Response Receptor
Signal
Response Response
transduction
Response
Target cell Target cell Target cell Target cell
(a) Direct cell signaling (b) Autocrine and (c) Endocrine signaling (d) Neural signaling
paracrine signaling
Figure 1 An overview of cell signaling Cells messengers called hormones travel long distances via the
communicate either directly, via aqueous pores that connect circulatory system. When the hormone reaches the target cell it
adjacent cells, or indirectly when the signaling cell releases binds to a receptor, initiates signal transduction pathways, and
a chemical messenger into the extracellular environment. causes a response. (d) In neural signaling, electrical signals
(a) Direct cell signaling can occur through pores called gap travel across long distances within a single cell. The electrical
junctions.(b) Paracrine signaling occurs when chemical signal then either passes directly to the target cell via gap
messengers diffuse from the signaling cell to nearby target cells junctions, or triggers the release of a chemical messenger
where they bind to receptors and initiate signal transduction called a neurotransmitter. The neurotransmitter carries the
pathways that cause a response. Autocrine signaling is similar signal to the target cell by diffusing across a short distance,
except that the chemical messenger causes a response in the where it binds to receptors on the target cell, initiates signal
signaling cell. (c) Endocrine signaling occurs when chemical transduction pathways, and causes a response.
118
diffusion is insufficient to carry signals to distant through cell membranes, but do not dissolve well in
target cells. For long-distance cell-to-cell commu- aqueous fluids such as cytoplasm or blood. Hy-
nication, animals use the endocrine system and drophilic chemical messengers are soluble in the
nervous system. In the endocrine system, the cytoplasm and extracellular fluids, but do not pass
chemical messenger travels from the signaling cell through cell membranes. These fundamental
to the target cell carried by the circulatory system. chemical properties pose a problem that cells must
These endocrine messengers are called hormones. solve in order to communicate with each other.
In the nervous system, an electrical signal travels
across a long distance within a single cell (the neu-
ron), and is transferred to the target cell over a very
General Features of Cell Signaling
short distance, often in the form of a chemical mes- Cells can circumvent the problem of moving a hy-
senger called a neurotransmitter. Animals can drophilic chemical messenger through the lipid
even send chemical messengers between individu- environment of the membrane by communicating
als, a system termed exocrine communication. via gap junctions. Gap junctions are specialized
Although these systems appear to be rather dis- protein complexes that create an aqueous pore
tinct, they actually share many features in common between the cytoplasms of two adjacent cells
at the biochemical level. In this chapter, we first ex- (Figure 2). Gap junctions are composed of inter-
amine the biochemical basis of cell signaling, out- locking cylindrical proteins (called connexins in
lining the shared features of different signaling vertebrates, or innexins in invertebrates) assem-
systems. We look at how cells release chemical bled in groups of four or six to form doughnut-like
messengers, how these messengers travel to the pores (hemichannels or connexons) in the cell
target cell, how they bind to receptors, and how membrane. The hemichannels of two adjacent
they exert their effects through signal transduction cells come together to form a hollow tube, con-
pathways. We devote much of this chapter to a dis- necting the two cells via an aqueous bridge. Thus,
cussion of the fundamental properties of receptors chemical messengers can travel from the signaling
and signal transduction mechanisms, not only be-
cause these processes are involved in the regulation
of every physiological system, but also because you
will encounter receptors and signal transduction
Cell A
mechanisms many times throughout your course.
We then step back from the cellular details of com-
munications mechanisms to take a closer look at Cell B
one of the important cellular communication sys-

tems in animals: the endocrine system.
The Biochemical Basis Pore
of Cell Signaling Connexin

(or innexin)
Cells are separated from their environment by a
phospholipid membrane. Thus, any chemical mes- Hemichannel
senger traveling between two cells must first pass Plasma
from the aqueous cytoplasm of the signaling cell, membrane
of cell A
through its lipid membrane, and into the aqueous
extracellular fluid. At the target cell the messenger Plasma
membrane
must then signal across the lipid membrane of the of cell B
target cell into its aqueous cytoplasm. Since most Chemical
messenger
chemicals are either soluble in aqueous solutions
(hydrophilic) or soluble in lipids (hydrophobic), Figure 2 The structure of gap junctions Gap
junctions are protein complexes that form aqueous pores
sending a chemical messenger from one cell to an- between adjacent cells. Proteins called connexins (in
other presents a substantial challenge. For exam- vertebrates) or innexins (in invertebrates) form the structure
ple, hydrophobic chemical messengers can pass of the gap junction.
119
cell to the target cell via gap junctions without ever They can be opened and closed to regulate commu-
leaving an aqueous environment. nication of substances between cells. Increased in-
We can demonstrate that two cells are con- tracellular calcium and decreased intracellular pH
nected via gap junctions by injecting a fluorescent both cause gap junctions to close. The number of
dye that cannot cross the cell membrane into one gap junctions connecting two cells can also be reg-
of the cells. If gap junctions connect two cells, dye ulated on a physiological time scale.
that is injected into one cell will diffuse through Direct communication via gap junctions is a
the gap junctions into the adjacent cell (if the dye very efficient way to send signals, but gap junctions
is small enough to pass through the pore), and can only form between adjacent cells. Animals need
both cells will start to fluoresce. If no gap junctions other strategies for sending signals to more distant
are present, the dye will remain in the first cell be- cells, or to neighboring cells that are not connected
cause it is unable to cross the membrane, and the by gap junctions. This kind of signaling is called
second cell will not fluoresce. indirect cell signaling, and involves three steps:
In most physiological situations, direct com-
1. Release of a chemical messenger from the sig-
munication via gap junctions involves the move-
naling cell into the extracellular environment
ment of ions between cells. The movement of ions
into or out of a cell can act as a signal by causing 2. Transport of the chemical messenger through
a change in the membrane potential that triggers a the extracellular environment to the target cell
response in the target cell. This rapid communica- 3. Communication of the signal to the target cell
tion of signals between adjacent cells is a simple via receptor binding
way to coordinate cellular responses. The move-
ment of ions through gap junctions helps to coor-
dinate the contraction of smooth and cardiac
Indirect signaling systems form
muscle, and is involved in the transmission of
a continuum
electrical signals between some nerve cells. Other Although the systems that animals use for indirect
small molecules can also move between cells via signaling are often discussed as if they were quite
gap junctions, including a variety of intracellular different from each other, they are actually just
signaling molecules such as cyclic adenosine specialized ways of achieving the same result. In
monophosphate (cAMP). Thus, gap junctions fact, at the biochemical level they share a great
play a critical role in coordinating physiological deal in common. Table 1 shows some of the simi-
responses at the tissue level. Gap junctions are larities and differences between the various types
not just passive channels between adjacent cells. of cellular communication. In general, autocrine,
Table 1 Comparison of systems for cell-to-cell communication.
Autocrine/
Feature Paracrine Nervous Endocrine Exocrine
Secretory cell Various Neural Endocrine Various
Target cell Most cells in body Neuron, muscle, Most cells Sensory and neural
endocrine in body
Signal type Chemical Electrical and Chemical Chemical
chemical
Maximum signaling Short Long intracellularly, Long Very long
distance short across synapse
Transport Extracellular fluid Synapse Circulatory External environment
system
Speed Rapid Rapid Slower Various
Duration of Short Short Longer Various
response
120
paracrine, neural, endocrine, and exocrine com- the external environment (e.g., air or water) to ex-
munication systems differ largely in the type of cell ert its effects on a different individual.
involved in messenger secretion and in the way The differences in the mechanisms that the var-
that the messenger is transported to the target cell. ious types of communication systems use to trans-
In contrast, the mechanisms governing the release port chemical messengers from the signaling cell to
of the chemical messenger from the signaling cell, the target cell result in differences in the speed of
the types of chemical messengers utilized, and the communication of these systems. Autocrine and
mechanisms for communicating the signal to the paracrine communication are very rapid, because
target cell are actually very similar among systems. chemical signals need only diffuse across very small
The most important distinction among the dif- distances. Diffusion is a rapid process at these
ferent systems for cellular communication is the scales, so autocrine and paracrine communication
distance across which the chemical messenger occurs on a time scale of milliseconds to seconds.
must travel. In autocrine and paracrine communi- Nervous communication is similarly rapid. Propa-
cation, the chemical messenger simply diffuses gation of electrical signals within a neuron occurs
through the extracellular fluid from the signaling on a millisecond scale, and diffusion of a neuro-
cell to the target cell. Because the rate of diffusion transmitter across the synapse is also rapid. In con-
is limited by distance, autocrine and paracrine sig- trast, endocrine communication is usually slower,
nals are localized, affecting only those target cells because it relies on transport of hormones in the
that are within a short distance of the signaling circulatory system. Depending on the organism,
cell. Intercellular signaling also occurs across short blood may require several seconds to minutes to
distances in the nervous system, at a structure make a complete circuit around the body. In addi-
called the synapse, a region where the signaling tion, endocrine hormones are often longer-lived in
cell and the target cell are very close together. Sig- extracellular fluids than are paracrines or neuro-
nals can move from cell to cell across the synapse transmitters, increasing the length of time over
via gap junctions, if they are present, in a form of which they can have an effect.
direct cell-to-cell communication. Alternatively, Only neurons act as the secretory cells in ner-
neurotransmitters can carry a signal across the vous communication, but a variety of cell types can
synapse by diffusing from the signaling cell to the be involved in exocrine and endocrine communi-
target cell, where they bind to receptors. Because cation. The distinction between nervous and en-
neurotransmitters diffuse from the signaling cell to docrine signaling is, however, somewhat blurry.
the target cell across the synapse, this mechanism Some neurons can secrete neurotransmitters di-
of synaptic communication is similar to paracrine rectly into the circulatory system, in which case
communication. Although cell-to-cell communica- the messenger is termed a neurohormone, be-
tion in the nervous system can only occur across cause it is secreted by a neuron but acts like a hor-
short distances, nervous signals can be communi- mone. The secretory cells of the exocrine and
cated across very long distances. Unlike other endocrine tissues are often grouped into struc-
forms of cellular communication, however, long- tures called glands (Figure 3). Endocrine glands
distance nervous communication occurs within a release their secretions (hormones) directly into
single cell. The unique structure of neurons allows the circulatory system. The endocrine cells within
electrical signals to be propagated across a long these glands are typically very specialized for their
distance within a single cell without degrading. secretory function. However, there are many hor-
The endocrine system can regulate the activities of mones that are not secreted by endocrine glands.
distant cells, tissues, and organs by sending For example, cells within the atria of the heart re-
chemical signals through the blood in the form of lease a hormone called atrial natriuretic peptide
hormones. Because they are carried by the that is involved in the regulation of blood pressure.
circulatory system, rather than moving only by Thus, the distinction between endocrine commu-
diffusion, hormones can quickly travel across nication and other types of intercellular communi-
long distances through the body. In exocrine com- cation can be difficult to elucidate when viewed
munication, a chemical termed a pheromone from the perspective of the signaling cell.
is released by one individual and travels through Exocrine glands release their secretions into
ducts that lead to the surfaces of the body (including
121
External environment External environment
Epithelial
cells Duct
Acinus
Secretory
cells
Secretory
cells
Circulatory system Circulatory system
(a) Exocrine gland (b) Endocrine gland
Figure 3 The structure of exocrine and endocrine glands Exocrine glands

secrete chemicals into ducts that lead to the surface of the body, whereas endocrine glands
secrete hormones directly into the circulatory system.
the skin, respiratory surfaces, and the surface of the gers use different mechanisms for signaling than do
gut). Exocrine secretions that contain pheromones hydrophilic messengers, because hydrophobic
are involved in animal-to-animal communication, messengers can diffuse freely across cell
but exocrine secretions can also participate in many membranes whereas hydrophilic messengers can-
processes in addition to communication, including not. Table 2 summarizes the similarities and differ-
locomotion, digestion, and prey capture. For exam- ences between hydrophilic and hydrophobic
ple, exocrine mucus secretions form a protective chemical messengers in each step of indirect cell
layer over many epithelia, including the gills of fish signaling.
and the lungs of terrestrial animals. Mucus secre- There are six main classes of chemicals that
tions can also help in locomotion, as in the slime are known to participate in cellular signaling in an-
trails of slugs and snails. Saliva produced in the imals: peptides, steroids, amines, lipids, purines,
mouth of mammals begins digestion, and helps food and gases. All known hormones are peptides,
to slide down the esophagus. Spiders make silk, a steroids, or amines, whereas there are examples of
very specialized exocrine secretion, to trap prey. all six classes of messengers acting as autocrines,
Because all of the different forms of cell signal- paracrines, or neurotransmitters. In the next sec-
ing share so many features in common, in the next tions we look at each of these main classes of
sections we begin our consideration of the biochemical messengers to see how their biochemical
chemical basis of cell signaling without separating properties affect their release from the signaling
the different types of signaling used by animals. In cell, transport through the extracellular fluid, and
this way, we can clearly see how cells have solved actions on the target cell.
the general problem of sending chemical signals
across the cell membrane when direct communi-
cation is not possible.
Peptide Messengers
Amino acids, peptides, and proteins can all act as
The structure of the messenger determines signaling molecules. Amino acids typically act as
the type of signaling mechanism neurotransmitters, whereas peptides and proteins
The chemical structure of the messenger is the crit- may be autocrines, paracrines, neurotransmitters,
ical property that affects the way in which indirect neurohormones, hormones, or pheromones. Pep-
signaling is accomplished. Hydrophobic messen- tide and protein messengers consist of two or
122
Table 2 A comparison of hydrophilic and hydrophobic chemical messengers.
Feature Hydrophilic messengers Hydrophobic messengers

Storage Intracellular vesicles Synthesized on demand
Secretion Exocytosis Diffusion across membrane
Transport Dissolved in extracellular fluids Short distances: dissolved in extracellular fluid
Long distances: bound to carrier proteins
Receptor Transmembrane Intracellular or transmembrane
Effects Rapid Slower or rapid
more amino acids linked in series, and range in in cosmetic medicine to reduce facial wrinkles
size from 2 to 200 amino acids in length. Chains of such as frown lines.
fewer than 50 amino acids are usually called pep- Peptide hormones are often synthesized as large,
tides, while the word protein is used for longer inactive polypeptides called preprohormones
chains. Peptide and protein messengers are hy- (Figure 4). Preprohormones contain not only one or
drophilic chemicals that cannot diffuse across the more copies of a peptide hormone or hormones, but
membranes, but are soluble in aqueous solutions. also a signal sequence that targets the polypeptide
for secretion. The signal sequence is cleaved from the
preprohormone prior to being packaged into secre-
Peptide messengers are released tory vesicles, forming the prohormone, which like
by exocytosis the preprohormone is usually inactive. The secretory
Peptide and protein messengers are synthesized vesicle contains proteolytic enzymes that cut the pro-
on the rough endoplasmic reticulum along with hormone into the active hormone or hormones. The
most of the other proteins destined for secretion signaling cell then releases the active peptide hor-
from the cell. The peptides are then packaged into mone by exocytosis.
vesicles for either immediate release, or storage Figure 5 shows an example of a preprohor-
for later use. Most of the peptide hormones and mone, the one containing arginine vasopressin
neurotransmitters are synthesized in advance and (AVP), also known as antidiuretic hormone (ADH).
stored for later release, whereas paracrine pep- Ribosomes on the exterior of the rough endoplas-
tides such as the cytokines are synthesized only mic reticulum translate the preprovasopressin
on demand. We can see the importance of regu- mRNA into protein. The signal peptide directs the
lated exocytosis of stored messenger by examining newly synthesized polypeptide to the interior of the
the effects of botulinum toxin, a protein produced rough endoplasmic reticulum. The signal peptide is
by the bacterium Clostridium botulinum. This pro- then cleaved off, forming provasopressin, which is
tein blocks the regulated exocytosis of neurotrans- packaged into secretory vesicles. In the secretory
mitters traveling between nerves and muscles, vesicles it is cleaved into three different peptides:
preventing muscle contraction and causing paral- vasopressin, neurophysin, and a glycoprotein. Argi-
ysis. Exposure to a large dose of this toxin causes nine vasopressin is a hormone that acts on the kid-
the disease botulism, which is characterized by ney to regulate the reabsorption of water. The
weakness and paralysis, generally starting in the functions of neurophysin and the glycoprotein are
area of the head and progressing to paralysis of not yet well understood, but they may be involved
the muscles of the rest of the body, including those in the proper sorting and secretion of arginine va-
involved in swallowing and breathing. If un- sopressin.
treated, an individual with a severe case of botu-
lism is likely to die of respiratory failure. Although
the botulinum toxin (also called botox) is one of the
Peptide messengers dissolve
most potent poisons known, it can be used as a
in extracellular fluids
medical therapy. Injecting small amounts of botox Once released from the signaling cell, a chemical
directly into a muscle leads to local paralysis, and messenger must move through the extracellular
can be used to treat muscle spasms. It is also used fluid to the target cell. Hydrophilic chemical
123
Rough
Ribosome
endoplasmic
Golgi apparatus
reticulum
mRNA
Polypeptide
Preprohormone
Prohormone Prohormone
Secretory
vesicle
Peptide
fragment
Cleaved
preprohormone
Active
Signal hormone
sequence
Extracellular
fluid
Figure 4 Synthesis of peptide hormones Peptide further processing and sorting. In the Golgi apparatus, the
hormones are synthesized by ribosomes on the rough prohormone is packaged into secretory vesicles, where it is
endoplasmic reticulum, often as large preprohormones. The cleaved into active hormone and one or more peptide fragments.
preprohormone enters the rough endoplasmic reticulum, where The secretory vesicle fuses with the plasma membrane,
the signal sequence is cleaved off. The resulting prohormone is releasing its contents by exocytosis.
packaged into vesicles that move to the Golgi apparatus for
Arginine Glycoprotein
vasopressin messengers such as peptides and proteins dis-
Signal Neurophysin solve well in aqueous solutions and can easily
peptide move from the signaling cell to the target cell, ei-
ther by diffusion or carried by the circulatory
SP AVP NPH GP Preprovasopressin
system. Peptides messengers are usually broken
down and removed from extracellular fluids by
Signal peptide cleaved proteolytic enzymes. The rate of this breakdown
Rough
endoplasmic can be measured as the messenger’s half-life—
reticulum the time taken to reduce the concentration of the
messenger by half. Peptide messengers gener-
SP AVP NPH GP Provasopressin ally have half-lives ranging from a few seconds
to a few hours. As a result of these short half-
lives, the signaling cell must continually produce
messenger in order to cause a sustained re-
Cleavage
sponse in a target cell.
Secretory
vesicles
Peptides bind to transmembrane
receptors
AVP NPH GP Hydrophilic signaling molecules such as peptides
Figure 5 The synthesis of arginine vasopressin and proteins cannot pass through the membrane of
(AVP) AVP is synthesized on the rough endoplasmic reticulum as a the target cell, but instead bind to transmembrane
large polypeptide, preprovasopressin, which contains a signal peptide receptors (Figure 6). The extracellular portion of a
(SP), AVP, neurophysin (NPH), and a glycoprotein (GP). In the rough transmembrane receptor contains the ligand-bind-
endoplasmic reticulum the signal peptide is cleaved off, producing
ing domain. Ligand is the general term for any
provasopressin. The provasopressin passes to the Golgi apparatus,
where it is packaged into secretory vesicles. In the secretory vesicles, small molecule that binds specifically to a protein.
the provasopressin is cleaved into three peptides: AVP, NPH, and GP. Thus, a peptide chemical messenger acts as a
124
Extracellular fluid Chemical

and are important for fluid and electrolyte balance
messenger in the body. Aldosterone is the primary mineralo-
corticoid in mammals. The glucocorticoids (cor-
Ligand-binding
tisol, cortisone, and corticosterone), also called the
domain stress hormones, have widespread actions includ-
Transmembrane
ing increasing glucose production, increasing the
domain breakdown of proteins into amino acids, increasing
the release of fatty acids from adipose tissue, and
Intracellular regulating the immune system and inflammatory
domain
responses. The reproductive hormones (estrogens,
Cytoplasm progesterone, testosterone), regulate sex-specific
characteristics and reproduction.
(a) Unbound receptor (b) Bound receptor
The principal steroids in invertebrates are the
Figure 6 The structure of a transmembrane ecdysteroids, which play an important role in the
receptor (a) Transmembrane receptors have an regulation of molting in the arthropods (see Box 1,
extracellular ligand-binding domain, a membrane-spanning
domain, and an intracellular domain. (b) When the Evolution and Diversity: Ecdysone: An Arthropod
messenger (ligand) binds to the receptor, the conformation Steroid Hormone). Much less is known about the
of the receptor changes. role of these steroids in other invertebrate phyla,
but they are thought to play a role in development
and reproduction.
ligand for a transmembrane receptor protein. Because all steroids contain several carbon
Transmembrane receptors also have a membrane- rings, some synthetic chemicals with similar
spanning (transmembrane) domain and an intra- structures bind to steroid receptors and mimic or
cellular domain. When a ligand binds to the block the action of the natural hormone. Environ-
ligand-binding domain of a transmembrane recep- mental exposures to chemicals such as the insec-
tor, the receptor changes shape, communicating ticide DDT have been associated with low sperm
the signal carried by the ligand across the cell counts and increased incidence of breast and
membrane, without the ligand itself needing to prostate cancer in humans, developmental abnor-
cross the lipid-rich membrane. Transmembrane re- malities such as reduced penis size and feminiza-
ceptors activate cytoplasmic signal transduction tion in animals including fish and alligators, and
pathways that cause rapid changes in the activity of interference with molting in crustaceans. Environ-
the target cell, usually by altering membrane poten- mental chemicals such as DDT bind to and activate
tial, or phosphorylating and modifying the activity the receptor for estrogen, and other chemicals
of existing proteins. such as some pesticides interfere with other as-
pects of steroid metabolism—a phenomenon called
endocrine disruption.
Steroid Messengers
Steroids are derived from the molecule cholesterol,
Steroids bind to carrier proteins
and are important hormones in both vertebrates Because steroids can easily pass through biological
and invertebrates. Steroids can also act as membranes, they cannot be stored within the cell,
paracrine and autocrine signals in some tissues, and thus must be synthesized on demand. They
and are important pheromones involved in com- then diffuse across the membrane of the signaling
munication among animals. Figure 7 shows a gen- cell and into the extracellular fluid. Steroids can
eralized synthetic pathway for some of the diffuse across short distances dissolved in extracel-
important steroid hormones in vertebrates. The en- lular fluids, but for long-distance transport they are
zymes for steroid biosynthesis are located in the usually bound to carrier proteins. Some steroids
smooth endoplasmic reticulum or mitochondria. have specific carrier proteins (termed binding
There are three major classes of steroid hormones globulins), while others bind nonspecifically to
in the vertebrates. Mineralocorticoids are in- generalized carrier proteins, such as albumin, the
volved in regulating sodium uptake by the kidney,
125
CH3 resulting in an equilibrium between

HC CH2 C5 H11 free and bound messengers. As de-
CH3
scribed by the law of mass action, in
CH3 an equilibrium system the amounts
of reactants and products are al-
HO
ways in balance. Thus, you can de-
scribe the equilibrium between a
Cholesterol
chemical messenger and its carrier
CH3 protein using the following equation:
C O
CH3 M ⫹ C Δ M-C
CH3
where M is the concentration of un-
bound messenger, C is the concentra-
tion of carrier protein, and M-C is the
HO
concentration of messenger bound to
Pregnenolone
carrier protein. If the amount of free
CH3 messenger increases, the equilib-
C O rium will shift to the right, increasing
CH3
the amount of messenger bound to
CH3 carrier protein. If the amount of free
messenger decreases, the equilib-
O
rium will shift to the left, decreasing
the amount of messenger bound to
Progesterone
carrier protein.
The binding of a hydrophobic
CH2OH CH2OH
messenger to its carrier proteins is
C O C O OH
CH3 CH3 CH3
outlined in Figure 8. When a signal-
OH OH OH
ing cell releases a chemical messen-
CH3 CH3 CH3 ger into the extracellular fluid, the
free concentration of the messenger
O O O is high in the local environment, and
Cortisol Corticosterone Testosterone the messenger will tend to bind to its
CH2OH
carrier protein. For most hydropho-
OH
H
O CH3 bic chemical messengers, greater
C O
OH C than 99% of the messenger binds to
its carrier protein, but a small frac-
CH3
tion of the messenger is always free
HO
in solution. Both free and bound
O Estradiol 17-β messenger travel through the circu-
(an Estrogen)
Aldosterone latory system to the target cell. At
Figure 7 Synthetic pathways for some of the biologically active the target cell, the free messenger
steroids in vertebrates Cholesterol is the precursor for the three main classes diffuses into the cell and binds to its
of vertebrate steroids: the glucocorticoids (including cortisol and corticosterone), the receptor. The binding of the messen-
mineralocorticoids (including aldosterone), and the sex steroids (including ger to its receptor reduces the con-
testosterone and estradiol).
centration of free messenger in the
extracellular fluid adjacent to the
principal carrier protein in vertebrate blood. Car- target cell. The resulting low concentration of free
rier proteins help hydrophobic chemical messen- messenger causes the bound messenger to dissoci-
gers dissolve in aqueous solutions by surrounding ate from the carrier protein (because of the law of
the hydrophobic messenger and isolating it from mass action), delivering the messenger to the tar-
the aqueous solution. Hydrophobic chemical mes- get cell.
sengers bind reversibly to their carrier proteins,
126
BOX 1 EVOLUTION AND DIVERSITY

Ecdysone: An Arthropod Steroid Hormone
All arthropods have a rigid exoskeleton, OH

a hard outer covering that provides both pro-
tection and support. In order to grow, an arthropod must OH
shed its exoskeleton in a process called molting. The
hormones that regulate molting have been intensively
HO
studied in the insects, and one of the most important is OH
a steroid hormone called ecdysone. Most insects molt
HO
several times during larval development. In the
O
hemimetabolous insects, the larval stages and adult all
Ecdysone
resemble each other, with each stage simply being
larger than the preceding one. The younger stages may
differ slightly in shape or color from the adults, and lack
The steroid hormone ecdysone can stimulate an insect
sexual organs, but there is no major change in body
larva to molt to form a larger larva, a pupa, or an adult, de-
form. In contrast, the adults of the holometabolous in-
pending on the level of an additional hormone, juvenile
sects differ radically in shape from their larvae. Cater-
hormone. When juvenile hormone levels are high,
pillars and butterflies, for example, are the larval and
ecdysone stimulates molting from one larval stage to an-
adult stages of the holometabolous Lepidopteran in-
other. When juvenile hormone levels are low, ecdysone
sects. Holometabolous insects have an additional de-
triggers the formation of the pupa in holometabolous in-
velopmental stage, called a pupa, between the larva and
sects. When juvenile hormone is absent, ecdysone trig-
the adult, during which they undergo the process of
gers the emergence of the adult insect.
metamorphosis—a complete remodeling of their body
The structure of ecdysone is similar to that of the ver-
structures.
tebrate steroid hormones, but it contains more hydroxyl
groups. Ecdysone secretion is regulated by a neurohor-
mone called prothoracicotropic hormone (PTTH) pro-
duced by the insect brain. This neurohormone stimulates
the prothoracic gland to secrete ecdysone. Ecdysone is
actually a prohormone, and is rapidly converted to the ac-
tive hormone 20-hydroxyecdysone (also called ecdy-
sterone) by enzymes found in the hemolymph and various
peripheral tissues. 20-Hydroxyecdysone binds to an in-
tracellular receptor that regulates gene expression by
binding to a hormone responsive element, as do the ver-
tebrate steroid hormones.
Although 20-hydroxyecdysone is structurally similar
to the vertebrate steroids, it does not appear to be bio-
Juvenile hormone level
logically active in vertebrates, and does not have de-

tectable effects on the reproductive system. However, a
Threshold
for pupation few studies have reported that ecdysterone has anabolic
effects in vertebrates, increasing muscle growth and
lean muscle mass.
References
q Gilbert, L. I., R. Rybczynski, and J. T. Warren. 2002. Control and
Threshold for eclosion biochemical nature of the ecdysteroidogenic pathway. Annual Re-
view of Entomology 47: 883–916.
Larva Pupa Adult
q Slama, K., K. Koudela, J. Tenora, and A. Mathova. 1996. Insect
Developmental stage hormones in vertebrates: Anabolic effects of 20-hydroxy-
ecdysone in Japanese quail. Experientia 52: 702–706.
127
Signaling cell 1 The local concentration

Steroids bind to intracellular receptors
of messenger is high
near the signaling cell.
The lipophilic steroids can easily cross the mem-
brane of the target cell, and thus they can bind ei-
ther to transmembrane receptors or to receptors
1 inside the cell. The intracellular receptors are the
best-studied class of steroid receptor. Intracellular
2 Most (but not all) of the
High concentration chemical messenger steroid receptors act as transcription factors, con-
of messenger binds to carrier proteins. trolling the expression of target genes. Because
Messenger this pathway relies on changes in transcription
bound to
carrier 2 and translation, there is a detectable lag time be-
protein tween binding of the messenger and observation of
Free 3 The circulatory system the initial effects. In contrast, when a steroid mes-
messenger carries the free and senger binds to a transmembrane receptor, it acti-
bound messenger to the
3 target cell. vates a cytoplasmic signal transduction pathway,
which causes rapid non-genomic effects that do not
require changes in transcription or translation.
4
Target cell 4 Free messenger enters

the target cell and Biogenic Amines
binds to its receptor,
Receptor decreasing the Amines are chemicals that possess an amine
concentration of free
messenger.
(–NH2) group attached to a carbon atom. Amines
that function in cellular signaling are termed
biogenic amines. Many amines are synthesized
5 from amino acids. The catecholamines (dopamine,
5 This causes the bound norepinephrine, and epinephrine) are synthesized
Low messenger to dissociate
concentration from the carrier protein, from the amino acid tyrosine. Dopamine, which is
of free allowing it to enter the found in all animal taxa, acts as a neurotransmit-
messenger target cell.
ter. Norepinephrine and epinephrine are known
Figure 8 Transport of hydrophobic chemical only from vertebrates, and can act as neurotrans-
messengers mitters, paracrines, and hormones. Octopamine
and tyramine, which are also synthesized from
the amino acid tyrosine, are important neurotrans-
mitters in the invertebrates. Although octopamine
Because free and bound chemical messen- and tyramine have activity when administered to
gers are in equilibrium, changes in the concen- vertebrates, their physiological role in the verte-
tration of any of the reactants or products brates is not clear. The thyroid hormones are syn-
influence the concentrations of the others. Thus, thesized from a polypeptide containing the amino
increases in the amount of messenger that is re- tyrosine. These messengers are found only in the
leased from the signaling cell will increase the vertebrates, and act as hormones. They are not
amount of messenger delivered to the target cell. thought to function as neurotransmitters or
Conversely, increases in the concentration of the paracrines. Serotonin, which is synthesized from
carrier protein will tend to decrease the concen- the amino acid tryptophan, is a neurotransmitter
tration of free chemical messenger, whereas de- found in all animal taxa. Melatonin, which is also
creases in the concentration of carrier protein synthesized from the amino acid tryptophan, is
will increase the concentration of free messenger. found in almost all organisms and acts as a neuro-
As we discuss in the next section, the amount of transmitter and a hormone. In the vertebrates,
free messenger influences the response of the melatonin plays a critical role in regulating sleep-
target cell. Thus, changes in both the amount of wake cycles and seasonal rhythms. Although mela-
messenger and the amount of carrier protein can tonin is found in most invertebrate taxa, its role in
affect cell signaling. these organisms is not well understood. As is the
128
case in vertebrates, most evidence suggests that it is

HO CH2 CH COOH
involved in the regulation of activity patterns. Hist-
NH2
amine is synthesized from the amino acid histidine.
Tyrosine (in thyroglobulin)
This biogenic amine functions as a neurotransmit-
ter and a paracrine signaling molecule in both ver-
Iodinase Iodinase
tebrates and invertebrates. Histamine plays an
important role in immune responses and allergic re- I I
actions. Acetylcholine, a neurotransmitter found in
HO CH2 CHNH2 COOH HO CH2 CHNH2 COOH
all animals, is synthesized from choline, an amine
that is not an amino acid, and acetyl-coenzyme A. It Monoiodotyrosine (MIT) I Diiodotyrosine (DIT)
is the primary neurotransmitter at the neuromuscu-
lar junction of vertebrates, and because of its impor-
tance, and the fact that it is not synthesized from an I I
amino acid, it is sometimes classified separately
HO O CH2 CHNH2 COOH
from the other biogenic amines.
DIT
Most biogenic amines are hydrophilic mole- I
cules that are packaged into vesicles and released T3
into the extracellular fluid by exocytosis. They can
I I
either be synthesized on demand or be stored for
later release. In this chapter we focus on the thy- HO O CH2 CHNH2 COOH
roid hormones, which are an interesting exception
I I
to the general rules governing the synthesis and re- T4 (Thyroxine)
lease of biogenic amines.
Figure 9 Synthetic pathways for the thyroid
hormones Thyroid hormone synthesis begins when the enzyme
iodinase adds one or more iodine molecules to the amino acid
tyrosine within the protein thyroglobulin. Monoiodotyrosine (MIT)
Thyroid hormones diffuse across has a single iodine molecule added per tyrosine residue;
the membrane diiodotyrosine (DIT) has two iodine molecules per tyrosine residue.
If one molecule of MIT and one molecule of DIT combine, they form
Thyroid hormone synthesis begins when the en- triiodothyronine (T3). Adding an additional molecule of DIT forms
zyme iodinase adds one or more iodine molecules tetraiodothyronine (T4), also known as thyroxine. Collectively, T3 and
to tyrosine residues in the protein thyroglobulin T4 are termed the thyroid hormones.
(Figure 9). If a particular tyrosine residue is iodi-
nated once, the resulting compound is called Although thyroid hormones are derived from
monoiodotyrosine (MIT). If a particular tyrosine a hydrophilic precursor (a protein), the thyroid
residue is iodinated twice, the resulting compound hormones are hydrophobic and thus easily diffuse
is called diiodotyrosine (DIT). The iodinated tyro- out of the lysosome and cross the plasma mem-
sine residues in the thyroglobulin molecule are brane of the signaling cell.
then coupled via a covalent bond. If two DIT groups
combine, the result is 3,5,3′,5′-tetraiodothyronine,
called T4 (or thyroxine). Alternatively, if one DIT Thyroid hormones are hydrophobic
group and one MIT group combine, the result is messengers
3,5,3′-triiodothyronine, called T3. Collectively, T3 The hydrophobic thyroid hormones are carried in
and T4 are called the thyroid hormones. At this the blood bound to a carrier protein, and bind to an
point, the T3 and T4 are still part of the thyroglob- intracellular receptor in the target cell. Like all in-
ulin protein, which is packaged into vesicles. The tracellular receptors for chemical messengers, the
vesicles then fuse with the lysosome, an organelle thyroid-hormone receptor acts as a transcription
that contains proteinases (or proteases). The pro- factor when bound to thyroid hormone, altering
teinases digest the thyroglobulin, releasing the T3 the transcription of target genes. Thus, although
and T4. thyroid hormones are derived from a protein, they
129
behave more like steroid hormones than like pep- aspirin and ibuprofen) work by blocking
tide hormones. Thyroid hormones play an impor- prostaglandin synthesis.
tant role in setting metabolic rate and regulating Eicosanoids can also function as neurotrans-
body temperature in mammals. mitters. For example, one of the eicosanoids is
thought to bind to the cannabinoid receptor in the
brain. These receptors were so-named because
they also bind to the drug tetrahydrocannabinoid
Other Classes of Messenger (THC), a lipid that is the bioactive component of
All hormones are peptides, steroids, or amines, but the marijuana plant, Cannabis sativa.
a number of other classes of molecules can act as
neurotransmitters or paracrine chemical messen-
Nitric oxide is a gaseous chemical
gers, including certain lipids, purines, and even
messenger
gases. Many of these molecules have only recently
been identified as important chemical signaling Only three gases are known to act as chemical
molecules, but research in these areas is extremely messengers in animals: nitric oxide, carbon
active, because these molecules are involved in monoxide, and hydrogen sulfide. Nitric oxide
many important disease-related processes in hu- (NO) was the first gas identified as a chemical
mans, including inflammation, pain, and vascular messenger, and a great deal is now known about
disease. its mechanisms of action. Nitric oxide is produced
by the enzyme nitric oxide synthase (NOS), which
catalyzes the reaction of the amino acid arginine
Eicosanoids are lipid messengers with oxygen to produce nitric oxide and citrulline
A class of lipids known as the eicosanoids can act (another amino acid). Animals have several iso-
as neurotransmitters and paracrine chemical mes- forms of NOS, some of which are inducible (syn-
sengers. The hydrophobic eicosanoids diffuse out of thesized in response to specific signals), and some
the membrane of the signaling cell and diffuse to the of which are consititutive (present all the time).
target cell, where they bind to transmembrane re- Like the eicosanoids, nitric oxide has an ex-
ceptors. Most eicosanoids have an extremely short tremely short half-life (2–30 seconds) in extra-
half-life in extracellular fluids, and degrade within a cellular fluids and thus can act as a paracrine
few seconds. As a result, they
cannot be transported across
Membrane
long distances, and thus cannot phospholipid
act as hormones. Most Phospholipase A2
eicosanoids are derivatives of
COOH
arachidonic acid, a 20-carbon
fatty acid common in plasma Arachidonic acid
membrane phospholipids. The
pathway for eicosanoid synthe- Cyclooxygenase Lipoxygenase
pathway pathway
sis is shown in Figure 10.
Eicosanoid synthesis proceeds
through either the lipoxygenase Prostaglandins Leukotrienes
pathway, which produces the Prostacyclins
Thromboxanes O
leukotrienes and lipoxins, or the O COOH
COOH
cyclooxygenase pathway, which
CH3
produces prostaglandins, pro- O
stacyclins, and thromboxanes. OH
Prostaglandins are one of the Example: prostaglandin H2 Example: leukotriene A4
most studied groups of
eicosanoids because they are in- Figure 10 Synthetic pathway for eicosanoids Phospholipase A2
catalyzes the conversion of membrane phospholipids into arachidonic acid, the
volved in pain perception. Many substrate for eicosanoid synthesis. The cyclooxygenase pathway produces
common painkillers (including prostaglandins, prostacyclins, and thromboxanes. The lipoxygenase pathway produces
leukotrienes.
130
messenger or neurotransmitter but cannot act as transmembrane receptors known as purinergic

a hormone. Nitric oxide plays a critical role in reg- receptors.
ulating many physiological functions because it is
a vasodilator. It causes the smooth muscle around
blood vessels to relax, increasing the diameter of
the blood vessel and causing more blood to flow Communication of the Signal
into the local area. Nitric oxide is also important to the Target Cell
for paracrine communication in the immune Each of the classes of chemical messengers de-
system. scribed above exerts its effects by binding to a re-
Because it is a gas, nitric oxide can freely dif- ceptor protein. When a ligand binds to its receptor,
fuse across the cell membrane from the signaling the receptor undergoes a conformational change.
cell to the target cell. Nitric oxide can act within This change in the shape of the receptor sends a
the cell in several ways. One important action of signal to the target cell. Hydrophilic ligands bind
nitric oxide is to activate the intracellular enzyme to transmembrane receptors, and the conforma-
guanylate cyclase. Guanylate cyclase catalyzes the tional change of that receptor communicates the
formation of cyclic cGMP, which then activates a signal to the inside of the cell without the need for
specific protein kinase, which goes on to phos- the ligand to cross the membrane. Hydrophobic
phorylate a variety of target proteins. The cGMP ligands can either bind to transmembrane recep-
produced by guanylate cyclase is quickly removed tors, or pass through the membrane of the target
from the cell by a series of enzymes termed phos- cell and bind to intracellular receptors. Because
phodiesterases (PDE), thus terminating the nitric intracellular receptors are located within the cell
oxide signal. Drugs such as Viagra block the iso- (either in the cytoplasm or nucleus), changes in
form of PDE that is found in the smooth muscle the shape of intracellular receptors can easily be
cells surrounding blood vessels of the penis. Block- communicated to other biochemical pathways in-
ing PDE results in prolonged elevation of cGMP side the cell.
within the cell, causing the cells to relax and the
blood vessels to vasodilate. The net result of this
vasodilation is increased blood flow to the penis, Ligand-receptor interactions are specific
which is necessary to sustain erection. Ligand-receptor interactions are extremely spe-
cific, because the ligand-binding site of a receptor
has a particular shape, allowing only molecules
Purines can act as neurotransmitters sharing related structures to bind efficiently to the
and paracrines receptor. Just as only the correctly shaped key will
A variety of purines including adenosine, adeno- open the lock on your door, only the correctly
sine monophosphate (AMP), adenosine triphos- shaped ligand can bind to a given receptor (Figure
phate (ATP), and the guanine nucleotides are 11a). Some chemicals with structures similar to
known to act as neurotransmitters, neuromodu- the natural ligand can mimic the action of a ligand
lators, or paracrines. A neuromodulator is a cellu- on its receptor. Chemicals that bind to and activate
lar signaling molecule that alters the activity of receptors are termed receptor agonists (Figure
other signaling molecules, such as neurotransmit- 11b). Chemicals that bind to but do not activate re-
ters. Purines have a very wide range of functions. ceptors are termed receptor antagonists (Figure
For example, adenosine acts on the immune sys- 11c). Many drugs are receptor agonists or antago-
tem to promote wound healing, can change the nists. For example, tubocurarine is a plant com-
rhythm of the heartbeat in vertebrates, and is a pound that is the active ingredient in poison darts
potent calming neurotransmitter in the brain. used by South American indigenous hunters to
Purines are released from signaling cells via a va- paralyze their prey. Tubocurarine binds to a re-
riety of mechanisms. Adenosine can be moved ceptor at the neuromuscular junction. Because
across the membrane by specific proteins termed tubocurarine is a receptor antagonist, binding of
nucleoside transporters. Other purines are packaged tubocurarine blocks the receptor, which prevents
into secretory vesicles, often along with other classes communication from nerves to muscles and
of neurotransmitters, and released by exocytosis. causes paralysis.
When involved in cellular signaling, purines bind to
131
Ligand Nonligand
The hundreds of chemical messengers found
in animals can be used in millions of combina-
Ligand binds Nonligand
tions. But any given cell responds to only a fraction
to receptor cannot bind of these signals, depending on the types of recep-
to receptor tors that are present in the cell. Although no cells
in the body are capable of responding to all possi-
ble ligands, most cells express receptors for many
types of ligands. It is the particular combination of
Response No response
receptors expressed by a cell that generates the
(a) Ligand binding causes a response specificity of cellular responses to different combi-
nations of chemical signals.
Natural ligand Agonist
Receptors have several domains
Ligand binds Agonist
to receptor binds to Receptors are large proteins that are composed
receptor of several domains. The ligand-binding domain
contains the binding site for the chemical mes-
senger. The remaining domains of the protein
convey its functional activity by interacting with
Response Response
signal transduction molecules within the cell.
(b) Agonist binding causes a response The structure of the ligand-binding domain de-
termines the nature of the ligands that can inter-
act with the receptor. The remaining functional
Natural ligand Antagonist domains determine the nature of the effects of
that receptor on the target cell. For many recep-
Ligand binds Antagonist tors it is possible to construct recombinant pro-
to receptor binds to
receptor teins with the ligand-binding domain of one
receptor and the functional domains of another.
The types of functional domains present in the
recombinant protein determine the nature of the
Response No response response in the target cell, not the type of ligand-
binding domain.
(c) Antagonist binding does not cause a response
Figure 11 Ligand-receptor interactions

A ligand is a small molecule that binds specifically to a larger A ligand may bind to more than one
macromolecule such as a receptor, causing a response in the receptor
target cell. Both agonists and antagonists can bind to a
receptor, but only agonists cause a response. Many receptors are part of large gene families.
These genes are transcribed into similar proteins,
termed isoforms, with distinct properties. Recep-
Receptor type determines the cellular tor isoforms often share similar ligand-binding
response domains, but differ in their functional domains.
A target cell can respond to a ligand only if the ap- The presence of these isoforms allows the same
propriate receptor is expressed on or in the target signaling molecule to have very different effects on
cell. Two cells side by side in the body may be different target cells. For example, epinephrine
bathed in a chemical signal, but only the cell that causes the smooth muscle cells surrounding the
possesses the appropriate receptor will respond. bronchioles of the lung to relax, but causes the
Thus, chemical signaling is a bit like a radio sig- smooth muscle cells surrounding the blood vessels
nal. Two people jogging side by side along a city leading to the intestine to contract. The smooth
street are both exposed to radio waves, but only muscle cells in these different locations express
the person who has a portable radio (the appropri- different adrenergic receptor isoforms (different
ate receptor for radio waves) will receive the infor- versions of the receptor for epinephrine).
mation signal carried by the broadcast.
132
Ligand-receptor binding obeys the law The number of receptors on a target cell can
of mass action change over time. These effects can easily be ob-
served following the administration of certain
Like the binding of chemical messengers to their
drugs. For example, opiate drugs (opium, mor-
carrier proteins, ligand-receptor interactions are
phine, codeine, and heroin) bind to and activate
governed by the law of mass action. Natural lig-
opiate receptors that are found on cells through-
ands usually bind reversibly to their receptors;
out the body, and particularly in the brain. The
thus, the following equation represents the bind-
normal function of these receptors is to induce
ing of a ligand to its receptor:
pleasure and block pain. When a person regularly
L ⫹ R Δ L-R → response consumes a drug such as heroin, the number of
where L is the free ligand, R is the receptor, and opiate receptors on the target cells decreases in an
L-R is the bound ligand-receptor complex. Binding attempt to reduce the intensity of the pleasure
of the ligand to its receptor causes a response in the signal and maintain homeostasis—a phenome-
target cell. As ligand concentration increases, the non termed down-regulation. As a result,
balance shifts to the right, and the proportion of re- heroin users must consume more and more of
ceptor bound to ligand increases. The more recep- the drug in order to achieve the same effects.
tor that is bound to ligand, the greater the response When a habitual heroin user stops taking the
in the target cell. However, the amount of ligand drug, the low levels of opiate receptors in the
bound to the receptors on a cell cannot increase in- brain reduce the brain’s sensitivity to endor-
definitely. Instead, the receptors eventually be- phins, the natural ligands of the opiate receptors.
come saturated with ligand, once all the available The reduced signal from the endorphins causes
receptors are bound to ligand (Figure 12). Once the withdrawal symptoms, including nausea, vomit-
saturation point is reached, adding more ligand ing, muscle pain, and bone pain, when an ad-
will not increase the response in the target cell. dicted individual stops taking the drug. After a
period of time without heroin, receptor number
returns to normal, and the withdrawal symptoms
Receptor number can vary gradually abate.
Target cells vary in the number of receptors they Receptors can also be up-regulated. For ex-
possess. The more receptors on a cell, the more ample, caffeine (the active ingredient in coffee)
likely it is that a ligand will bind to the receptor at any binds to receptors for the neurotransmitter adeno-
given concentration of ligand (Figure 13a), and the sine. Adenosine is an inhibitory neurotransmitter,
greater the response in the target cell. Target cells so when it binds to its receptor it tends to reduce
with high concentrations of receptors will be more brain activity, producing a calming effect. Caffeine
sensitive to the presence of the ligand than target is an antagonist for these receptors, binding but
cells with lower concentrations of the receptor. not activating them. The net result is that caffeine
acts as a stimulant by removing the calming ef-
fects of adenosine. The brain responds to the re-
Percentage of receptors bound
moval of this calming signal by increasing the

100
number of adenosine receptors on these brain
cells. Up-regulation results in increased sensitivity
All available to the naturally occurring adenosine, and thus
receptors bound
(saturated)
homeostatically regulates brain activity, restoring
brain activity to normal by balancing out the effects
of the ingested caffeine. As a result of this up-
regulation, coffee drinkers must drink more and
more coffee over time to obtain the same stimula-
tory effect. A habitual coffee drinker may need sev-
Concentration of messenger [M]
eral cups of coffee just to fully wake up in the
Figure 12 Effects of messenger concentration morning because they need higher levels of caffeine
As messenger concentration increases, the percentage of
to cancel out the effects of adenosine on their highly
receptors bound to messenger increases up to the
saturation point, at which all available receptors are bound sensitive up-regulated target cells. If a habitual
to messenger. coffee drinker attempts to suddenly stop drinking
133
Receptor affinity for ligand can vary

100 Many receptors Receptors can also vary in the strength with
per cell
Number of receptors bound
which they bind a ligand. The strength of

binding between a ligand and a receptor
can be expressed using the dissociation
60 Fewer receptors
constant (Kd) for that receptor. The disso-
per cell ciation constant is defined as the concen-
50 tration of messenger at which half of the
receptors on the cell surface are bound to
30
ligand (Figure 13b). Thus receptors with
high affinity have a low dissociation con-
stant, and receptors with low affinity have
Concentration of messenger [M] a high dissociation constant. Alternatively,
we can express the strength of receptor-
(a) Effect of receptor concentration
ligand interactions with the affinity con-
stant (Ka), which is defined as the inverse
High-affinity receptor of the dissociation constant (or the inverse
100
of the concentration of messenger at which
Percentage of receptors bound
half of the receptors are bound). The larger

the Ka value, the higher the affinity, and the
more tightly the ligand binds to the recep-
Low-affinity receptor
tor. Figure 13b illustrates the effects of dif-
ferences in the affinity constant. A
50 high-affinity receptor causes greater activ-
ity in the target cell at low-ligand concen-
tration than does a low affinity receptor.
High-affinity receptors also saturate at
lower ligand concentrations.
Kd Kd The affinity constants of some hor-
Concentration of messenger [M] mone receptors are very large (>108 l/mol).
(b) Effect of receptor affinity
Thus, a receptor can bind to these messen-
gers even when they are present at very
Figure 13 Effects of receptor concentration and affinity low concentrations. In contrast, the affinity
on the percentage of bound receptors (a) Cells that have a higher
concentration of receptors have a larger number of bound receptors at any
constants for some neurotransmitter and
given concentration of messenger, and these cells respond to the messenger paracrine receptors are lower (˜104 l/mol),
more strongly than cells with fewer receptors. (b) At a given concentration requiring higher concentrations of messen-
of messenger, cells with high-affinity receptors have a higher percentage of ger to stimulate their receptors.
bound receptors, and a greater response than cells with low-affinity
receptors, as long as the messenger concentration is low. At messenger
concentrations where all receptors are saturated, there is no difference in
response between the cells if the total number of receptors is similar. The Ligand signaling must be inactivated
dissociation constant (Kd), or the concentration of messenger at which the
receptor is 50% saturated, is an indication of the affinity of the receptor for As long as a ligand remains bound to its re-
the messenger. Receptors with high Kd have low affinity for the messenger, ceptor, it will continue to activate that recep-
whereas receptors with low Kd have high affinity for the messenger. tor and cause a response in the target cell.
Alternatively, affinity can be expressed using the affinity constant (Ka), which
is the inverse of Kd. This signal must be terminated in order for
the body to be able to respond to changing
conditions. The activity of ligand-receptor
coffee, the high levels of adenosine receptor in the complexes can be regulated in a variety of ways
brain cause these individuals to be unusually sen- (Figure 14). The simplest way to terminate signal-
sitive to naturally occurring adenosine in their sys- ing is to remove the ligand from the extracellular
tem, and thus they will tend to feel sleepy without fluid. For example, enzymes in the liver and kidney
their morning coffee. degrade many circulating hormones. When hor-
134
Circulatory system mone levels fall in the blood, they will also fall in the
Ligand fluid surrounding a cell, causing bound hormone to
Receptor dissociate from its receptor (according to the law of
Degradation
of ligand in mass action). When the receptor is no longer bound
liver or kidney
to the hormone, signaling terminates.
Membrane of target cell Removal of a hormone from the blood is a rela-
(a) Ligand removed by distant tissues tively slow process, requiring several minutes to
hours. Most signaling molecules must be regulated
over much shorter time periods. These molecules
Ligand Endocytosis can be inactivated or removed in several ways. Ad-
Receptor jacent cells can take up signaling molecules from
the extracellular fluid, thus reducing the concentra-
Membrane Membrane of
tion of the signaling molecule and causing them to
of target cell adjacent cell dissociate from the receptor. This is a common
(b) Ligand taken up by adjacent cells mechanism for the removal of neurotransmitters
from the synapse. This process is the target of a
number of drug therapies. For example, drugs
Ligand Enzymatic called selective serotonin reuptake inhibitors
Receptor digestion (SSRIs) inhibit the reuptake of serotonin from the
Degraded synapse, increasing the concentration of serotonin
ligand
in the synapse, which causes increased binding of
serotonin to its receptors. SSRIs are commonly used
Membrane of target cell
to treat depression. An alternative means of remov-
(c) Ligand degraded by extracellular enzymes
ing a signaling molecule from its receptor is to use
enzymes that degrade the signaling molecule. The
ligand-receptor complex can also be removed from
Degraded receptor Receptor
and ligand
Ligand the membrane by endocytosis. Internalized recep-
tors can then either be degraded (resulting in re-
ceptor down-regulation) or recycled to the cell
Endocytosis membrane, once the ligand has been removed. In-
Membrane of target cell tracellular enzymes can degrade hydrophobic
(d) Ligand-receptor complex removed by endocytosis chemical messengers that diffuse into cells. Recep-
tors can also be inactivated by phosphorylation or
Ligand other similar mechanisms. Inactivation of compo-
Receptor
nents of the signaling pathways within the cell that
Phosphorylation Membrane of are stimulated by ligand-receptor complexes can
target cell also be used to terminate signaling.
(e) Receptor inactivation

2 C O NC E P T C H E CK
Ligand
1. Compare and contrast hydrophilic and
Receptor hydrophobic messengers in terms of the three
main steps of indirect signaling.
Membrane of
target cell 2. Are amines hydrophilic or hydrophobic
Inactivated intracellular messengers? How does this affect their release,
signaling protein
transport, and signaling?
3. Why do some cells respond to a chemical
(f) Inactivation of signal transduction pathway messenger while other cells ignore it?
Figure 14 Termination of ligand-receptor 4. Compare and contrast receptor up-regulation
signaling and down-regulation. How do these phenomena
help to maintain homeostasis?
135
Signal Transduction Pathways Extracellular fluid
Ligand binds to receptor,

So far, we have seen that the type and concentra- causing conformational change
tion of both the ligand and receptor can affect the
response of the target cell, but we have not yet dis-
cussed the details of how the binding of the ligand
to the receptor causes a response in the target cell.
When a ligand binds to a receptor, the receptor un- Inactive Active
dergoes a conformational change. But how does a substance A substance A
simple signal like the change in the shape of a pro-
tein get converted into a complex response in the
target cell? The cell uses signal transduction path- Inactive Active
ways to convert the change in the shape of a re- substance B substance B
ceptor to a complex response. Transducers are

devices that convert signals from one form to an-
other. Signal transduction in the cell is analogous Inactive Active
substance C substance C
to signal transduction in familiar transducing de- Cytoplasm
vices like a radio. All transducers have four impor-
tant components: a receiver, a transducer, an Figure 15 Amplification by signal transduction
amplifier, and a responder. In the cell, the ligand- pathways When a single molecule of ligand binds to a
single receptor, the receptor undergoes
binding domain of the receptor acts as a receiver, a conformational change. The change in shape of the
receiving the signal by binding to the incoming receptor converts inactive substance A to active substance A.
chemical messenger. The ligand-binding domain, As long as the ligand remains bound to the receptor, it will
together with other domains within the receptor, continue to activate substance A. Thus, a single molecule
of ligand can activate many molecules of substance A.
acts as a transducer by undergoing a conforma-
Substance A then goes on to activate substance B, and so on
tional change that activates a signal transduction down the chain. At each step, one molecule of a substance
pathway. The signal transduction pathway acts as can activate many molecules of the next substance in the
an amplifier, increasing the number of molecules chain. Thus, signal transduction cascades can greatly amplify
the signal.
affected by the signal.
All signal transduction pathways have the
same general structure (Figure 15). When a lig-
and binds to its receptor, the receptor undergoes Cells have many signal transduction path-
a conformational change. The conformational ways, some of them very complex. In your course
change in the receptor acts as a signal that con- you will focus on the signal transduction path-
verts an inactive substance (A) to its active form. ways that are the most important in regulating
The activated substance A in turn activates sub- physiological processes. These signal transduc-
stance B, which activates substance C, and so on, tion pathways are associated with intracellular
until the end of the cascade. The change in con- receptors, ligand-gated ion channels, receptor-en-
formation of a single receptor caused by the bind- zymes, and G-protein-coupled receptors (Figure
ing of a single molecule of chemical messenger 16). As the name suggests, intracellular recep-
can result in the conversion of many molecules of tors are located inside the cell, and interact with
substance A to their active forms. Each one of hydrophobic chemical messengers. Hydrophilic
these many molecules of substance A can then go chemical messengers generally interact with
on to activate many molecules of substance B, transmembrane receptors. Ligand-gated ion
and so on down the chain, potentially producing channels initiate a response in the target cell by
millions of molecules of the final product. As a re- changing the ion permeability of the membrane.
sult, signal transduction cascades greatly amplify Receptor-enzymes induce a response by activat-
the original signal caused by binding of a mole- ing or inactivating intracellular enzymes. G-pro-
cule of chemical messenger. The longer the signal tein-coupled receptors send signals to an
transduction cascade, the greater the degree of associated G protein, which then initiates a signal
signal amplification. transduction pathway that causes a response in the
target cell.
136
Intracellular Receptors Extracellular fluid

Ligand- Ligand-
When a ligand binds to an intracellu- binding site binding site
lar receptor, the receptor changes Ligand-
binding site Plasma
shape and becomes activated (Figure membrane
17). Activated intracellular receptors
act as transcription factors that regu-
late the transcription of target genes G protein
by binding to specific DNA se- Ligand-gated Receptor- G-protein-
ion channel enzyme coupled receptor Ligand-
quences, and increasing or decreas- binding
ing mRNA production from the target site
Intracellular
gene. Intracellular receptors have Cytoplasm receptor
three domains: a ligand-binding do-
Figure 16 Types of receptors in animals Some of the physiologically
main, a DNA-binding domain, and important receptors in animals are intracellular receptors, ligand-gated ion channels,
a transactivation domain, each of receptor-enzymes, and G-protein-coupled receptors.
which performs specific steps in sig-
nal transduction. Once a hydropho-
bic ligand has diffused across the cell Extracellular fluid 1 Hydrophobic ligands pass
Ligand through the cell membrane.
membrane, the ligand binds to the
ligand-binding site. Ligand binding
causes a conformational change in 2 Inside the cell, the ligand
the receptor that activates it. Some 1 binds to the ligand-binding
domain of the intracellular
intracellular receptors are located in receptors.
the cytoplasm, and only move to the
Ligand-binding
nucleus once they bind to the ligand. domain
Other intracellular receptors are 3 Ligand binding changes
the shape of the receptor.
found in the nucleus, already bound DNA-binding
domain
to DNA and ready to be activated. 2
The DNA-binding domain of an 4 The receptor-ligand complex
intracellular receptor binds to spe- 3 translocates to the nucleus.
cific sequences, termed responsive
elements, adjacent to their target Cytoplasm
5 The DNA-binding domain of
genes. Because the DNA-binding do- the receptor binds to
main of each intracellular receptor 4
responsive element DNA
sequences, and the
recognizes a specific responsive se- Transactivation transactivating domain
quence, and only the intended target 5 interacts with other
DNA- domain
binding Target gene transcription factors bound
genes contain appropriate respon-
domain in this region.
sive element sequences, intracellular
receptors bind only to their target 6
genes and not to other genes in the Responsive Modulation of 6 Together, these transcription
DNA element transcription factors alter the rate of
genome. Once the receptor is bound Transcription transcription of the target
to the responsive element, the trans- Nucleus factors genes into mRNA.
activation domain of the receptor in-
teracts with other transcription Figure 17 Signal transduction by intracellular receptors
factors to regulate the transcription
of the target genes, increasing or decreasing the The changes in transcription initiated by the
production of mRNA. Together, the DNA-binding binding of a ligand to its receptor set off a cascade
domain and the transactivation domain act as the of events within the target cell (Figure 18). The
transducer in this signal transduction pathway. first step of the response is often activation of a
Many important endocrine hormones bind to intra- small number of specific genes, usually coding for
cellular receptors, including estrogen, testosterone, other transcription factors. The gene products
and the glucocorticoid stress hormones. then go on to activate other genes. This cascade of
137
Receptor while decreasing the transcription of others. In

this way, a hydrophobic ligand can have complex
Target gene A
effects on a target cell. Because these ligands exert
DNA
their effects by altering transcription, the response
mRNA of the target cell is generally slow, with the first ef-
Transcription fects detectable within about 30 minutes and the
secondary effects occurring over hours or days.
Gene product A
(acts as transcription
Hydrophobic ligands can also bind to trans-
factor and regulates membrane receptors, in which case the responses
multiple genes) within the target cell are very rapid, because they do
not rely upon transcription. However, the specific
signal transduction pathways involved in these rapid
non-genomic responses are not well understood.
Ligand-Gated Ion Channels

Signal transduction by ligand-gated ion channels
is relatively simple and direct compared to signal
transduction by other receptors. When a ligand
Effects on multiple biochemical pathways
binds to a ligand-gated ion channel, the protein
undergoes a conformational change, opening an
Figure 18 Transcriptional cascades initiated by ion channel within the protein—a route for ions to
intracellular receptors In the first step of signal move across the cell membrane (Figure 19). When
transduction by intracellular receptors, the messenger- the ion channel opens, ions move into or out of the
receptor complex binds to target gene A, altering its
transcription. The product of target gene A then goes on to cell, as dictated by their electrochemical gradients,
interact with DNA and regulate the transcription of additional altering the membrane potential of the cell. The
genes. The products of these additional genes may also act resulting change in membrane potential acts as a
as transcription factors or go on to have effects on many signal within the target cell. Changes in mem-
biochemical pathways.
brane potential as a result of the opening of lig-
gene regulation acts as the amplifier in the signal and-gated ion channels are very rapid, and a
transduction pathway. The interactions between single molecule of chemical messenger can open
activated intracellular receptors and transcription an ion channel that could allow many individual
factors vary among genes, and the same receptor ions to cross the cell membrane, allowing for some
may increase the transcription of some genes signal amplification.
Extracellular fluid
Ions cannot Ions can cross Signal Transduction via

cross the membrane the membrane
Receptor-Enzymes
Ligand-binding Ligand-binding
site (unoccupied) site (occupied) Receptor-enzymes contain an extra-
cellular ligand-binding domain, a
Plasma
membrane transmembrane domain, and an in-
tracellular catalytic domain (Figure
Ion channel Ion channel 20a). The ligand-binding domain
closed open
contains a region that binds specifi-
Cytoplasm
cally to a chemical messenger. When
(a) Unbound ligand-gated ion channel (b) Bound ligand-gated ion channel ligand binds to the ligand-binding do-
main, the receptor changes shape,
Figure 19 The structure and function of ligand-gated ion channels
and the transmembrane domain
(a) When no ligand is bound to the receptor, the ion channel is closed and ions cannot
cross the membrane. (b) When a ligand binds to the ion channel, the channel changes transmits this shape change across
conformation and the ion channel opens, allowing ions to cross the membrane. the membrane, activating the cat-
138
Extracellular fluid
Guanylate Tyrosine Serine/threonine
cyclase kinase kinase
Ligand-
binding
domain
Trans-
Plasma
membrane
membrane
domain
Catalytic
domain
Tyrosine Serine or
GTP cGMP threonine P Serine
Pi i P
or
Tyrosine P threonine P
Cytoplasm
(a) Structure of a receptor-enzyme (b) Types of receptor-enzymes
Figure 20 Receptor-enzymes (a) Structure of a receptor-enzyme. A receptor-enzyme

has an extracellular ligand-binding domain, a transmembrane domain, and an intracellular
catalytic (enzyme) domain. (b) Three types of receptor-enzymes in animals. Receptor guanylate
cyclases convert GTP to cGMP. Receptor tyrosine kinases phosphorylate tyrosine residues in
proteins. Receptor serine/threonine kinases phosphorylate serine or threonine residues in
proteins.
alytic domain of the enzyme. The catalytic domains Extracellular fluid 1 Ligand binds to a
of receptor-enzymes act as enzymatic catalysts that Ligand receptor guanylate
initiate the next link in the signal transduction cas- cyclase, changing
1 its conformation.
cade. The signal transduction pathways of receptor-
enzymes involve phosphorylation cascades in which
proteins at each step phosphorylate or dephospho-
rylate other proteins within the target cell. Phospho- Plasma 2 The activated
receptor catalyzes
rylation cascades amplify the original signal, causing membrane
the conversion of
a response in the target cell. GTP to cGMP.
Receptor-enzymes are named based on the re- Receptor
guanylate
action catalyzed by the intracellular catalytic do- cyclase
main.We discuss three types of receptor-enzymes: GTP 2
3 The cGMP acts
(1) receptor guanylate cyclases, (2) receptor tyro- as a second
cGMP
sine kinases, and (3) receptor serine/threonine messenger, and
3 binds to binds to PKG.
kinases (Figure 20b). In animals, the majority of
known receptor-enzymes are tyrosine kinases.
Animals also have many forms of receptor PKG
4
serine/threonine kinase, some of which play im- 4 The activated
portant roles in growth and development and in Serine or Pi Serine P G-kinase
threonine or phosphorylates
the response to environmental stressors. Only a in proteins threonine P proteins on serine
few receptor guanylate cyclases are known. in proteins or threonine
Cytoplasm residues.
Receptor guanylate cyclases generate Figure 21 Signal transduction via guanylate

cyclic GMP cyclase receptor-enzymes
When a ligand binds to a receptor guanylate cy- phate (cGMP). The cGMP acts as a second messen-
clase, the receptor undergoes a conformational ger within the cell. Second messengers are low-
change, activating the guanylate cyclase domain of molecular-weight diffusible molecules that act as
the receptor (Figure 21). The activated guanylate part of signal transduction pathways to communi-
cyclase produces cyclic guanosine monophos- cate signals within the cell. The second messenger
139
cGMP binds to and activates a protein called eration, such as insulin, epidermal growth factor,
cGMP-dependent protein kinase (PKG). Kinases and vascular endothelial growth factor. When a
are enzymes that phosphorylate other proteins. chemical messenger binds to a receptor tyrosine
PKG phosphorylates proteins at serine or threo- kinase, the bound receptor associates with other
nine residues. The phosphorylated proteins then tyrosine kinase receptors in the membrane to form
go on to activate other proteins, propagating and dimers (Figure 22). The dimerized receptors then
amplifying the signal through the cell. Many of phosphorylate each other on multiple tyrosine
these downstream proteins are also protein ki- residues, a process called autophosphorylation.
nases that phosphorylate other proteins. Thus, the The phosphorylated receptors interact with and
signal transduction pathway initiated by receptor activate one of many intracellular signaling mole-
guanylate cyclases is termed a phosphorylation cules, most of which are protein kinases.
cascade. Each step in this cascade acts to amplify In the case of the growth factor receptors,
the original signal from the receptor. these activated kinases signal to the Ras protein,
The receptors for atrial natriuretic peptides which acts as the next step in the signal transduc-
(ANPs) are the best-characterized class of receptor tion pathway. Ras proteins bind to and hydrolyze
guanylate cyclases. ANPs are a group of closely re- GTP and function as switches by cycling between
lated peptides that are produced by muscle cells in the active state, when GTP is bound, and the inac-
the heart in response to increases in blood pres- tive state, when GDP is bound. GTPase-activating
sure. ANPs trigger vasodilation and induce the proteins (GAPs) and guanine nucleotide–releasing
kidney to reduce blood volume. Both of these re- proteins (GNRPs) catalyze the transition between
sponses lower blood pressure, returning it to nor- active and inactive Ras. Receptor tyrosine kinases
mal. Thus, ANPs are part of the negative feedback signal through GAPs and GNRPs to regulate Ras.
system that homeostatically regulates blood pres- Ras activates a serine/threonine phosphoryla-
sure. tion cascade that sends a signal through the cell.
There are many serine/threonine phosphorylation
cascades in animal cells, but one particularly impor-
Receptor tyrosine kinases signal tant one involves the MAP kinases (Figure 23). Acti-
through Ras proteins vated Ras signals to a MAP-kinase-kinase-kinase
There are more than 50 known receptor tyrosine (MAPKKK), which phosphorylates a MAP-kinase-
kinases, most of which bind to chemical messen- kinase (MAPKK). In turn, the MAP-kinase-kinase
gers that are critical for cellular growth and prolif- phosphorylates a MAP kinase (MAPK). The MAP
Extracellular fluid 1 Ligand binds to receptor.
Ligand
1 2 Receptors dimerize and

2 autophosphorylate.
Plasma membrane 3 Phosphorylated receptors

interact with protein kinases.
GAP
P P Ras Ras
4 5
P P Kinases
P P GNRP
3 4 Protein kinases signal to Ras
GDP GTP
Receptor protein.
tyrosine (Inactive) (Active)
kinase
5 Ras switches between the

Cytoplasm Response active and inactive forms.
Figure 22 Signal transduction via receptor tyrosine kinases
140
Extracellular fluid
other tyrosine kinase receptors, the insulin recep-
tor functions as a dimer. Binding of insulin to the
Plasma membrane extracellular ligand-binding domain (also called the
alpha subunit) causes the receptor to dimerize.
Ras Cytoplasm Dimerization causes the intracellular domains (also
called the beta subunits) to autophosphorylate each
Stimulates
GTP other on their tyrosine residues and become active.
The intracellular domains of the receptor dimer
also act as a tyrosine kinase that phosphorylates
MAPKKK MAPKKK P other target proteins on their tyrosine residues. The
Phosphorylates best-known target of the insulin receptor is called
Pi the insulin receptor substrate (IRS). The insulin re-
ceptor substrate acts as a docking protein that
MAPKK MAPKK P binds to other intracellular signaling proteins that
Phosphorylates participate in insulin signal transduction.
Pi
MAPK MAPK P Receptor serine/threonine kinases directly

activate phosphorylation cascades
Phosphorylates
Receptor serine/threonine kinases directly acti-
Pi
vate phosphorylation cascades, without working
through Ras proteins. When a ligand binds to a re-
Other protein kinases, ceptor serine/threonine kinase, the conforma-
transcription factors,
and cellular proteins tional change in the receptor directly activates a
serine/threonine kinase (Figure 24a). The acti-
vated serine/threonine kinase then phosphory-
Figure 23 Signal transduction via the MAP-
kinase phosphorylation cascade The Ras proteins lates other proteins, activating a phosphorylation
that are activated by receptor tyrosine kinases phosphorylate cascade. The signaling pathways activated by re-
MAP-kinase-kinase-kinase, and the phosphorylated MAPKKK ceptor serine/threonine kinases are not yet fully
then phosphorylates a MAP-kinase-kinase, which in turn understood, but are similar to the pathways used
phosphorylates a MAP kinase, which then phosphorylates
other protein kinases, transcription factors, and diverse
by receptor tyrosine kinases in that they involve
cellular proteins. phosphorylation cascades that greatly amplify the
signal in the target cell.
kinase then phosphorylates other protein kinases, The transforming growth factor ␤ (TGF-␤) re-
cellular proteins, and the transcription factors Elk-1 ceptors are among the most intensively studied re-
and Jun. These transcription factors regulate the ceptor serine/threonine kinases, because mutations
transcription of other transcription factors, which in TGF-␤ receptors and the associated signal
regulate the transcription of various genes. Thus, transduction pathways have been implicated in
the phosphorylation cascades triggered by recep- the development of human cancers. TGF-␤ recep-
tor tyrosine kinases greatly amplify the original tors are present as a complex consisting of two
chemical signal. Because they activate extensive distinct proteins, called TGF-␤ Type I and Type II
phosphorylation cascades within the cell, the Ras receptors (Figure 24b). When TGF-␤ binds, the
proteins have wide-ranging effects on cellular Type I and Type II receptors associate with each
growth and metabolism. Approximately 30% of other. The Type II receptor then phosphorylates
human cancers involve mutations in the genes en- the Type I receptor, activating the intracellular cat-
coding Ras. These mutations turn the Ras protein alytic domain of the Type I receptor. The catalytic
“on” constitutively so that it is active even in the domain of the activated Type I receptor then phos-
absence of a ligand. The activated Ras sends a phorylates a series of target proteins called SMADs
strong signal to the cell, stimulating it to grow and on specific serine and threonine residues. The
divide uncontrollably, causing cancer. phosphorylated SMADs move to the nucleus where
The insulin receptor is another example of a they interact with other proteins to regulate the
critically important tyrosine kinase receptor. Like transcription of target genes.
141
Extracellular 1 Ligand binds to a receptor

control many critical physiological
fluid
Ligand
serine/threonine kinase, functions, and there is enormous di-
changing its conformation. versity in these receptors and the
1 signal transduction pathways with
which they interact (see Box 2, Evo-
2 The conformational
change activates the lution and Diversity: G-Protein-Cou-
serine/threonine kinase pled Receptors). All of these
domain of the receptor.
Plasma receptors, however, share a com-
membrane
mon first step in their signal trans-
Receptor
2 3 The serine/threonine duction pathways: activation of one
serine/
threonine-
kinase phosphorylates of the members of the
proteins on serine or
kinase
threonine residues.
heterotrimeric G protein family.
Heterotrimeric G proteins are
Intracellular Intracellular
named for their ability to bind and
proteins proteins P hydrolyze GTP, and the fact that
they are composed of three differ-
Cytoplasm ent subunits (␣, ␤, and ␥). The ␣
(a) General structure of receptor serine/threonine kinase
subunit contains the binding sites
for the guanosine nucleotides,
while the ␤ and ␥ subunits are
Extracellular 1 Ligand binds to the Type I
fluid TGF–β receptor. tightly bound to each other, and
Ligand usually referred to as a single func-
tional group, the ␤␥ subunit. The
1 2 2 The bound receptor general features of the signaling
dimerizes with the
Type II receptor.
pathways from G-protein coupled
receptors via G proteins to amplifier
Plasma enzymes are outlined in Figure 25.
membrane
3 The Type II receptor When a ligand binds to a G-protein-
Type II phosphorylates the Type I
P 3 receptor
coupled receptor, the receptor
receptor, activating it.
Type I changes shape, sending a signal to
P Type I
receptor receptor the ␣ subunit of the G protein, in-
4
4 The activated receptor ducing a conformational change in
phosphorylates a SMAD the G protein. The conformational
SMAD protein.
SMAD P change causes the ␣ subunit of the
G protein to release GDP, bind a
molecule of GTP, and become ac-
5 5 The activated SMADs
enter the nucleus and tive. The activated ␣ subunit then
Cytoplasm regulate gene expression. dissociates from the ␤␥ subunit.
SMAD P Both the ␤␥ and ␣ subunits can then
Nucleus go on to interact with downstream
targets.
DNA
The best-characterized targets
(b) Signal transduction by TGF-β receptors of the ␤␥ subunit are ion channels.
Figure 24 Signal transduction via receptor serine/threonine Interaction with the ␤␥ subunit
kinases causes these ion channels to open,
allowing ions to move into or out of
the cell, depending on their electrical and con-
Signal Transduction via G-Protein- centration gradients. Ion movements cause
Coupled Receptors changes in membrane potential, which act as
G-protein-coupled receptors are a large family of signals within the cell. Thus, G protein signaling
membrane-spanning proteins with seven trans- via ion channels is a relatively direct pathway to
membrane domains. G-protein-coupled receptors generate a response in the cell.
142
Extracellular 1 Ligand binds to a G-protein-

fluid Ligand coupled receptor, causing a
G-protein conformational change.
1 Receptor
α or βγ
G protein subunit Amplifier
(inactive) (active) enzyme 2 The activated receptor signals to
an associated G protein, causing
Plasma
3 the α subunit to release GDP and
membrane bind GTP.
γ Subunit
GTP 4
β Subunit 3 The activated α or βγ subunits
2
move through the membrane and
GDP
α Subunit interacts with an amplifier enzyme.
Inactive Active
second second
messenger messenger 4 The activated amplifier enzyme
converts an inactive second
5 messenger into its active form.
Activates
or inhibits
5 The activated second messenger
cellular
activates or inhibits cellular
Cytoplasm pathways
pathways.
Figure 25
Signal transduction via G-protein-coupled receptors

G-Protein-Coupled Receptors
G protein signaling is involved in cell-to- nication in multicellular organisms. The human

cell communication in a wide variety of organ- genome, for example, contains approximately 1000 se-
isms, including fungi, plants, and animals, but the quences related to the G-protein-coupled receptors.
number and diversity of G-protein-coupled receptors Approximately 700 of these are involved in the senses of
have greatly increased during the evolution of the meta- smell and taste, or other chemosensory functions. The
zoans. The single-cell budding yeast Saccharomyces remaining 300 likely interact with chemical signaling
cerevisiae has only three G-protein-coupled receptors, molecules, and are thus involved in cell-to-cell commu-
but even relatively simple metazoans have hundreds of nication. Of the G-protein-coupled receptors that are
different G-protein-coupled receptors. For example, the involved in cell signaling, approximately 140 have no
genome of the nematode Caenorhabditis elegans con- known ligand or function, and are termed orphan
tains almost 1100 different genes with sequences simi- receptors. Evolutionary analyses suggest that all of the
lar to G-protein-coupled receptors. Although we do not G-protein-coupled receptor genes in animals have a
yet know whether all of these sequences encode func- common ancestor, and arose by duplication and descent
tional receptors, it is likely that at least several hundred with modification over evolutionary time to perform dif-
of these genes function in cell-to-cell communication in ferent roles in complex multicellular animals.
nematodes. This high diversity of G-protein-coupled re-
References
ceptors is not unique to nematodes. In fact, in all of the
q Bockaert, J., S. Claeysen, C. Becamel, S. Pinloche, and A. Du-
animal genomes that have been fully sequenced to date,
muis. 2002. G-protein-coupled receptors: Dominant players in
somewhere between 1% and 5% of the entire protein- cell-cell communication. International Review of Cytology 212:
coding part of the genome consists of sequences simi- 63–132.
lar to G-protein-coupled receptors. q Jones, A. M. 2002. G-protein-coupled signaling in Arabidopsis.
G-protein-coupled receptors recognize many differ- Current Opinion in Plant Biology 5: 402–407.
ent ligands and stimuli including light, odors, and q Pierce, K. L., R. T. Premont, and R. J. Lefkowitz. 2002. Seven-
chemical messengers, and thus play an important part transmembrane receptors. Nature Reviews. Molecular Cell Biol-
in both environmental sensing and cell-to-cell commu- ogy 3: 639–650.
143
G proteins can act through Ca2⫹-calmodulin enzyme, either increasing or decreasing its activity
(depending on the particular G protein involved in
If a G protein interacts with and opens a Ca2⫹ chan- the signaling). These amplifier enzymes then go on
nel, the increase in cytoplasmic [Ca2⫹] initiates sig- to initiate signal transduction pathways that result
nal transduction cascades within the target cell. in diverse indirect effects within the target cell.
Most Ca2⫹-mediated signal transduction cascades
act through the protein calmodulin, a Ca2⫹-binding
protein that is present in every eukaryotic cell. Amplifier enzymes alter the concentration
Calmodulin has four binding sites for Ca2⫹. Bind- of second messengers
ing of Ca2⫹ to all four sites activates the protein, Amplifier enzymes catalyze the conversion of a
which then interacts with numerous other pro- small molecule second messenger between its in-
teins. Calmodulin is known to interact with and active and active forms. A single molecule of acti-
regulate over 100 different cellular proteins. One vated amplifier enzyme can catalyze the conversion
important group of these target proteins is a di- of thousands of molecules of second messenger,
verse family of serine/threonine kinases called the greatly amplifying the signal. Second messengers
Ca2⫹-calmodulin-dependent protein kinases (CaM then go on to activate or inhibit a variety of path-
kinases). One of the best-studied examples of a ways within the cell.
CaM kinase is CaM kinase II, which is found in high Despite the enormous diversity of G-protein-
concentration in neurons that secrete neurotrans- coupled receptors, all G proteins act through one of
mitters called catecholamines. When cytoplasmic only four second messengers: Ca2⫹, cyclic GMP,
Ca2⫹ increases in these neurons, the change in Ca2⫹ phosphatidylinositol, and cyclic adenosine mono-
concentration activates CaM kinase II. CaM kinase phosphate (cAMP). Table 3 summarizes the simi-
II phosphorylates tyrosine hydroxylase (one of the larities and differences between these second
key enzymes in catecholamine biosynthesis). CaM messenger cascades. All of these cascades amplify
kinases play many other important roles in ani- the signal within the target cell, inducing responses
mals. For example, one of the CaM kinase genes is that may occur in milliseconds or hours.
implicated in the process of learning and memory.
Transgenic mice that have this CaM kinase gene
Guanylate cyclase generates cGMP
knocked out have altered brain activity and are un-
able to learn how to swim through a water maze. Most of the G proteins that use cGMP as a second
messenger activate the amplifier enzyme guanylate
cyclase, which catalyzes the conversion of GTP to
G proteins can interact with amplifier cGMP. The cGMP then goes on to activate PKG,
enzymes which goes on to phosphorylate many other pro-
In addition to acting via ion channels, the ␤␥ and ␣ teins. In addition, some G-protein-coupled recep-
subunits of G proteins can also interact with a vari- tors use a different signal transduction pathway.
ety of other kinds of target molecules here given the When a ligand binds to these G-protein-coupled re-
generic name “amplifier enzyme.” The activated G ceptors, the ␣ subunit of the associated G protein
protein subunits alter the activity of the amplifier moves laterally through the membrane and binds
Table 3 Second messengers.
Synthesized by
Second messenger the enzyme Action Effects
2⫹
Ca None Binds to calmodulin Alters enzyme activity
cGMP Guanylate cyclase Activates protein kinases Phosphorylates proteins
(usually protein kinase G) Opens and closes ion channels
cAMP Adenylate cyclase Activates protein kinases Phosphorylates proteins
(usually protein kinase A) Opens and closes ion channels
Phosphatidyl inositol Phospholipase C Activates protein kinase C Alters enzyme activity
Stimulates Ca2⫹ release from Phosphorylates proteins
intracellular stores
144
to and activates the amplifier enzyme phosphodi- an electrical signal. This signal transduction path-
esterase. The activated phosphodiesterase cat- way plays a part in vertebrate vision.
alyzes the conversion of cGMP to GMP, causing
cGMP levels in the cytoplasm to drop. The decrease
in cytoplasmic cGMP causes cGMP to dissociate
Phospholipase C generates
from Na⫹ channels in the membrane, closing them.
phosphatidylinositol
The closing of the Na⫹ channels prevents Na⫹ from The inositol-phospholipid signaling pathway
entering the cell, which changes the membrane po- (Figure 26) was first discovered as the signal
tential and thus transduces the chemical signal into
Extracellular 1 Ligand binds to a G-protein-

fluid coupled receptor, causing
a conformational change.
Ligand
1 2 The α subunit of the
Receptor G protein releases GDP
Phospholipase C and binds GTP and moves
through the membrane.
Plasma 2 4 COOH
3
membrane Arachidonic acid
3 The activated α subunit
PKC activates phospholipase C,
PIP2 DAG
5 10 which cleaves PIP2
into IP3 and DAG.
GDP GTP
IP3 Protein Protein P 4 DAG is cleaved in the

membrane to form
arachidonic acid, the
9 substrate for the synthesis
6 of chemical messengers
Diverse P
effects PKC called eicosanoids.
Pi
IP4
5 IP3 is released into the
Response cytoplasm.
7
in cell
Cytoplasm
6 IP3 can be phosphorylated
to IP4, which has diverse
effects.
Ca2+
7 IP3 also binds to Ca2+
8 channels on the endoplasmic
reticulum, releasing
Ca2+ into the cytoplasm.
Ca2+-calmodulin 8 The Ca2+ binds to

calmodulin, causing diverse
effects within the cell.
9 The Ca2+ also stimulates

protein kinase C (PKC) to
Diverse
move to the membrane
Membrane of the effects
where it interacts with DAG.
endoplasmic
reticulum
10 DAG activates the PKC,
which then phosphorylates
proteins, stimulating
a phosphorylation cascade.
Figure 26 The inositol-phospholipid signaling pathway
145
transduction pathway responsible for regulating brane, DAG activates PKC. Activated PKC phos-
secretion from the salivary glands of insects, but phorylates serine and threonine residues on a va-
a huge variety of G-protein-coupled receptors riety of proteins including MAP kinase, which we
that signal through the inositol-phospholipid have already discussed. Through these pathways,
pathway are now known from most animal taxa. activated PKC can alter the activities of existing
These pathways regulate a diversity of physiolog- proteins and influence the transcription of genes
ical functions including smooth muscle contrac- and thus the production of new proteins.
tion, glycogen degradation in the liver, water
reabsorption by the vertebrate kidney, and many
aspects of immune function. Cyclic AMP was the first second
When a chemical messenger binds to one of messenger to be discovered
these receptors, the activated receptor stimulates Many physiologically important processes involve
a G protein called G q, which in turn activates G proteins that signal via the adenylate
inositide-specific phospholipase C (phospholipase cyclase–cyclic AMP system, using cAMP as a sec-
C-␤). In less than a second, this enzyme cleaves a ond messenger. Cyclic AMP was the first intracel-
phosphorylated membrane phospholipid, called lular second messenger to be identified, and as a
phosphatidylinositol bisphosphate (PIP2). Cleav- result we know a great deal about these signal
age of PIP2 produces two products: inositol transduction pathways. Two types of G proteins
trisphosphate (IP3) and diacylglycerol (DAG). interact with the cAMP signal transduction path-
Both IP3 and DAG act as second messengers in way: stimulatory G proteins (Gs) and inhibitory G
two branches of the phosphatidylinositol signal proteins (Gi) (Figure 27). Gs and Gi proteins differ
transduction cascade. in their ␣ subunits, although their ␤ and ␥ subunits
The IP3 produced by PIP2 hydrolysis is water can be similar. Both Gi and Gs proteins interact
soluble and rapidly leaves the plasma membrane with the amplifier enzyme adenylate cyclase,
by diffusion. IP3 binds to IP3-gated Ca2⫹ release which catalyzes the conversion of ATP to cAMP.
channels in the membrane of the endoplasmic When a ligand binds to a receptor that interacts
reticulum, activating them. The activated channels with a Gs protein, the ␣s subunit of the activated Gs
open, allowing Ca2⫹ efflux from the endoplasmic protein binds to and activates the membrane-
reticulum. The increased cytoplasmic Ca2⫹ con- bound enzyme adenylate cyclase. When a ligand
centration further activates the channel, causing binds to a receptor that interacts with a Gi protein,
an even greater Ca2⫹ efflux. Increases in cytoplas- the αi subunits of the Gi protein inhibit adenylate
mic Ca2⫹ act as a third messenger, causing diverse cyclase. Gi and Gs proteins act together to regulate
effects within the cell. intracellular cAMP levels.
IP3 is rapidly inactivated by specific dephospho- In the next step of the cAMP signal transduction
rylases, and the Ca2⫹ is quickly removed from the pathway, cAMP binds to protein kinase A (PKA) at
cytoplasm by active transport, terminating the re- sites on the regulatory subunit of the inactive ki-
sponse. The actions of IP3 generally last less than a nase. Binding of cAMP alters the conformation of
second after the chemical messenger dissociates the regulatory subunits, causing them to dissociate
from the receptor. Some of the IP3 can be further from the catalytic subunits. The unbound catalytic
phosphorylated to form 1,3,4,5-tetrakisphosphate subunits are active, and catalyze the phosphoryla-
(IP4), which mediates slower and more prolonged tion of specific proteins. Protein phosphorylation
responses in the cell. causes a response in the target cell.
DAG, the other cleavage product of PIP2, initi- Cells have mechanisms to rapidly dephos-
ates two different signal transduction pathways. phorylate the proteins phosphorylated by PKA,
Unlike IP3, DAG remains in the membrane and can ensuring that cAMP-dependent signals persist only
be cleaved to form arachidonic acid, which is the for short periods (seconds to minutes). Serine/
substrate for the synthesis of eicosanoids—a type threonine phosphatases remove the phosphates
of chemical messenger. Alternatively, DAG can ac- added by PKA. The activity of proteins regulated by
tivate protein kinase C (PKC), a Ca2⫹-dependent ki- phosphorylation depends on the balance between
nase. An increase in cytoplasmic Ca2⫹ (caused by the activities of PKA and the serine/threonine phos-
signals from IP3) triggers PKC to move to the mem- phatases. When cAMP stimulates PKA activity, the
brane, where it interacts with DAG. At the mem- balance of the reaction tends to swing toward
146
Extracellular Ligand Ligand 1 Ligand binds to a Gs-protein-coupled

fluid receptor, causing a conformational
1 Adenylate change.
cyclase
Gs Gi
2 7 2 The α s subunit releases GDP, binds
Plasma Activates Inhibits GTP, moves through the membrane,
membrane and activates adenylate cyclase.
3
3 Activated adenylate cyclase catalyzes
GDP GTP GTP GDP
the conversion of ATP to cAMP.
α s subunit ATP α i subunit
cAMP
4 cAMP binds to the regulatory subunit

4 of protein kinase A (PKA), which
dissociates from the catalytic subunit,
Regulatory PKA Catalytic activating it.
subunit of PKA subunit of PKA
5 The activated catalytic subunit

Active catalytic
PKA phosphorylates proteins, causing
subunit of PKA
a response.
ATP ADP 5
Protein Protein 6 The phosphorylated proteins are
P
Pi rapidly dephosphorylated by serine/
threonine phosphatases, terminating
the response.
6
7 When ligand binds to a G i-protein-
coupled receptor, the α i subunit
Serine/threonine inhibits adenylate cyclase, inhibiting
Cytoplasm phosphatase the signal transduction pathway.
Figure 27 G-protein signal transduction via adenylate cyclase G-protein-

coupled signal transduction through adenylate cyclase can be either stimulatory or inhibitory.
phosphorylation of the target proteins. In con- pathway. Both protein kinase A and CaM kinase
trast, when cAMP levels are low, the balance of the often phosphorylate different sites on the same
reaction tends to swing toward the dephosphory- target proteins. From this example, it is clear that
lation of the target proteins. signal transduction cascades in the cell are not
simple linear connections from the binding of a
chemical messenger, through several amplifica-
Signal transduction pathways can interact
tion steps, culminating in a cellular response. In-
Ca2⫹ and cAMP signal transduction pathways instead, signal transduction in the cell acts more like
teract with each other at several levels. For exam- a network of intertwined threads that combine to
ple, Ca2⫹-calmodulin interacts with adenylate generate complex responses. In vivo, the network
cyclase. Adenylate cyclase is the first amplifier en- is even more complex, because cells may receive
zyme of the cAMP-mediated signal transduction multiple signals, many of which may have inter-
pathway, and catalyzes the production of cAMP. acting effects.
Similarly, Ca2⫹-calmodulin also interacts with
cAMP phosphodiesterase, the enzyme that breaks
down cAMP. Therefore, Ca2⫹ plays a role in regu- 2 C O NC E P T C H E CK
lating the cAMP signaling pathway. Conversely,
5. Compare and contrast intracellular and
PKA, one of the steps in the cAMP signaling path- transmembrane receptors.
way, can phosphorylate Ca2⫹ channels and 6. Compare and contrast the different types of
pumps, altering their activity. Thus, the cAMP sig- membrane receptors and their signal
naling pathway can regulate the Ca2⫹-calmodulin transduction pathways.
147
7. What are second messengers and what is their When a cell or tissue becomes very active metabol-
functional importance? ically, its oxygen consumption increases. For ex-
8. Explain how signal transduction pathways cause ample, when oxidative muscles contract, they use
signal amplification. Select one signal aerobic metabolism to generate energy, which
transduction pathway, and outline specific
causes the mitochondria to become more active
examples of amplification.
and consume more oxygen, leading to a drop in lo-
cal oxygen concentration. When local oxygen con-
centration drops in the contracting muscle cells,
Introduction to Endocrine the endothelial cells that line the blood vessels that
supply oxygen to the tissues secrete paracrine sig-
Systems naling molecules. These paracrine signaling mole-
One of the unifying themes in physiology is that cules act on the smooth muscle cells that surround
physiological processes are often highly regulated. the blood vessels, causing them to relax. Relax-
The cellular signaling pathways that we have dis- ation of the smooth muscle cells causes the blood
cussed in this chapter are a critical component of vessels to dilate, and allows more blood to flow
the complex control systems that monitor and ad- into the tissue. The flow of blood delivers addi-
just the activity of essentially all physiological sys- tional oxygen, restoring local oxygen concentra-
tems. tions, removing the signal for the release of
Like mechanical control systems, biological paracrine signaling molecules, thus forming a
control systems are composed of a sensor that de- negative feedback loop. The exact nature of the
tects the state or level of a regulated variable, a con- paracrine signals that cause local vasodilation is
troller that acts as an integrating center by hotly debated, because multiple factors change
evaluating the incoming information and sending within a tissue when oxygen concentrations drop.
out a signal that provokes an appropriate response It is likely that several of these variable factors
in an effector—a target tissue that causes (effects) a contribute to the vasodilation. The purine messen-
change in the regulated variable. In a negative feed- ger adenosine is one candidate for an important
back loop the effector brings the variable back to- paracrine signaling molecule involved in vasodila-
ward a predetermined set point. Thus, negative tion. As we have already discussed, adenosine is a
feeback loops help to maintain homeostasis by purine that binds to a G-protein-coupled receptor.
maintaining a regulated variable within a small The adenosine receptor on smooth muscle cells in
range around the set point. In a positive feedback most vascular beds is of the A2 subtype, which sig-
loop the system responds to a change in the regu- nals via a cAMP-mediated signal transduction
lated variable by causing further deviation from the pathway. Activation of the receptor causes the
set point. Positive feedback is less common in phys- smooth muscle to relax, causing vasodilation of
iological systems than is negative feedback, but it is the blood vessel. Vasodilation brings more blood
sometimes used to reinforce and amplify signals. (and thus oxygen) to the local area, turning off the
Feedback loops require close communication be- signals for adenosine release.
tween the cells and tissues that act as sensors, inte-
grating centers, and effectors, and thus the correct Reflex control mediates long-distance
functioning of feedback loops depends upon cellu- regulation
lar signaling pathways.
In animals, the nervous and endocrine systems
are responsible for regulating physiological sys-
tems across long distances. The simplest types of
Feedback Regulation these long-distance regulatory systems involve
Feedback regulation occurs both at a local level only the endocrine system and are termed direct
and across long distances in animals. Paracrine feedback loops (Figure 28a). In a direct feedback
and autocrine signals are responsible for local loop the endocrine cell itself senses a change in the
physiological control. The regulation of local blood extracellular environment and releases a chemical
flow provides an example of the importance of messenger that acts on target cells elsewhere in
paracrine signals in local feedback regulation. the body. Thus, the endocrine cell acts as the inte-
148
Stimulus Stimulus Stimulus Stimulus
Endocrine Sense Sense Sense

gland organ organ organ
Sensory Sensory Sensory

– – neuron – neuron
– neuron
Integrating Integrating Integrating

center center center
Target Neuron Neuron Neuron

organ
Target Endocrine Endocrine

organ gland gland 1
Response
Circulatory Circulatory
(a) Direct feedback loop system system
Response
– –
Hormone 1
(b) First-order feedback loop
Target
organ Endocrine
gland 2
Circulatory
Response system
(c) Second-order feedback loop – Hormone 2
Target
organ
Response
(d) Third-order feedback loop
Figure 28 Feedback regulatory systems in neurohormone) between the integrating center and the
animals (a) Direct feedback loops involve only the target organ. (c) Second-order feedback loops have two steps
endocrine system, and the endocrine gland acts both as the (a neuron and an endocrine gland) between the integrating
integrating center and as the tissue that communicates with center and the target organ. (d) Third-order feedback loops
the target organ. (b) First-order feedback loops have one contain an additional endocrine gland in the pathway,
step (a neuron that releases a neurotransmitter or a providing a third point of feedback regulation.
grating center that interprets the change in the blood pressure. The lowered blood pressure feeds
stimulus variable. The response of the target cell to back by reducing the tension on the atrial cells, re-
the secreted hormone then brings the stimulus ducing the release of ANP.
variable back into the normal range. Atrial natri- First-order feedback loops provide a slightly
uretic peptide (ANP), a hormone that we discussed more sophisticated level of regulation, involving
earlier in the chapter, is an example of a hormone the nervous system (Figure 28b). In these types of
involved in a direct feedback loop. Stretch-sensitive pathways, a sensory organ perceives a stimulus
cells in the atrium of the mammalian heart can and sends a signal via the nervous system to an in-
sense the increased tension in the cell membranes tegrating center (such as the brain) that interprets
of atrial cells caused by increased blood pressure the signal. Neurons then transmit the signal (in the
within the atrium. These cells then secrete ANP, form of either a neurotransmitter or a neurohor-
which travels to target cells in the blood vessels mone) to a specific target organ, causing a re-
and kidneys and causes responses that lower sponse. Neural and neurohormonal pathways are
149
both termed first-order response pathways be-

cause only a single step links the integrating cen-
Neurosecretory
ter and the response. cells
Most regulatory pathways in the vertebrates,
however, are more complicated than direct or
first-order pathways, and involve both the ner-
Hypothalamus
vous and endocrine systems. These pathways can
be classified as either second- or third-order
feedback loops. Every step in a response loop
may act as a control point over the pathway.
Thus, direct and first-order response pathways Artery
can be regulated at only one control point, second- Infundibulum Blood
order pathways can be regulated at two points, enters
and third-order pathways can be regulated at
three points. Third-order feedback loops provide Neuron
secretes
the most sophisticated and tightly regulated Pituitary neurohormone
feedback. into blood
Figure 28c shows a typical second-order feed-
back loop. In this case, a sense organ perceives a
Posterior
stimulus and sends a signal to the integrating cen- Anterior pituitary
ter, which sends a signal via a neuron that secretes pituitary
either a neurohormone or a neurotransmitter that
Blood exits
acts on an endocrine gland. The endocrine gland (carrying
then secretes a hormone into the blood. The hor- hormones)
mone travels to the target cell, causing a response.
Figure 29 The hypothalamus and the posterior
In third-order feedback loops (Figure 28d), a pituitary gland The pituitary gland is located at the base
sense organ perceives a stimulus and sends a sig- of the brain, and is divided into the anterior pituitary and the
nal to the integrating center. The integrating cen- posterior pituitary. The infundibulum connects the
ter then sends a signal via a neuron that secretes hypothalamus—a part of the brain—and the posterior
pituitary, which is made up of the endings of neurons that
either a neurohormone or a neurotransmitter that originate in the hypothalamus. The nerve endings of the
acts on an endocrine gland. The endocrine gland posterior pituitary secrete neurohormones into the blood. The
then secretes a hormone that binds to a receptor anterior pituitary secretes hormones into the blood, under
on a second endocrine gland and triggers the se- the control of neurohormones released by the hypothalamus.
cretion of a second hormone, which then induces
a response in the target cells.
secretes melanocyte-stimulating hormone (MSH).
In adult mammals, this region is simply a thin
Pituitary hormones provide examples sheet of cells that cannot be easily distinguished
of several types of feedback loops from the anterior lobe of the pituitary, but it can be
The vertebrate pituitary gland secretes many important quite large in other vertebrates.
hormones that regulate growth, reproduction, and me-
tabolism. These hormones regulate many physiological
functions. The pituitary gland is closely associated with The posterior pituitary secretes
a part of the brain called the hypothalamus (Figure 29) neurohormones
and is connected to the hypothalamus by a narrow stalk The posterior pituitary is not really an independent
called the infundibulum. The pituitary gland is divided organ but is instead an extension of the hypothala-
into two distinct sections called the anterior pituitary mus. Neurons that originate in the hypothalamus
(or adenohypophysis) and the posterior pituitary (or terminate in the posterior pituitary (Figure 29). In
neurohypophysis). The pituitary also has a third the hypothalamus, the cell bodies of these neurons
division, called the intermediate lobe, located be- synthesize the hormones oxytocin and vasopressin
tween the anterior and posterior pituitary, which
150
and package them into secretory vesicles. The vesi-

cles are transported along the neuron via a process
called axonal transport. The neural endings, in the
posterior pituitary, secrete these hormones into
the blood. Because only a single step (a hypothal-
amic neuron that secretes a neurohormone) con- Hypothalamus
nects the integrating center and the effector
Neuron
organs, oxytocin and vasopressin are examples of secretes
neurohormones involved in first-order feedback neurohormone
loops. into blood
Anterior
Blood
pituitary Artery
Oxytocin is involved in a positive feedback enters
Neurohormone
loop stimulates Portal vein
endocrine
Most hormonal regulation involves negative feed- cell to release
Pituitary
back loops, but oxytocin is an example of a hor- hormone
mone that is involved in a positive feedback
pathway. Oxytocin has a wide range of functions,
and is both a neurotransmitter and a hormone. In
mammals, one of its important endocrine func- Posterior
pituitary
tions involves regulation of uterine contraction. At
the onset of parturition, the process of expelling a Blood exits
fetus from the uterus at birth, the fetus changes (carrying hormones)
position, putting pressure on the cervix (the open- Figure 30 The anterior pituitary and the
ing of the uterus). Stretch-sensitive cells in the hypothalamic-pituitary portal system Neurons
from the hypothalamus secrete neurohormones into the
cervix send a signal to the brain that causes the re-
hypothalamic-pituitary portal circulatory system. The portal
lease of oxytocin from the posterior pituitary. Oxy- vein carries the neurohormones to the anterior pituitary
tocin binds to receptors on the smooth muscle where they stimulate endocrine cells to release hormone
cells of the uterus, causing them to contract. Uter- into the blood. The blood exits from the pituitary, carrying
ine contractions push the fetus against the cervix, the hormones throughout the body via the circulatory
system.
increasing the stimulus on the stretch-sensitive
cells. This increases the signal and causes even
more oxytocin to be released. This positive feed- to the pituitary without being diluted in the gen-
back loop continues until the fetus is delivered, re- eral circulation.
leasing the pressure on the cervix and terminating Figure 31 shows the relationship between the
the signal. hypothalamic neurohormones and the hormones of
the anterior pituitary. Prolactin is best known for
Hypothalamic neurohormones regulate regulating the secretion of milk from the mammary
anterior pituitary hormones glands in mammals, but it also has diverse effects
on sexual behavior and growth. It is also involved in
The hypothalamus controls the secretion of hor- the regulation of larval development and ion and
mones from the anterior pituitary by secreting water balance in some nonmammalian vertebrates.
neurohormones into a specialized microcircula- Prolactin is the one anterior pituitary hormone that
tion, called the hypothalamic-pituitary portal only functions as part of a second order feedback
system (Figure 30).1 The portal system carries loop. The brain acts as the integrating center that
the neurohormones secreted by the hypothalamus regulates the secretion of prolactin, stimulating
to the anterior pituitary, where they stimulate the hypothalamus to release the neurohormones
or inhibit the release of pituitary hormones. The prolactin-releasing hormone or prolactin-inhibiting
hypothalamic-pituitary portal system allows neu- hormone into the hypothalamic-pituitary portal
rohormones to be carried from the hypothalamus system. These neurohormones regulate the release
1
A portal system is a specialized arrangement of blood vessels of prolactin, which has direct effects on its target
with two capillary beds separated by a portal vein. tissues such as the breast.
151
Prolactin- Prolactin- Thyrotropin- Corticotropin- Growth Growth Gonadotropin-

releasing inhibiting releasing releasing hormone– hormone– releasing
Hypo- hormone hormone hormone hormone releasing inhibiting hormone
thalamus (PRH) (PIH/ (TRH) (CRH) hormone hormone (GnRH)
dopamine) (GHRH/ (GHIH/
Somatocrinin) Somatostatin)
+ + + + + + +
Prolactin Thyroid- Adrenocortico- Growth Follicle- Luteinizing

Anterior (PRL) stimulating tropic hormone (GH) stimulating hormone (LH)
pituitary hormone hormone (Somatotropin) hormone
(TSH) (ACTH) (FSH)
+ +
+ + +
Thyroid Adrenal Liver Endocrine

gland cortex cells in
gonads
Thyroid Cortisol Somato- Androgens Estrogens

hormones medins Progesterone
(T3,T4) (IGF)
Breast Many Germ cells

tissues of gonads
Figure 31 The relationship between the stimulate or inhibit the release of the pituitary hormones.
hypothalamic hormones and the hormones of The circulatory system carries these hormones to their
the anterior pituitary The hypothalamus secretes target tissues, causing a response. Some of these target
releasing or inhibiting neurohormones into the tissues are endocrine glands, which secrete hormones into
hypothalamic-pituitary portal system. These neurohormones the blood. The circulatory system carries these hormones to
act on the endocrine cells of the anterior pituitary to their target tissues, causing a response.
Many anterior pituitary hormones tuitary, which in turn causes the release of gluco-
participate in third-order pathways corticoid hormones from the adrenal cortex,
which goes on to affect the activity of many tar-
In contrast to prolactin, the majority of anterior pi-
get tissues. Third-order feedback loops are sub-
tuitary hormones can go on to regulate the release
ject to very complex regulation because change
of yet more hormones, and thus they participate in
in the concentration of any of the hormones in
third order feedback loops. Hormones that cause
the hypothalamic-pituitary axis can regulate the
the release of other hormones are called tropic
concentrations of other hormones in the path-
(or trophic) hormones, from the Greek root
way, generally via negative feedback.
tropos, “to turn toward.” (The alternate term,
which is often heard, is from the Greek root
trophikos, “nourishment.”) For example, the neu-
rohormone corticotropin releasing hormone from
Regulation of Glucose Metabolism
the hypothalamus regulates the secretion of Hormones are involved in regulating almost all
adrenocorticotropic hormone (ACTH) from the pi- physiological processes. In this chapter we discuss
152
two processes that involve endocrine regulation as

“case-studies” to illustrate some of the important
principles of endocrine regulation. Alpha cell
Islet of
In this section, we focus on the endocrine regu- Beta cell Langerhans
lation of glucose metabolism as a case study in hor- cells
monal regulation. The metabolism of a cell can be (endocrine)
divided into a series of catabolic and anabolic

processes involving the breakdown or buildup of Acinar cells
biological macromolecules. Hormones regulate (exocrine)
the balance between anabolism and catabolism in Capillary

the body and thus help cells to maintain home-
Figure 32 The mammalian pancreas The pancreas
ostasis between energy supply and energy de- consists of both exocrine and endocrine tissues. The islets of
mand. By mediating these processes, the Langerhans contain cells called beta cells that secrete the
endocrine system regulates the metabolic activity hormone insulin and cells called alpha cells that secrete the
of essentially every cell in the body. hormone glucagon.
The actions of insulin illustrate gated Ca2⫹ channel to open, causing Ca2⫹ to enter
the principle of negative feedback the cell. The increase in intracellular Ca2⫹ acts as
a signal to cause the exocytosis of vesicles contain-
Most animals maintain some level of homeostatic ing insulin. The insulin released from the ␤ cell
regulation over the concentration of sugars in their travels through blood to target cells such as liver,
extracellular fluids. Mammals have particularly pre- adipose tissue, and muscle. At the target cell, in-
cise control over the glucose levels in their blood, sulin binds to and activates its receptor, which, as
because the mammalian brain is entirely reliant on we have already discussed, is a receptor tyrosine
glucose as a fuel. If glucose levels fall too low, the kinase. The activated receptor is then autophos-
brain cannot function. In contrast, if glucose levels phorylated, initiating a complex network of signal
rise too high, the osmotic balance of the blood will transduction pathways. The ultimate effect of
be disturbed. This precise homeostatic regulation is these signal transduction pathways is to promote
governed by negative feedback control. the uptake and storage of glucose, resulting in a
Insulin is one of several hormones involved in decrease in blood glucose levels. The decrease in
the homeostatic regulation of blood glucose in mam- blood glucose removes the signal for the pancre-
mals. In mammals, a gland called the pancreas se- atic ␤ cell to release insulin, and insulin levels de-
cretes the peptide hormone insulin when blood cline, in an example of negative feedback
glucose rises. The pancreas is a complex gland with regulation. In humans, defects in insulin signal
both exocrine and endocrine functions (Figure 32). transduction cause the disease diabetes mellitus
The exocrine pancreas secretes digestive enzymes (see Box 3, Applications: Cell-to-Cell Communica-
into the gut. Dispersed among the exocrine tissue are tion and Diabetes).
small clumps of cells, termed the islets of Langer-
hans, which perform the endocrine functions of the
pancreas. Pancreatic ␤ cells within these islets se- Multiple types of feedback control
crete insulin when blood glucose rises. can regulate blood glucose
Increases in blood glucose cause the metabolic The regulation of blood glucose by insulin is an ex-
rate of the ␤ cell to increase, resulting in an in- ample of a direct feedback loop because the pan-
crease in ATP levels within the cell. The increased creas secretes insulin when it senses increases in
[ATP] sends a signal to an ATP-dependent potas- blood glucose, without involving integrating cen-
sium (KATP) channel, causing it to close. Closing of ters like the brain. But insulin secretion can be
a K⫹ channel will cause the cell to depolarize. This regulated in multiple ways (Figure 33). Stretch re-
change in membrane potential causes a voltage- ceptors in the gut can detect the presence of food
153
Eat a meal
sensitive cells in the gut detect the presence of glu-
cose in a meal. Note that the CCK-mediated path-
way does not fit neatly into our classification of
2 3
pathway types, since it involves two hormones but
does not utilize the nervous system. This example
Glucose Stretch emphasizes the concept that pathways of feedback
receptors in receptors in
Blood the digestive the digestive regulation represent a continuum of design, rather
glucose tract tract than discrete organizational systems, and that
– many of these pathways can interact to form even
more complex regulatory networks. In the case of
Negative CCK
feedback
1 insulin, many pathways interact to regulate in-
sulin secretion and provide for homeostatic regu-
lation of blood glucose.
Integrating
Pancreas
center Insulin and glucagon illustrate the
Secretes principle of antagonistic control
The second major hormone involved in glucose
Insulin
homeostasis in mammals is the peptide hormone
glucagon. Glucagon is secreted from ␣ cells in the
pancreatic islets of Langerhans. When blood glu-
cose falls, ␣ cells release glucagon into the circula-
tion, where it binds to receptors on target cells,
initiating pathways that cause them to release glu-
Target organs
cose, thus causing blood glucose to rise (another
Figure 33 Interaction of pathways regulating insulin example of negative feedback). Glucagon binds to
secretion Insulin is an example of a hormone that is regulated a G-protein-coupled receptor that stimulates an
by several feedback pathways. A direct stimulus-response pathway adenylate cyclase–mediated signal transduction
(pathway 1) regulates insulin synthesis. The pancreas senses
pathway and activates protein kinase A (PKA).
increases in blood glucose and secretes insulin into the
bloodstream. Insulin binds to receptors on target organs, causing PKA phosphorylates a variety of target proteins,
responses that reduce blood glucose, reducing the stimulus for causing biochemical changes that ultimately pro-
insulin secretion in a direct feedback loop. Insulin is also part of a mote the release of glucose into the blood. Thus in-
second-order control pathway 3, in which stretch receptors in the sulin and glucagon have opposite, or antagonistic,
digestive tract sense the change in gut volume caused by eating a
meal. The stretch receptors send a signal to an integrating center in effects on blood glucose (Figure 34).
the neurons surrounding the digestive tract. This integrating center Both insulin and glucagon act as important
sends a signal via the nervous system to the pancreas to release feedback controllers of blood glucose concentra-
insulin. At the same time, in pathway 2, glucose receptors in the tion. When blood glucose concentration rises
digestive tract cause the digestive tract to release the hormone
cholecystokinin (CCK). The circulatory system carries CCK to the
above the set point, the pancreas secretes insulin,
pancreas, stimulating it to secrete insulin. causing target cells to take up and store glucose,
lowering blood glucose levels. When blood glucose
in the digestive tract, and send a signal to an inte- falls below the set point, the pancreas secretes
grating center in the enteric nervous system (the glucagon, causing target cells to release stored
neurons surrounding the digestive system. The glucose, increasing blood glucose levels. The rela-
enteric nervous system then sends a neural signal tionship between insulin and glucagon is termed
directly to the pancreas, causing an increase in the an antagonistic pairing, in which one hormone in-
secretion of insulin even before blood glucose creases the rate of glucose production and the
starts to rise. This kind of direct control of hor- other decreases it. Antagonistic pairings also con-
mone secretion by the nervous system is an exam- trol many familiar mechanical devices. For exam-
ple of a second-order feedback loop. In addition, ple, the gas pedal and the brake in a car are an
the pancreas secretes insulin in response to the antagonistic pairing of control devices. When you
hormone cholecystokinin (CCK), which is secreted depress the gas pedal, the car speeds up, and
by the gut. The gut releases CCK when glucose-
154
BOX 3 APPLICATIONS
Cell-to-Cell Communication and Diabetes
Diabetes, one of the most common dis- When insulin binds to its receptor (a tyrosine kinase),
eases in the Western world, results when the the receptor is autophosphorylated and the tyrosine ki-
body fails to either secrete or respond to insulin. There nase domain then phosphorylates a protein called the
are two major types of diabetes: type 1 (or juvenile on- insulin receptor substrate (IRS). Phosphorylated IRS
set) and type 2 (or adult onset). In type 1 diabetes the activates the phosphatidylinositol and MAP-kinase sig-
body does not produce sufficient insulin in response to nal transduction pathways. The phosphatidylinositol
increases in blood glucose. In type 2 diabetes, the target pathway stimulates glucose uptake from the blood,
cells do not fully respond to insulin, even if it is present. while the MAP-kinase pathway stimulates cell growth.
So both types of diabetes result from failures in cell-to- Because so many different proteins are involved in in-
cell communication, although in type 1 diabetes the pri- sulin signal transduction, the precise defect associated
mary defect is in the signaling cell, whereas in type 2 with type 2 diabetes is not yet known, and may vary from
diabetes the problem is in the target cells. Type 2 dia- person to person or among tissues.
betes is by far the more common of the two types. Cur- Obesity is a major risk factor for type 2 diabetes, and
rently, over 90% of North Americans with diabetes have most patients with type 2 diabetes are obese when diag-
type 2, and the incidence of type 2 diabetes in Western nosed. Lack of exercise and a diet high in simple carbo-
populations is growing as millions of additional people hydrates such as sugars also predispose a person to
with type 2 diabetes are diagnosed every year. Particu- type 2 diabetes. Genetic factors also contribute to type 2
larly alarming is the rapid rate of increase in type 2 dia- diabetes, so having a close relative with type 2 diabetes
betes in teenagers. indicates an increased risk that a person will develop
Type 2 diabetes is a progressive disease that begins the disease. Scientists do not yet understand why obe-
with defects in the signal transduction pathway for in- sity is related to increased risk of type 2 diabetes, but
sulin. The initial symptoms of the disease are usually studies in mice have shown that adipocytes (fat cells)
mild, and may involve frequent urination, thirst, and fa- release a hormone called resistin, and levels of resistin
tigue. In the early stages of the disease, diabetes can be are elevated in obese mice. Resistin is thought to down-
controlled with a careful diet and a limited intake of glu- regulate the insulin signal transduction pathway, sug-
cose, but as the disease progresses, the pancreas se- gesting the possibility of a link between obesity and type
cretes more and more insulin in an attempt to signal to 2 diabetes.
the target tissues. Eventually, the pancreas loses its
References
ability to secrete high amounts of insulin, and insulin
q Bevan, P. 2001. Insulin signalling. Journal of Cell Science 114:
levels fall. At this point, the disease must be treated with 1429–1430.
injections of insulin to regulate blood glucose. Un-
q Steppan, C. M., S. T. Bailey, S. Bhat, E. J. Brown, R. R. Banerjee,
treated diabetes has many serious complications in- C. M. Wright, H. R. Patel, R. S. Ahima, and M. A. Lazar. 2001. The
cluding blindness, vascular disease, kidney failure, hormone resistin links obesity to diabetes. Nature 409: 307–312.
heart attack, and stroke. q White, M. F. 2002. IRS proteins and the common path to diabetes.
The signal transduction pathways for insulin are American Journal of Physiology: Endocrinology and Metabolism
rather complex and have only recently been identified. 283: E413–422.
when you depress the brake the car slows down. docrine system to exert extremely precise control
It would be possible to design a car with only a gas over physiological functions.
pedal, but this kind of car would only be able to
come to a gradual stop, which would make it much
more difficult to control. Similarly, insulin and Hormones can demonstrate additivity
glucagon allow rapid and precise regulation of
and synergism
blood glucose by speeding up or slowing down glu- Like glucagon, the hormones epinephrine (also
cose release into the blood. By acting together, in- called adrenalin) and cortisol can increase blood
sulin and glucagon maintain blood glucose levels glucose. Figure 35 illustrates the results of an ex-
within a very narrow range. Many hormones are periment in which glucagon, epinephrine, corti-
grouped into antagonistic pairs, allowing the en- sol, or combinations of these hormones were
155
Plasma glucose Glucagon + epinephrine + cortisol

250
Blood glucose (mg/dL)

+ –
200
Beta cells Alpha cells

of pancreas of pancreas
150
Glucagon + epinephrine
Insulin Glucagon
– secretion secretion
100 Epinephrine
Glucagon
Cortisol
Target tissues Target tissues 0 1 2 3 4 5

Time (hours)
Figure 35 Additivity and synergism Infusion

Glucose uptake Glucose release of cortisol, glucagon, or epinephrine into dogs results in an
increase in blood glucose. These effects are larger when
the hormones are injected in combination. Infusion of
epinephrine and glucagon results in additive effects on blood
Plasma Plasma glucose. Infusion of all three hormones in combination has a
glucose glucose
synergistic effect.
(Data from Eigler et al., 1979)
Figure 34 Antagonistic regulation of blood
glucose by insulin and glucagon Increases in
plasma glucose stimulate the beta cells of the pancreas to
Cortisol is a steroid hormone that is involved in
increase insulin secretion. At the same time, this causes the
alpha cells of the pancreas to decrease glucagon secretion. the stress response. As can be seen from Figure 35,
Increased insulin stimulates its target tissues to increase cortisol causes an increase in blood glucose, but
glucose uptake. Decreased glucagon causes its target this effect is smaller than the responses to glucagon
tissues to decrease glucose release. Together these actions or epinephrine. As a steroid hormone, cortisol in-
decrease plasma glucose in a negative feedback loop.
Similarly, if plasma glucose declines, insulin secretion teracts with an intracellular receptor, and thus ex-
decreases and glucagon secretion increases, stimulating erts its effects through a different signal
glucose release into the plasma. transduction pathway than does either epineph-
rine or glucagon, and typically acts more slowly.
When cortisol, glucagon, and epinephrine are in-
injected into dogs. Alone, injection of glucagon, jected in combination, however, the net effect is
epinephrine, or cortisol causes an increase in much greater than the sum of the effects observed
blood glucose. When both glucagon and epineph- when any one hormone is injected alone. This is an
rine are injected together, the increase in blood example of a phenomenon called synergism.
glucose is larger, and is equivalent to the sum of
the increase in blood glucose in response to epi-
nephrine plus the increase in blood glucose in re-
Hyperglycemic hormones control
sponse to glucagon. This phenomenon is termed
extracellular glucose in arthropods
additivity. As is the case in the vertebrates, many invertebrates
Epinephrine binds to a G-protein-coupled re- have mechanisms to regulate extracellular glucose.
ceptor on the liver. This receptor signals via an For example, in crustaceans (crabs, prawns, and
adenylate cyclase–mediated signal transduction shrimp) a neurohormone termed crustacean hyper-
pathway that activates PKA. This is similar to glycemic hormone (CHH) plays a principal role in
glucagon signaling, which also occurs via activa- glucose regulation. CHH was first discovered when
tion of PKA. Thus, although these two hormones researchers injected crabs with extracts of tissues
bind to different G-protein-coupled receptors, they from the eyestalks of other crabs and found that
both activate PKA, and the effect of the hormones these extracts caused hyperglycemia—an increase
in combination is equal to the sum of the actions in circulating glucose. CHH is synthesized in the cell
of each hormone alone. bodies of secretory neurons that are clustered into
156
an area termed the X-organ within the crustacean Low blood

glucose 1 Low blood
eyestalk. Projections from these cell bodies extend glucose stimulates
into a region called the sinus gland, which acts as K+ ion channels
to close in sinus
a storage and release site for the neurohormone. 1 Closed K+ gland cells.
Because CHH is released by neural tissue, it is channel
considered to be a neurohormone or neuropep- Sinus
tide. The sinus gland releases CHH into the circu- gland 2 Sinus gland
cell cell depolarizes,
latory system, which carries the neurohormone to causing the cells
target cells throughout the body. At the target cell, to release CHH
– 2
CHH binds to a transmembrane receptor that ac- via exocytosis.
Crustacean
tivates guanylate cyclase and increases the con- hyperglycemic
centration of cGMP within the target cell. The 3 hormone (CHH)
3 CHH binds to
cGMP acts as a second messenger, activating a receptors on
signaling pathway that results in release of glu- Target
target cell.
cose from the target cell into the circulatory sys- cell
tem, causing hyperglycemia.
CHH regulates blood glucose via a negative 4 4 Target cell releases
glucose into blood.
feedback mechanism (Figure 36). When blood glu- Glucose
cose levels are high, a K⫹ channel on the membrane Figure 36 Regulation of circulating glucose by
of the neurosecretory cells within the sinus gland is crustacean hyperglycemic hormone
in the open conformation, allowing K⫹ to leave the
cell. This hyperpolarizes the membrane (makes the
inside of the cell more negative. When blood glucose The Vertebrate Stress Response
levels drop, this K⫹ channel closes, and the cell de- Our second case study in endocrine regulation is
polarizes. Depolarization causes the cells to release the vertebrate stress response, because it provides
CHH. The CHH then travels through the circulatory an example of the ways in which the nervous and
system and causes target cells to release glucose endocrine systems work together to regulate phys-
into the circulation, causing glucose levels to return iological responses.
to normal. As is the case for many hormones, other When the sense organs of a vertebrate perceive
factors can also modulate the release of CHH. For an alarming stimulus (such as the presence of a
example, inputs from the nervous system alter the predator), the organism initiates a complex set of
activity of the sinus gland cells in response to exter- behavioral and physiological responses that are of-
nal cues including season, time of day, temperature, ten called the “fight-or-flight” response. The fight-
and changes in environmental salinity. CHH also or-flight response involves both the endocrine
has other functions in addition to the regulation of system and the nervous system acting together to
circulating glucose, including the regulation of lipid coordinate this complex but critically important be-
metabolism. havioral and physiological response (Figure 37).
Although CHH is primarily regulated via nega-
tive feedback from circulating glucose levels, crus-
tacean hyperglycemic hormone can also be Stressful stimuli activate the sympathetic
regulated by positive feedback. When CHH binds nervous system
to its receptor on target cells, the activated recep- When an animal detects the presence of an alarm-
tor increases flux through glycolysis. One of the ing stimulus (such as a predator), sensory nerves
end products of glycolysis is a three-carbon unit send a signal to the brain. The brain acts as an in-
called lactate. When stimulated by CHH, target tegrating center that takes information from the
cells produce lactate, which is released into the various senses and makes a decision regarding
circulation. The neurosecretory cells of the X-or- the “threat level” of the stimulus. If the brain de-
gan–sinus gland complex are sensitive to circulat- cides that the stimulus represents a threat, it
ing lactate, which causes them to release more sends out a signal via motor neurons, which
CHH in a positive feedback loop. The signals from causes muscles to contract, causing the animal to
lactate and glucose work together to regulate CHH
secretion.
157
Stressful stimulus
toward the working muscles and
away from tissues such as the gut.
The sympathetic nervous system
Brain also increases the rate and depth of
breathing. Together these re-
sponses help to provide the skeletal
muscles with the oxygen they need
Hypothalamus Sympathetic nervous system Muscles
to contract and thus engage in the
fight-or-flight response.
CRH Movement
The sympathetic nervous

system stimulates the adrenal
Anterior pituitary Pancreas Adrenal medulla
medulla
In addition to the target tissues dis-
ACTH Insulin Epinephrine cussed above, the sympathetic ner-
Glucagon in blood
vous system also affects the activity of
several endocrine glands. For exam-
Adrenal cortex
ple, stimulation of the sympathetic
nervous system reduces the release
Cortisol of insulin from the pancreas and in-
creases the release of glucagon. Tar-
get tissues respond to the change in
insulin and glucagon levels by in-
Target tissues Target tissues Target tissues creasing blood glucose, which can
be used as an energy source during
the fight-or-flight response. The
sympathetic nervous system also
Blood glucose Heart rate and contraction
stimulates the adrenal glands. In
Breathing rate
mammals, the adrenal glands are
Redistribute blood flow
compact organs located adjacent
Figure 37 The vertebrate stress response When an organism perceives a to each kidney, which consist of
stimulus such as the presence of a predator, sensory neurons send various signals to two types of tissue. The adrenal
the brain, which acts as an integrating center to decide whether these stimuli cortex, on the outside of the gland,
represent a stressful event. If the brain interprets the stimuli as stressful, it sends out
signals to various target tissues using three main pathways. (1) It stimulates the
is composed of interrenal tissue,
sympathetic nervous system, which directly regulates the activity of a variety of tissues. and secretes mineralocorticoid and
(2) The stimulated sympathetic nervous system also stimulates the release of glucocorticoid hormones such as al-
epinephrine and norepinephrine from the adrenal medulla. These hormones then act dosterone and cortisol. The inside
on a variety of target tissues. (3) The brain also sends signals to the hypothalamus,
causing it to release corticotropin releasing hormone (CRH). The CRH binds to
of the adrenal gland is called the
receptors on the anterior pituitary, causing it to release adrenocorticotropic hormone adrenal medulla and is composed
(ACTH). The ACTH then binds to receptors on cells in the adrenal cortex, causing them of chromaffin cells that secrete the
to release glucocorticoid hormones, which have diverse effects on a variety of target catecholamines, epinephrine and
tissues.
norepinephrine.
The sympathetic nervous system releases the
run away or fight, as necessary. At the same time, neurotransmitter acetylcholine onto chromaffin
the hypothalamus activates a portion of the ner- cells of the adrenal medulla. These cells then re-
vous system termed the sympathetic nervous sys- lease either norepinephrine or epinephrine into
tem. The sympathetic nervous system sends out the circulatory system. The ratio of norepineph-
signals to target organs including the heart, vascu- rine to epinephrine that is released varies among
lar smooth muscle, and other tissues. These re- species. In dogfish sharks, norepinephrine is the
sponses help to increase blood flow and redirect it only catecholamine released by chromaffin cells,
158
whereas in frogs norepinephrine makes up about cytoplasmic signal transduction pathways, the ef-
55–70% of the released catecholamines. In con- fects of glucocorticoids are much slower, and are
trast, mammals release mostly epinephrine. involved in recovery from the effects of the imme-
As we have already discussed, epinephrine diate fight-or-flight response. The glucocorticoids’
and norepinephrine bind to members of a family metabolic functions help the body to restore en-
of G-protein-coupled receptors, termed the adren- ergy balance following the energetically costly
ergic receptors, that activate signal transduction fight-or-flight response.
pathways that alter the activity of existing pro-
teins. Thus, epinephrine and norepinephrine have
very rapid effects within their target cells. Epi- The structure of adrenal tissue varies
nephrine and norepinephrine interact with many among vertebrates
target organs including the heart, lungs, and mus- The catecholamines and the glucocorticoids are in-
cles to galvanize the body into action. volved in the stress response in all vertebrates, but
there is substantial diversity among taxa in the
structure of the tissue that secretes these hormones
The hypothalamo-pituitary axis stimulates (Figure 38). Mammals have a compact and highly
the adrenal cortex
organized adrenal gland. The adrenal glands of
The fight-or-flight response also involves the acti- reptiles and birds are also quite compact, as they
vation of the hypothalamo-pituitary endocrine re- are in mammals, but the interrenal (glucocorticoid-
sponse. When the hypothalamus is activated by a secreting) and chromaffin (epinephrine-secreting)
stressful stimulus, it increases the secretion of tissues are intermingled, rather than being sepa-
corticotropin-releasing hormone (CRH) into the rated into a distinct cortex and medulla. The inter-
hypothalamic-pituitary portal system. CRH binds renal and chromaffin cells of amphibians are
to its receptors on target cells in the anterior pitu- intermingled in a diffuse stripe along the kidney.
itary and causes them to release adrenocorti- In elasmobranch fishes, the interrenal cells form a
cotropic hormone (ACTH) into the bloodstream. fairly compact organ that is located on the kidney,
ACTH binds to G-protein-coupled receptors in the but the chromaffin cells are found in the body cav-
membranes of cells in the adrenal cortex. Activa- ity anterior to the kidney, grouped into loose clus-
tion of this receptor stimulates adenylate cyclase, ters. Bony fish entirely lack a discrete adrenal
which catalyzes the formation of cAMP. The cAMP gland; their interrenal cells are generally located
activates protein kinase A, which phosphorylates in a single layer around the blood vessels of the
and activates an enzyme that causes cholesterol to anterior kidney, while the chromaffin cells vary in
be released from intracellular stores. This choles- location, often being associated with interrenal
terol is transported to the mitochondria where it is cells. However, despite these differences in the
used as a substrate for the synthesis of glucocorti- structure of the target organs among vertebrates,
coid hormones. In humans and fish, cortisol is the the overall organization and functions of the stress
primary glucocorticoid hormone, whereas the response are similar. This transition from a dis-
structurally similar corticosterone is the primary persed group of hormone-secreting cells toward a
glucocorticoid hormone in rats and mice. In all compact and organized gland is a general trend in
these species, however, the effects of glucocorti- the evolution of endocrine systems in both the ver-
coids in the stress response are similar. tebrates and the invertebrates.
As hydrophobic hormones, glucocorticoids
bind to an intracellular receptor located in the cy-
toplasm of target cells. Glucocorticoid binding in-
duces a conformational change that causes the
Evolution of Endocrine Systems
hormone-receptor complex to move to the nucleus Cellular signaling plays an important role in the
and regulate transcription. Glucocorticoids have maintenance of homeostasis and the coordination
diverse functions, including the breakdown of of reproduction, growth, and development in all
lipids and proteins, and increasing blood glucose. animals. There are substantial similarities in
Because these effects are mediated through changes the structure and function of nervous systems
in transcription and translation, in contrast to the across all taxa. In contrast, the organization of
rapid effects of epinephrine, which acts through
159
endocrine systems is quite diverse. Unlike nervous

Adrenal Adrenal
gland cortex systems, which were present very early in the evo-
Interrenal lution of animals, endocrine systems could only
Kidney
cells arise following the evolution of a circulatory system
Chromaffin that could carry hormones from one part of the
Adrenal cells
medulla
body to another. Because circulatory systems are
thought to have arisen independently several times
(a) Mammal (e.g., human) in different animal groups, we can conclude that
endocrine systems have arisen multiple times and
Interrenal the endocrine systems of, for example, vertebrates
Adrenal
gland cells and arthropods are not closely related.
Chromaffin Although there are substantial differences in
cells
Kidney the organization of animal endocrine systems,
there are also substantial similarities. These simi-
(b) Bird (e.g., Herring gull) larities likely stem from the evolution of endocrine
systems from a shared set of basic signal trans-
duction mechanisms involved in paracrine com-
munication in the ancestral metazoans. Over time,
however, animal cell-to-cell communication mech-
Interrenal and anisms have diverged and diversified into the
Kidney
chromaffin cells complex endocrine systems we see in various
taxa. In all animals, however, endocrine systems
rely upon a similar set of chemical messengers, re-
ceptors, and signal transduction pathways. For
example, the insulin receptor and its associated
(c) Amphibian (e.g., Necturus)
signal transduction pathways are present in both
vertebrates and invertebrates. Both invertebrates
and vertebrates have steroid receptors, phospho-
Chromaffin lipase C, and adenylate cyclase.
cells All vertebrates, including the jawless lampreys
and hagfish, use a series of related steroid hor-
Kidney
mones as chemical messengers, including estro-
gens, androgens, and glucocorticoids. Of these
Interrenal
cells hormones, only estrogen has been found in inver-
tebrates. Instead, insects and crustaceans use a
different series of steroid hormones related to
(d) Elasmobranch (e.g., shark)
ecdysone. Like the vertebrate steroid hormones,
ecdysone binds to an intracellular receptor that in-
Interrenal and teracts with DNA and regulates gene transcription.
chromaffin cells Despite the similarities at the molecular level,
the organization of endocrine systems varies be-
Kidney tween invertebrates and vertebrates. Inverte-
brates have relatively few endocrine glands, and
most endocrine signaling utilizes neurohormones
rather than hormones. In general, in both verte-
(e) Bony fish (e.g., trout) brates and invertebrates, there is a correlation be-
tween the complexity of the endocrine system and
Figure 38 Comparative anatomy of adrenal
tissues in the vertebrates Chromaffin cells (shown the complexity of body form or organization. For
in gray) and interrenal cells (shown in black) are associated example, the so-called lower invertebrates (such
with the kidneys of vertebrates. In mammals, birds, and as cnidarians and platyhelminths) have a limited
reptiles they form discrete adrenal glands, while in fishes number of neurohormones that are mostly in-
and amphibians the cells are in isolated clusters.
volved with regulating growth and development.
160
They appear to have few physiologically active 11. Compare and contrast negative feedback and
hormones. In contrast, the “higher” invertebrate positive feedback. Which type of control allows
maintenance of homeostasis?
phyla (such as the annelids, molluscs, and arthro-
pods), the cephalochordates, and the vertebrates 12. Compare and contrast additivity and synergism.
have many complex endocrine pathways that reg- 13. Provide an example of a hormone controlled by a
third-order endocrine pathway, and outline each
ulate most physiological processes. This increase
step in the regulatory cascade.
in complexity of the endocrine system is related to
the increase in complexity of the circulatory sys-
tem that allows hormones to be transported
across long distances in these groups.
2 CO NC E P T C HE C K
9. What are the primary functions of endocrine
systems?
10. What are antagonistic pairings? What are the
advantages of this organization of control
systems?
Table 4 Major hormones of the vertebrates.
Secretory tissue Hormone Chemical class Effects

Pineal gland Melatonin Amine Circadian and
seasonal rhythms
Hypothalamus Trophic hormones Peptides Regulation of
(clusters of secretory (see Figure 31) anterior pituitary
neurons)
Posterior pituitary Oxytocin Peptides Breast and uterus in

(extensions of mammals; also
hypothalamic involved in social
neurons) bonding and
behavior
Vasopressin Water reabsorption
in excretory system
Vasotocin (fish, Activities similar to
amphibians, birds) both oxytocin and
vasopressin
Anterior pituitary Prolactin (PRL) Peptides Milk production in
gland mammals,
osmoregulation,
growth, metabolism
Growth Hormone (GH) Growth, metabolism
Adrenocorticotropic Release of
hormone (ACTH) corticosteroids
Thyroid stimulating Synthesis and

hormone (TSH) release of thyroid
hormones
Follicle stimulating Egg or sperm
hormone (FSH) production; sex
hormone production
Luteinizing hormone Sex hormone
(LH) production; egg or
sperm production
(continued)
161
Table 4 Major hormones of the vertebrates (continued).
Secretory tissue Hormone Chemical class Effects

Thyroid gland Triiodothyronine (T3) Iodinated amines Metabolism, growth,
and thyroxine (T4) and development
Calcitonin Peptide Regulation of plasma
Ca2⫹ (in non-human
vertebrates)
Parathyroid gland Parathyroid hormone Peptide Regulates plasma
Ca2⫹ and phosphate
Thymus gland Thymosin, thymopoitin Peptides Immune system
Heart (individual Atrial natriuretic Peptide Regulation of sodium
cells in atrium) peptide (ANP) levels and blood
pressure
Liver (various cells) Angiotensinogen Peptides Regulation of
aldosterone;
regulation of blood
pressure
Insulin-like growth Growth and
factors (IGF) metabolism
Stomach and small Gastrin, cholecystokinin Peptides Digestion and
intestine (various (CCK), secretin, ghrelin, absorption of
cells) and many others nutrients; regulation
of food intake
Pancreas Insulin, glucagon, Peptides Regulation of blood
somatostatin, pancreatic glucose and other
polypeptide nutrients; regulation
of metabolism
Adrenal gland Steroids Aldosterone (mammals Ion regulation
(cortex) in mammals; only) Stress response;
dispersed cells in Corticosteroids metabolism
other vertebrates (e.g., cortisol) Sex drive in females;
Androgens bone growth at
puberty in males
Adrenal gland Amines Epinephrine, Stress response;
(medulla) in norepinephrine regulation of
mammals; chromaffin cardiovascular
cells in other system
vertebrates
Kidney (various cells) Peptide Erythropoietin (EPO) Red blood cell
production
Adipose tissue Peptides Leptin and others Food intake,
(various cells) metabolism,
reproduction
Testes (male) Steroids Androgens Sperm production;
secondary sexual
characteristics
Ovaries (female) Steroids Estrogens and Egg production;
progesterone secondary sexual
characteristics
Placenta (pregnant Steroids Estrogens and Fetal and maternal
female mammals progesterone, chorionic development
only) somatomammotropin
(CS), chorionic
gonadotropin (CG)
162
Summary
The Biochemical Basis of Cell Signaling vertebrate steroid hormones are the ecdy-
k There are many types of cell-to-cell communi- steroids.
cation in animals, including direct, autocrine,
k Amines can be paracrines, hormones, or neuro-
paracrine, neural, endocrine, and exocrine.
transmitters. These messengers are derived
These types of communication vary in the dis-
from hydrophilic amino acids or peptides, and
tance that the chemical messengers travel from
are often hydrophilic messengers, but the
one cell to another.
amine thyroid hormones are hydrophobic.
k Chemical messengers involved in indirect cell
k Chemical messengers involved in indirect cell
signaling must travel through both aqueous and
signaling bind specifically to specific receptor
lipid environments. Thus, hydrophobic and hy-
proteins on or in the target cell. Thus, chemi-
drophilic chemical messengers face different
cal messengers act as specific ligands for those
challenges during cell signaling.
receptors.
k Hydrophilic messengers can travel between ad-
k Hydrophobic chemical messengers can interact
jacent cells via gap junctions, but more complex
with intracellular receptors or transmembrane
mechanisms are required for indirect cell-to-
receptors. Hydrophilic chemical messengers can
cell communication between cells that are not
only interact with transmembrane receptors.
adjacent.
k Ligand-receptor binding obeys the law of mass
k Indirect cell signaling involves three steps:
action, and exhibits saturation. The affinity
(1) release of the messenger from the signaling
constant describes the tightness of binding be-
cell, (2) transport through the extracellular en-
tween a ligand and a receptor.
vironment, and (3) communication with the tar-
get cell. k Ligand-receptor signaling must be terminated
for signaling to be effective. Signal termination
k The mechanisms involved in these steps of in-
can be accomplished in a variety of ways, in-
direct cell signaling differ depending on
cluding removal of the ligand, removal of the re-
whether the signaling molecule is hydrophobic
ceptor from the membrane, inhibition of the
or hydrophilic.
receptor, or inhibition of downstream signaling
k Hydrophilic messengers are often peptides. pathways.
They are released from the signaling cell by
exocytosis, and bind to transmembrane recep-
tors on the target cell. Signal Transduction Pathways
k Each step in a signal transduction pathway can
k Peptide hormones are often synthesized as amplify the signal.
large preprohormones that are processed
within the signaling cell prior to the release of k Signal transduction via ligand-gated ion chan-
the active hormone. nels is relatively simple and direct, but the other
signal transduction pathways have many steps.
k Hydrophobic messengers are synthesized on
demand and diffuse out of the signaling cell. k Intracellular receptors regulate gene transcription.
Carrier proteins transport them to target cells
k Receptor-enzymes activate intracellular phos-
where they bind to intracellular receptors.
phorylation cascades.
Some hydrophobic messengers also bind to
transmembrane receptors. Hydrophobic mes- k G-protein-coupled receptors interact with het-
sengers are often steroids. erotrimeric G proteins. G proteins can signal to
ion channels or to amplifier enzymes that acti-
k Steroids are derived from cholesterol. The pri-
vate small molecules called second messengers.
mary vertebrate steroid hormones are the
mineralocorticoids, the glucocorticoids, and k G-protein-coupled receptors use four different sec-
the reproductive hormones. The primary in- ond messengers: Ca2⫹, cGMP, inositol phosphates,
163
and cAMP. Each of these messengers links to a k Negative feedback systems allow the mainte-
different signal transduction cascade. nance of homeostasis (e.g., control of blood glu-
cose by insulin).
k Cells have numerous types of transmembrane
and intracellular receptors, and thus several k Positive feedback allows explosive responses.
signal transduction cascades can be activated at
k Hormones are often grouped into antagonistic
any given time. Thus, signal transduction cas-
pairs that allow extremely precise homeostatic
cades in living cells operate as complex net-
regulation (e.g., insulin and glucagon).
works that integrate the various signals and
convert them into appropriate physiological k Hormones can also work additively or synergis-
responses. tically (e.g., glucagon, cortisol, and epinephrine).
k Hormones can regulate other hormones by neg-
Introduction to Endocrine Systems
ative feedback, in regulatory loops of varying
k The organization of endocrine systems varies
complexity (e.g., the hormones of the vertebrate
among animals. Endocrine communication in
anterior pituitary).
the invertebrates generally involves neurohor-
mones, whereas hormones are more common k Hormones can also be involved in positive feed-
in the vertebrates. back regulation (e.g., oxytocin).
k Endocrine systems are responsible for main- k The vertebrate stress response is an example of
taining homeostatis and regulating growth, de- coordination of physiological functions by mul-
velopment, and reproduction. tiple signaling systems.
Review Questions
1. What are the three major steps involved in in- 10. What are the three main domains of a trans-
direct chemical signaling? membrane receptor, and what are their
2. Would you expect the chemical signaling mol- functions?
ecules involved in signaling via gap junctions 11. Describe the phenomenon of “endocrine
to be hydrophilic or hydrophobic? Justify your disruption.”
answer. 12. Compare and contrast the functions of intra-
3. Compare and contrast autocrine, paracrine, cellular and transmembrane steroid receptors.
endocrine, and neural communication. 13. How do the thyroid hormones differ from all of
4. You read an article in the newspaper about the the other biogenic amines?
discovery of a new steroid hormone. What can 14. What would be the effect of increasing recep-
you predict about how it is synthesized and/or tor number on the response of a target cell to
stored by the signaling cell, how it is trans- the ligand for that receptor?
ported through the blood, and how it acts on
15. How do selective serotonin reuptake inhibitors
the target cell?
(SSRIs) affect the response of a target cell to
5. If the newspaper article were about a peptide serotonin?
hormone, how would your predictions change?
16. Compare and contrast the signal transduction
6. What is the difference between a neurohor- cascades initiated by intracellular receptors
mone and a neurotransmitter? and G-protein coupled receptors.
7. From the perspective of the target cell, is 17. Compare and contrast the function of het-
there a fundamental difference between a erotrimeric G proteins and a small soluble G
paracrine signal and an endocrine signal? protein such as Ras.
Why or why not?
18. What is the difference between signaling
8. List the main classes of chemicals involved through Gs and Gi?
in indirect cell signaling in animals. Which
19. What are the major parts of any control sys-
of these classes are utilized for endocrine
tem (mechanical or biological)? Choose an ex-
communication?
ample of a biological control system and show
9. Why are peptide messengers released by how it fits the general description of control
exocytosis? systems that you provided.
164
20. Compare and contrast positive and negative 22. Compare and contrast the insulin/glucagon
feedback. Provide a biological example for system for blood glucose regulation in the ver-
each type of feedback. tebrates with the function and regulation of
21. Compare and contrast the anterior and poste- crustacean hypoglycemic hormone (CHH).
rior pituitary. 23. Outline the major steps of the vertebrate stress
response.
Synthesis Questions
1. Epinephrine and glucagon both act to increase 4. What are the advantages of a multistep sig-
blood glucose, but they act on a different subset nal transduction pathway in cell-to-cell
of tissues. What characteristics are likely to de- communication?
termine whether a particular tissue responds to 5. Epinephrine binds to a G-protein-coupled re-
epinephrine, glucagon, or to both hormones? ceptor that signals via Gs. Acetylcholine binds
2. People who do not regularly drink coffee often to a G-protein-coupled receptor that signals
feel much greater effects when they ingest via Gi. You construct a recombinant receptor
modest doses of caffeine than do heavy coffee with the extracellular domain of the acetyl-
drinkers. Explain at a molecular level why this choline receptor and the intracellular domain
might be so. of the epinephrine receptor, and transfect it
3. The anticancer drug tamoxifen binds to the es- into cultured cells. Your preliminary experi-
trogen receptor. Tamoxifen inhibits the growth ments indicate that the receptor is processed
of breast tissue but promotes growth of uter- correctly, and inserted into the plasma mem-
ine tissues, thus reducing the risk of breast brane. If you applied acetylcholine to your
cancer but potentially increasing the risk of transfected cells, what would you expect to
uterine cancer. Explain how the same chemi- happen to intracellular cAMP levels? What
cal messenger could have opposite effects in would happen if you applied epinephrine? Ex-
two different tissues. plain your answers
1. The graph below outlines the results of an ex- (c) If the receptor number on the adipocytes
periment to determine the binding character- were doubled, what would be the pre-
istics of a ligand to its receptor on the surface dicted maximum binding of the ligand?
of adipocytes (fat cells). (d) If the receptor number on the adipocytes
were doubled, would the affinity constant
of the receptor change?
Percentage of receptors
100
2. In insects, the Malpighian tubules are involved
bound to ligand
80 in the maintenance of ion and water balance.

When the peptide hormone diuretic hormone
60 is applied to Malpighian tubules isolated from
the blood sucking insect Rhodnius prolixus,
40
the tubule epithelium begins to secrete fluid at
20 a rate of approximately 5 nL/min. The bio-
genic amine serotonin has similar effects,
0 causing secretion at a rate of approximately
2 4 6 8 10
4 nL/min. When both chemical messengers
Concentration of ligand (nM)
are applied together, however, fluid secretion
occurs at a rate of approximately 45 nL/min.
(a) What is the minimum concentration of lig-
Is this an example of additivity, synergism, or
and at which the receptor is saturated?
antagonism? Justify your answer.
(b) What is the affinity constant of the receptor?
165
For Further Reading

See the Additional References section at the end Cheskis, B. J. 2004. Regulation of cell signalling
of the chapter for more readings related to the cascades by steroid hormones. Journal of
topics in this chapter. Cellular Biochemistry 93: 20–27.
Losel, R., and M. Wehling. 2003. Nongenomic
The Biochemical Basis of Cell Signaling actions of steroid hormones. Nature Reviews:
Molecular Cell Biology 4: 46–56.
The review paper below highlights some of the
important features of exocytosis in the release of Losel, R. M., E. Falkenstein, M. Feuring, A.
peptides and other cell signaling molecules Schultz, H-C. Tillmann, K. Rossol-Haseroth,
and M. Wehling. 2003. Nongenomic steroid
Burgoyne, R. D., and A. Morgan. 2003. Secretory action: Controversies, questions, and answers.
granule exocytosis. Physiological Reviews 83: Physiological Reviews 83: 965–1016.
581–632.
The paper below discusses the evolution of signal
The review below outlines the role of carrier transduction pathways and their role in the
proteins in the regulation of steroid hormone evolution of the earliest metazoans.
activity.
Suga, H., M. Koyanagi, D. Hoshiyama, K. Ono,
Bruener, C. W., and M. Orchinik. 2002. Beyond N. Iwabe, K-I. Kuma, and T. Miyata. 1999.
carrier proteins: Plasma binding proteins as Extensive gene duplication in the early
mediators of corticosteroid action in evolution of animals before the parazoan-
vertebrates. Journal of Endocrinology 175: eumetazoan split demonstrated by G proteins
99–112. and protein tyrosine kinases from sponge and
hydra. Journal of Molecular Evolution 48:
Written by the scientist who discovered the 646–653.
physiological actions of nitric oxide, the paper
below provides a fascinating look at the process
of scientific discovery.
Introduction to Endocrine Systems
Moncada, S. 2006. Adventures in vascular
biology: A tale of two mediators. Philosophical This book contains a collection of essays
Transactions of the Royal Society of London: outlining the development of concepts in
Biological Sciences 361: 735–759. endocrinology from Aristotle to the present,
telling the stories of some of the scientists
This book provides a good general introduction involved in discovering the fundamental
to signal transduction pathways. principles of endocrinology.
Sitaramayya, A. 1999. Introduction to cellular McCann, S. M., ed. 1997. Endocrinology: People
signal transduction. Boston: Birkhauser. and ideas: An American Physiological Society
book. New York: Oxford University Press.
Signal Transduction Pathways This highly accessible book provides a review of

These reviews and others from a special issue of the function of the endocrine system in humans.
Science magazine entitled “Mapping Cellular Neal, M. J. 2001. How the endocrine system
Signaling” summarize recent advances in signal works. New York: Blackwell Science.
transduction research.
Attisano, L., and J. Wrana. 2002. Signal This book provides an introduction to the
transduction by the TGF-␤ superfamily. extensive literature on invertebrate
Science 296: 1646–1647. endocrinology.
Neeves, S. R., P. T. Ram, and R. Iyengar. 2002. Nijhout, H. F. 1998. Insect Hormones. New York:
G protein pathways. Science 296: 1636–1639. Princeton University Press.
These reviews highlight some of the recent This paper summarizes the current state of
findings regarding signal transduction via steroid knowledge on CHH.
hormones, through both intracellular and Fanjul-Moles, M. L. 2006. Biochemical and
transmembrane receptors. functional aspects of crustacean hyperglycemic
166
hormone in decapod crustaceans: Review and Flik, G., P. H. Klaren, E. H. Van den Burg, J. R.
update. Comparative Biochemistry and Metz, and M. O. Huising. 2006. CRF and stress
Physiology C: Toxicology and Pharmacology in fish. General and Comparative
142: 390–400. Endocrinology 146: 36–44.
DeRijk, R., de and E. R. Kloet. 2005.
These reviews provide some additional insights Corticosteroid receptor genetic polymorphisms
into the stress response and its regulation in the and stress responsivity. Endocrine 28:
vertebrates. 263–270.
Gade, G., K. H. Hoffmann, and J. H. Spring. 1997. Hormonal Comparative Biochemistry and Physiology. A Molecular
regulation in insects: Facts, gaps, and future directions. and Integrative Physiology 126: 471–480.
Physiological Reviews 77: 963–1032. Pandi-Perumal, S. R., V. Srinivasan,
Garofalo, R. S. 2002. Genetic analysis of insulin signaling in G. J. Maestroni, D. P. Cardinali,
Drosophila. Trends in Endocrinology and Metabolism 13: B. Poeggeler, and R. Hardeland. 2006. Melatonin. FEBS
156–162. Journal 273: 2813–2838.
Gilmour, K. M. 2005. Mineralocorticoid receptors and Simonet, G., J. Poels, I. Claeys, T. Van Loy, V. Franssens, A.
hormones: Fishing for answers. Endocrinology 146: De Loof, and
44–46. J. V. Broeck. 2004. Neuroendocrinological and molecular
Guillemin, R. 2005. Hypothalamic hormones a.k.a. aspects of insect reproduction. Journal of
hypothalamic releasing factors. Journal of Endocrinology Neuroendocrinology 16: 649–659.
184: 11–28. Spratt N. T., Jr. 1971. Developmental biology. Belmont CA:
Maddrell, S. H. P., W. S. Herman, R. W. Farndale, and J. A. Wadsworth.
Riegel. 1993. Synergism of hormones controlling epithelial Stoka, A. M. 1999. Phylogeny and evolution of chemical
fluid transport in insects. Journal of Experimental Biology communication: An endocrine approach. Journal of
174: 65–80. Molecular Endocrinology 22: 207–225.
McFall-Ngai, M. J. 2000. Negotiations between animals and
bacteria: The “diplomacy” of the squid–Vibrio symbiosis.
Credits
90 imagequestmarine.com, Roger
Steene/imagequestmarine.com
91 Mark J. Grimson & Richard L. Blanton.
91 Nature Picture Library, Anup Shah/naturepl.com.
167
Neuron Structure and Function
With an anxiety that almost amounted to agony, I collected somehow involved in controlling the activities of the body.
the instruments of life around me, that I might infuse a spark
of being into the lifeless thing that lay at my feet. This was a revolutionary idea, since at the time nerves
Frankenstein (or, the Modern Prometheus) were thought to be similar to pipes or canals that carried
Mary Shelley, 1818 fluid. Although Galvani’s interpretation of animal electric-
ity ultimately proved to be incorrect (because he thought it
It was no coincidence that Mary Shelley chose to use elec- was a unique property of living things and distinct from
tricity as the animating force that brought Frankenstein’s other electrical phenomena), his pioneering discoveries
monster to life. In writing her novel, Mary Shelley was in- led the way to the modern study of neurophysiology.
fluenced by the work of the scientist Luigi Galvani, who had We now know that nerves are composed of groups of
demonstrated about 30 years earlier what we now under- cells termed neurons that are specialized for processing
stand as electrical transmission in the nervous system. and conveying information in the form of electrical signals
Galvani showed that the muscles of a dead frog twitch rapidly and precisely across long distances. Neurons per-
when you apply an electrical current to the frog’s nerves. form this function by coding incoming information into
After many careful experiments, Galvani concluded that changes in the electrical potential across the cell mem-
nerves must transmit “an animal electricity” that was brane. In particular, neurons use a specialized form of
168
Galvani’s experiments on frog’s legs.
electrical impulse, called the action potential, to transmit

electrical signals across long distances. Along with muscle
cells, another class of electrically excitable cells, neurons
allow animals to sense and respond to their environments
in ways that no other organisms can.
Venus flytrap.
Only metazoans have neurons, but they are not the
only organisms capable of generating rapid and coordi-
nated responses to their environments. Charles Darwin
was fascinated with plants such as the Venus flytrap, which
he called the most wonderful plants in the world. The that the plant responded by generating an electrical signal
leaves (or lobes) of the Venus flytrap resemble a set of open that was very similar to an action potential.
jaws. When an insect or other small animal lands on the In fact, the Venus flytrap does not have neurons. In-
lobe of the Venus flytrap and disturbs one of the trigger stead, action potentials travel through the structural tis-
hairs on the surface of the lobes, the jaws snap shut, trap- sues of the plant, transferred from one plant cell to
ping the insect. The Venus flytrap then digests the trapped another via plasmodesmata—intercellular connections
insect, and this digested material provides the plant with a analogous to gap junctions in animals. This kind of conduc-
supplementary source of the nitrogen and minerals that tion is very slow compared to conduction in neurons. In
are lacking in their boggy habitats. Because of the plant’s plants, action potentials typically travel at speeds between
ability to actively catch animal prey, Darwin hypothesized 1 and 3 centimeters per second, whereas in animals action
that the Venus flytrap must possess neurons similar to potentials can travel along neurons at speeds up to 100
those in animals. He contacted John Burdon-Sanderson, meters per second (or 10,000 cm/sec). The high-speed
an eminent medical physiologist at the University College conduction of action potentials is a unique property of ani-
London, to test his hypothesis about the basis of movement mals. In this chapter, we will see how the special proper-
in the Venus flytrap. Burdon-Sanderson placed electrodes ties of neurons allow the rapid and precise conduction of
on the lobes of the Venus flytrap, and recorded what hap- electrical signals that is the hallmark of animal life.2
pened when he touched one of the trigger hairs. He found
169
Overview rons participate in cell-to-cell communication. Us-

ing a vertebrate motor neuron as an example, we
Chemistry, Biochemistry, and Cell Physiology, ani- follow a signal as it travels from one end of the mo-
mal cells have a voltage difference across their cell tor neuron to the other, discussing the features of
membranes, termed the resting membrane poten- the electrical signals in each part of the cell, and
tial. This voltage difference, together with con- how the neuron transmits signals to its target
centration gradients across the membrane, cells, vertebrate skeletal muscles. We conclude the
results in an electrochemical gradient that acts as first half of the chapter with a brief discussion of
a form of potential energy that cells can harness how the muscle responds to these signals.
to move substances across the membrane. In ad- In the second half of the chapter, we look at
dition to using this electrochemical potential as a how each of these steps has been modified and
form of energy, cells can also use changes in the specialized in different neurons and in neurons
membrane potential as communication signals. In from different kinds of organisms. We first discuss
fact, certain classes of cells, termed excitable variation in the structure of neurons, and then ad-
cells, can rapidly alter their membrane potential dress variation in the functional properties of neu-
in response to an incoming signal. rons. We end the chapter with a discussion of the
Animals have a variety of types of excitable evolution of neurons.
cells, including some endocrine cells, and cells such
as fertilized eggs. However, the best-known ex-
citable cells are neurons—cells that are specialized
to carry electrical signals, often across long dis-
tances.
Neurons vary in their
structure and properties, but Motor neuron Sensory neuron Purkinje cell
all neurons use the same basic
mechanisms to send signals.
Figure 1 illustrates the struc-
ture and function of some rep- Signal reception
resentative neurons. Each part
of the neuron plays a different
role in neural signaling. At one
end of the cell is a zone special- Signal integration
ized to receive incoming sig-
nals. Farther along the cell is a
zone that integrates these sig-
nals. The next zone of the neu-
ron is specialized to conduct
these integrated signals along Signal conduction
the neuron, potentially across
long distances. Finally, the
fourth zone of the neuron is
specialized to transmit signals
to other cells. As a result of this
organization, neurons typically
have a specific polarity: signals Signal transmission
are transmitted from one end
of the neuron to the other, but
not in the opposite direction.
In the first half of this Figure 1 An overview of neuron structure and function Neurons vary
in size and shape, but most neurons are divided into four functional regions, each
chapter we examine how these specialized for a particular task: signal reception, signal integration, signal
four functional zones of neu- conduction, or signal transmission to other cells.
170
Signaling in a Vertebrate rons and neural signaling, because these neurons

provide a good example of the mechanisms under-
Motor Neuron lying signal conduction.
Figure 2 illustrates the structure and function of a A motor neuron, like most neurons, can be di-
vertebrate motor neuron—a type of neuron that vided into four distinct zones, and each of these
sends signals from the central nervous system to zones plays a somewhat different role in neural
skeletal muscles and is thus involved in controlling signaling. In motor neurons, the first zone, which
animal movement. In the first half of this chapter, is specialized for signal reception, consists of the
we use this vertebrate motor neuron to illustrate dendrites and cell body (or soma) of the neuron.
some of the fundamental characteristics of neu- Dendrites are fine, branching extensions of the
Dendrites
Cell Incoming signals
body are received and
(soma) Incoming signal converted to a
change in
Nucleus membrane potential.
Signal
reception
Endoplasmic reticulum
Mitochondrion
Axon hillock A change in

Signal
membrane potential
integration
Axon initiates action
potentials.
Schwann cells
of myelin Direction
sheath of signal
Signal Action potentials are

conduction conducted to the
axon terminals.
Axon terminal
Axon Synapse
terminal (neuromuscular
Signal junction) Neurotransmitter
transmission release transmits a
Neurotransmitter signal to the
release target cell.
Muscle cell
Muscle cell
Figure 2 Structure and function of a typical vertebrate motor neuron Like

other neurons, motor neurons can be divided into four functional zones.
171
neuron, originating at the cell body. The word a signal in the muscle cell and causing the muscle
dendrite is derived from the Greek word for tree to contract.
(dendron) because of the highly branched appear- Thus, the overall process of signaling in a mo-
ance of the dendrites of many neurons. The den- tor neuron involves receiving an incoming signal,
drites are responsible for sensing incoming converting that signal to a change in the mem-
signals, converting these signals to an electrical brane potential, triggering action potentials that
signal in the form of a change in the membrane conduct the signal across long distances, and then
potential, and transmitting the signal to the cell transmitting the signal to target cells in the form of
body. The cell body contains the nucleus and the a neurotransmitter. In the following sections we
protein synthetic machinery of the cell, as well as examine each of these processes in detail, first
most of the organelles, such as mitochondria and considering the general properties of electrical
the endoplasmic reticulum. The cell body per- signals in neurons, and then looking at the types
forms all of the routine metabolic functions of the of signals that occur in each of the functional zones
neuron—synthesizing and degrading proteins, of a motor neuron.
providing energy, and helping to maintain the
structure and function of the neuron. Like the den-
drites, the plasma membrane of the cell body often
also contains receptors, and thus can participate in
Electrical Signals in Neurons
detecting incoming signals. As excitable cells, neurons can rapidly alter their
The second zone of the motor neuron, which membrane potential in response to an incoming
is specialized for signal integration, consists of the signal, and these changes in membrane potential
axon hillock. The axon hillock is located at the can act as electrical signals. Neurons are not the
junction of the cell body and the axon. Incoming only excitable cells. Muscle cells, fertilized eggs, some
signals from dendrites and the cell body are con- types of plant cells, and many unicellular organisms
ducted to the axon hillock. If the signal at the axon also have the capacity to rapidly alter their mem-
hillock is sufficiently large, an electrical signal, brane potentials. But it is this property of excitability
termed the action potential, is initiated. Action that gives neurons the ability to store, recall, and dis-
potentials occur in the axon, a long slender exten- tribute information, and which is the main subject of
sion leading off the cell body at the axon hillock. this chapter.
The axon forms the third functional zone of Most neurons have a resting membrane poten-
the neuron, and is specialized for signal conduc- tial of approximately 70 mV, meaning that when
tion. Axons are often quite short (just a few mil- the neuron is at rest and not involved in sending
limeters), but the axons of some neurons, such as an electrical signal, the inside of the cell mem-
motor neurons in large mammals, can be several brane is about 70 mV more negatively charged
meters long. Each neuron has only a single axon, than the outside of the membrane (Figure 3). Dur-
although the axon may branch into several ing depolarization, the charge difference be-
collaterals. Vertebrate motor neurons are wrapped tween the inside and outside of the cell membrane
in a myelin sheath that aids in the conduction of decreases, and the membrane potential becomes
nerve impulses to the axon terminal. less negative. Either positively charged ions enter-
The axon terminals make up the fourth func- ing the cell or negatively charged ions moving out
tional zone of the neuron, which is specialized for of the cell can make the inside of the cell mem-
signal transmission to target cells. In a motor neu- brane less negatively charged, causing depolariza-
ron, the end of the axon branches to form several tion. During hyperpolarization, the membrane
axon terminals. Each axon terminal is a swelling potential becomes more negative. Either nega-
of the end of the axon that forms a synapse with tively charged ions entering the cell or positively
the target skeletal muscle cell. At the axon termi- charged ions moving out of the cell can make the
nal of a motor neuron the electrical signal is trans- inside of the cell membrane more negative,
duced into a chemical signal in the form of a causing hyperpolarization. During repolariza-
chemical neurotransmitter. The neurotransmitter tion, the cell membrane returns to the resting
diffuses across the synapse and binds to specific membrane potential, following a depolarization
receptors on the muscle cell membrane, initiating or hyperpolarization.
172
an ion, that ion makes a large

Membrane potential (mV) contribution to the membrane
–50 potential. Thus, like other elec-
trically excitable cells such as
Depolarization
muscle cells, neurons depolar-
Repolarization ize or hyperpolarize by selec-
–70 tively altering the permeability
Repolarization
Resting of their membranes to ions,
membrane Hyperpolarization which they do by opening and
potential
closing gated ion channels in
–90 the membrane. This change in
Time (msec)
permeability alters the mem-
Figure 3 A recording of changes in membrane potential in a neuron brane potential and generates
Resting membrane potential of a neuron is usually about ⫺70 mV. During
electrical signals.
depolarization, the membrane potential becomes less negative. During hyperpolar-
ization, membrane potential becomes more negative. During repolarization, the Gated ion channels open
membrane returns to the resting membrane potential. and close in response to a
stimulus, such as the binding
of a neurotransmitter. It is pos-
The Goldman equation describes sible to record the changes in membrane potential
the resting membrane potential as ion channels open and close (see Box 1, Meth-
ods and Model Systems: Studying Ion Channels),
Three factors contribute to establishing the mem-
and these techniques have been crucial in devel-
brane potential of a cell: the distribution of ions
oping an understanding of the functions of neu-
across the plasma membrane, the relative perme-
rons. When a gated ion channel opens, the
ability of the membrane to these ions, and the
membrane becomes much more permeable to that
charges on these ions. These factors are included
ion than it is to the other ions. Under these condi-
in the Goldman equation, which describes the ef-
tions, the Goldman equation can be simplified,
fects of each of these factors on the membrane po-
and becomes essentially identical to the Nernst
tential. To review, the Goldman equation takes the
equation, which can be written as
form
3X4 outside
PK 3 K⫹ 4 o ⫹ PNa 3 Na⫹ 4 o ⫹ PCl 3Cl⫺ 4 i
RT
Eion ⫽
3 X 4 inside
RT ln
Em ⫽
PK 3 K⫹ 4 i ⫹ PNa 3 Na⫹ 4 i ⫹ PCl 3 Cl⫺ 4 o
ln zF
F
where [X] is the molar concentration of the ion. The
where Em represents the membrane potential, R is
Nernst equation can be used to calculate the equi-
the gas constant, T is the temperature (Kelvin), z is
librium potential (also called the reversal potential)
the valence of the ion, F is the Faraday constant,
for a particular ion.
[ion]o and [ion]i represent the concentration of that
The equilibrium potential is the membrane
ion outside and inside the cell, respectively, and PK,
potential at which the electrical and chemical gra-
PNa, and PCl are the permeabilities of the membrane
dients favoring the movement of a particular ion
to the respective ions. This form of the Goldman
exactly balance each other, and there is no net
equation considers only Na⫹, K⫹, and Cl⫺, because
movement of that ion across the membrane. If the
most neurons under resting conditions are only
membrane potential is far from the equilibrium
permeable to these ions to any measurable degree.
potential of an ion, and gated ion channels for that
ion open, ions will tend to move across the mem-
brane because under these circumstances the
Gated ion channels allow neurons to alter electrochemical driving force for movement of that
their membrane potentials ion is large. When the membrane potential
From the Goldman equation it is easy to see that if reaches the equilibrium potential, net ion move-
the membrane is not permeable to an ion, that ion ment stops because there is no electrochemical
does not contribute to the membrane potential. Al- driving force for ion movement. Although ions
ternatively, if the membrane is highly permeable to
173
continue to move across the membrane, there is ments continue, but the same amount of Na en-
no overall change in the distribution of ions, be- ters and leaves the cell, so there is no net change
cause the same number of ions move into the cell in ion distribution).
as move out. In contrast, opening of K channels typically
For example, we can use the Goldman and causes hyperpolarization (Figure 4b). From the
Nernst equations to calculate that under normal Nernst equation we can calculate that the equilib-
conditions in a vertebrate motor neuron, the rest- rium potential for K is approximately 90 mV,
ing membrane potential is approximately 70 mV, even more negative than the resting membrane
and the equilibrium potential for Na is approxi- potential of 70 mV. When K channels open, K
mately 60 mV. When ligand-gated Na channels ions tend to leave the cell, making the inside of the
open, Na ions tend to enter the cell, because of cell more negative, until the membrane has hyper-
the large difference between the membrane po- polarized from the resting membrane potential of
tential and the equilibrium potential for Na, 70 mV to approximately 90 mV, at which point
which provides a large electrochemical driving net K movement ceases.
force for Na entry (Figure 4a). As Na enters the It is important to once again emphasize that
cell, the inside of the cell becomes more and more these changes in membrane potential occur as a re-
positively charged until the membrane has depo- sult of the movement of relatively small numbers of
larized from the resting membrane potential of ions across the membrane, and thus a single depo-
70 mV to approximately 60 mV. At this point larization or hyperpolarization does not measura-
there is no electrochemical gradient driving Na bly alter the overall concentrations of ions inside or
entry, and net Na movement stops (ion move- outside of the cell (because of the very large number
of ions inside and outside of the cell, and the rela-
tively small number of ions that move across the
membrane during a typical depolarization or hy-
+70 Na+ equilibrium potential
perpolarization). Thus, it is changes in membrane
+50
permeability rather than measurable changes in
ion concentration that cause the membrane poten-
Membrane potential (mV)
+30
tial to deviate from the resting membrane potential
+10
during electrical signals.
–10
Na+
In the following sections we see how depolar-
–30 channels ization, repolarization, and hyperpolarization of
–50 open the membrane as a result of changes in membrane
Resting membrane potential
–70 permeability are involved in sending a signal
–90 along a vertebrate motor neuron from the den-
–110 drites to the axon terminal.
Time (msec)
(a) Opening of Na+ channels depolarizes the membrane
Signals in the Dendrites
and Cell Body
–10 Vertebrate motor neurons receive incoming sig-

nals in the form of a chemical neurotransmitter.
–30 K+ channels
open
Membrane-bound receptors in the dendrites or
–50
Resting membrane potential cell body transduce (convert) this incoming chem-
–70
ical signal into an electrical signal in the form of a
–90 change in the membrane potential. Receptors in
K+ equilibrium potential
–110 many cells, including neurons, transduce
incoming chemical signals into electrical signals.
Time (msec)
Recall that binding of neurotransmitter to a
(b) Opening of K+ channels hyperpolarizes the membrane specific ligand-gated receptor causes ion
Figure 4 Depolarization or hyperpolarization channels in the membrane to open or close,
due to opened ion channels changing the permeability of the membrane
174

Studying Ion Channels
One of the most widely used methods for

studying ion channels in single cells is the Amplifier
voltage clamp. The basic idea of a voltage-clamp exper-
iment is to hold the voltage across a membrane at a
constant level by injecting current into the cell via a
Micropipette
microelectrode any time the voltage across the mem-
brane changes (as a result, the voltage is said to be
clamped at a particular value). For example, suppose
that the resting potential of the cell is 70 mV, and you
set the voltage-clamp apparatus to hold the membrane
potential at 70 mV. If the cell is at the resting mem-
brane potential, then no current will be injected through Current
the microelectrode. But suppose you introduce into the Micropipette
fluid bathing the cell a neurotransmitter that binds to a
specific Na channel. The neurotransmitter will bind
and cause the Na channel to open. Na ions will enter
the cell, causing a depolarization. The apparatus takes a Ion
channels
measurement of the membrane potential and injects
current to hold the membrane at the resting membrane
potential, despite the influx of Na. In this way, a voltage-
clamp apparatus is analogous to a thermostatically con- Patch clamping.
trolled heater operating by negative feedback.
The amount of injected current is a direct measure of
natural ionic movements across the membrane. Neuro- then voltage-clamp this small region of membrane and
physiologists use voltage-clamp experiments to de- record the extremely small currents generated by a
scribe the electrical properties of intact membranes or single ion channel (they are measured in picoamperes,
whole cells. pico 1012). Patch clamping allows neurobiologists to
Neurobiologists also use patch clamping to study ion study the properties of a single ion-channel molecule,
channel function. The patch clamp is particularly useful while voltage clamping a whole cell, or a large region of
for studying the properties of single channels. In patch a membrane, provides information about the behavior
clamping, the experimenter fuses the tip of a glass mi- of populations of ion channels.
cropipette to the plasma membrane to act as a record- References
ing electrode. The region of membrane within the patch q Neher, E., and B. Sakmann. 1976. Single-channel currents
is extremely small (often less than 1 micron), and usu- recorded from membrane of denervated frog muscle fibres. Na-
ally contains a relatively low number of ion channels. In ture 260: 799–802.
fact, some of the patches will contain only a single ion q Neher, E., and B. Sakmann. 1992. The patch clamp technique.
channel, as shown in the figure. The experimenter can Scientific American 266: 44–51.
and altering the movement of ions. This change in strong stimulus, such as a high concentration of
permeability alters the membrane potential and neurotransmitter, increases the probability that a
causes an electrical signal. In the dendrites and given ion channel will open, thus causing more
cell bodies of neurons, these electrical signals are ion channels to open, and keeping them open for
called graded potentials. a longer time. If more ion channels open (or stay
open longer), more ions will move across the
plasma membrane, causing a larger change in
Graded potentials vary in magnitude membrane potential. Figure 5 illustrates what
Graded potentials vary in magnitude (are graded) happens when different concentrations of neuro-
depending on the strength of the stimulus. A transmitter are present near the dendrite of a
175
Extracellular fluid
As we discussed above, graded
Ion Ions cannot cross the membrane potentials can either hyperpolarize or
Receptor depolarize the cell, depending on the
type of ion channel that is opened or
Plasma closed. The most important ion chan-
membrane
nels in the dendrites and cell body of
a neuron are Na, K, Cl, and Ca2
Ion channel in “closed” conformation
channels. From the Nernst equation
Cytoplasm we can calculate that opening Na or
(a) No neurotransmitter
Ca2 channels will depolarize a neu-
ron, while opening K or Cl chan-
nels will hyperpolarize a neuron.
Neurotransmitter
bound to receptor Some ions can cross the membrane
Graded potentials are short-
distance signals
Graded potentials can travel through
Some ion channels
the cell, but they decrease in strength
in “open” conformation as they get farther away from the
opened ion channel, a phenomenon
called conduction with decrement.
(b) Low concentration of neurotransmitter
Figure 6 shows a neuron with a lig-
and-gated Na channel on the mem-
Neurotransmitter bound brane. When neurotransmitter (the
to most receptors Many ions can cross the membrane
ligand) binds to a ligand-gated Na
channel, the channel opens and Na
ions move into the cell. Na entry
causes a local depolarization in a
small area of the membrane sur-
Most ion channels rounding the opened channel. This
in “open” conformation positive charge then spreads along the
inside of the membrane, causing de-
(c) High concentration of neurotransmitter polarization, a phenomenon termed
Figure 5 Stimulus strength and graded potentials electrotonic current spread. The ex-
tent of this depolarization decreases
neuron. When no neurotransmitter is present, as it moves farther and farther from the opened
the ligand-gated ion channels on the surface of channels, just as ripples in a pond decrease in
the dendrite remain closed, no ions can move strength as they move farther away from their
across the membrane through those channels, source. The signal is conducted, but it gets fainter
and the membrane potential stays the same. and fainter as it travels. With ripples in a pond, the
When the neurotransmitter is present at low con- ripples decrease in size with distance due to the fric-
centrations, a few ion channels open, allowing a tional resistance of the water. As we discuss in more
small number of ions to cross the membrane, detail later in the chapter, several features of the neu-
causing a small change in membrane potential. ron influence why a graded potential decreases as it
When a high concentration of the neurotransmit- travels through the cell, including leakage of charged
ter is present, many ion channels open, and stay ions across the cell membrane, the electrical resis-
open longer, allowing more ions to cross the tance of the cytoplasm, and the electrical properties
membrane, causing a large change in membrane of the membrane. As a result of these features, al-
potential. Thus, the amplitude of the graded po- though graded potentials can travel the short dis-
tential directly reflects the strength of the incom- tance from the dendrites to the axon hillock, they
ing stimulus. cannot travel longer distances without dying away.
176
Neurotransmitter 1
Graded potentials that are even
Neurotransmitter binds to a
larger than needed to trigger an
ligand-gated Na+ channel.
Na+
1 action potential are called sup-
+
2 Na enters cell through the rathreshold potentials.
open channel. Because the axon hillock
2 must reach the threshold poten-
3 Current spreads through tial in order to generate an ac-
the cell.
tion potential, graded potentials
3 can either increase or decrease
4 The strength of the signal
decreases with distance. the likelihood of an action po-
tential firing in the axon. A de-

polarizing graded potential
moves the membrane potential
4
at the axon hillock closer to the
Cell body threshold potential. A hyperpo-
of neuron larizing graded potential moves
the membrane potential at the
axon hillock farther from the
0 1.0 2.0 threshold potential. A depolar-
Distance from opened channel izing graded potential is called
(mm)
an excitatory potential be-
cause it makes an action poten-
tial more likely to occur by
Figure 6 Conduction with decrement bringing the membrane poten-
tial closer to the threshold poten-
tial. A hyperpolarizing graded
Because graded potentials cannot be trans- potential makes an action potential less likely to
mitted across long distances without degrading, occur (by taking the membrane potential farther
neurons use another type of electrical signal, the from the threshold potential), and so is called an
action potential, to transmit information across inhibitory potential.
distances of more than a few millimeters. Action
potentials are triggered by the net graded poten-
tial at the membrane of the axon hillock. The axon Graded potentials are integrated to trigger
hillock is sometimes called the trigger zone of the action potentials
neuron because it acts in a way similar to the trig- The dendrites and cell body of a neuron have re-
ger on a gun. If you pull the trigger on a gun hard ceptors at many sites on the membrane, and each
enough, the gun will fire. If you don’t pull the trig- neuron may have multiple kinds of receptors and
ger hard enough the gun will not fire. Similarly, if ion channels. Thus, neurons can generate many
a graded potential causes the membrane potential graded potentials simultaneously. Graded poten-
at the axon hillock to depolarize beyond the tials from different sites can interact with each
threshold potential, the axon will “fire” an ac- other to influence the net change in membrane
tion potential. If the membrane potential at the potential at the axon hillock; this phenomenon is
axon hillock does not reach the threshold poten- called spatial summation. In the example of
tial, the axon will not initiate an action potential spatial summation shown in Figure 8, a neuro-
(Figure 7). In many neurons, the threshold poten- transmitter opens ligand-gated Na channels in
tial is approximately 55 mV. Thus, the axon one dendrite, causing Na to enter the dendrite,
hillock must depolarize by more than 15 mV from and depolarizing that area of the membrane, but
the resting membrane potential of 70 mV in or- alone this depolarization is not sufficient to trigger
der to initiate an action potential. A graded poten- an action potential. Similarly, in the other den-
tial that is not large enough to trigger an action drite a neurotransmitter also opens a ligand-gated
potential is called a subthreshold potential. Na channel, but again this depolarization is not
177
perpolarizes that area of the membrane. These

–10 two graded potentials travel through the cell to the
axon hillock. In this example there is no change in

Subthreshold
–30 membrane potential at the axon hillock despite
depolarization
–50 Threshold potential the changes in membrane potential in the den-
drites, because change in membrane potential
–70
Resting membrane potential caused by the movement of Na into the cell in one
–90
dendrite exactly balances the change in mem-
brane potential caused by the movement of K out
–110 of the cell in the other dendrite. Thus, the net
change in membrane potential at the axon hillock
0 1 2 3 4 5 6 7 reflects the relative strengths and sign of the sig-
Time (msec) nals in the dendrites.
(a) Subthreshold graded potential Depolarizations that occur at two slightly dif-
ferent times can also combine to determine the
net change in membrane potential at the axon
hillock, a phenomenon called temporal summa-
+30
tion (Figure 9). Consider two depolarizations, E1
+10 Action and E2, each of 10 mV. If depolarization E2 occurs

potential after depolarization E1 has died out, then the max-
–10 imum depolarization is 10 mV, which is not large
Threshold
–30 depolarization
enough to trigger an action potential. In contrast,
if depolarization E2 occurs before E1 has died out,
–50 Threshold potential the two depolarizations build on each other and
–70
Resting membrane potential result in an increased net depolarization to a max-
imum of 20 mV, bringing the cell from the resting
–90 membrane potential of 70 mV beyond the
threshold potential of 55 mV, triggering an ac-
0 1 2 3 4 5 6 7 tion potential.
Time (msec) The axon hillock acts as a decision point for the
(b) Suprathreshold graded potential neuron. The neuron will fire an action potential in
Figure 7 Subthreshold and suprathreshold po- the axon only if the combination of all the graded
tentials The resting membrane potential of most neurons is potentials in the dendrites and cell body causes the
around 70 mV and the threshold potential is 55 mV. (a) Sub- axon hillock to depolarize beyond threshold. Spa-
threshold graded potentials (less than 15 mV) do not trigger tial and temporal summation of graded potentials
an action potential. (b) Graded potentials that are at or above allow a neuron to integrate inputs from many dif-
the threshold potential (greater than 15 mV) trigger an action ferent stimuli, and determine whether the axon
potential. hillock is depolarized beyond threshold and if an
action potential will occur in the axon.
sufficient to trigger an action potential. Both of
these depolarizations travel to the axon hillock, and
when they meet, they sum together to result in a net
depolarization that exceeds the threshold potential 2 C O N C EP T CH E CK
and triggers an action potential. It is important to
1. List the structures of a typical neuron, and
note that the phenomenon of spatial summation summarize their functions.
can also prevent action potential generation. Imag-
2. Describe how membrane permeability and ion
ine a situation in which a suprathreshold depolar- concentrations affect the membrane potential.
ization as the result of the opening of a 3. What is a gated ion channel? Why are gated ion
ligand-gated Na channel occurs at the same time channels important in neural signaling?
that, in the other dendrite, a neurotransmitter 4. How do graded potentials code information
opens ligand-gated K channels. Opening of K about the intensity of the incoming signal?
channels causes K to leave the dendrite, and hy-
178

–60 –60
–70 Dendrite A Dendrite B –70

Neurotransmitter
–80 –80
Time (msec) Na+ Time (msec)
Ligand-gated
Na+ channel
+30

Action
Cell body
potential
of neuron
–50
–70
Spatial
–90 summation
Time (msec)
Figure 8 Spatial summation Graded potentials from neurotransmitter binds to a ligand-gated Na channel in
different locations can interact to influence the net change in dendrite B, also causing a subthreshold depolarizing graded
membrane potential at the axon hillock. In the neuron shown potential. Both graded potentials travel electrotonically
above, neurotransmitter binds to a ligand-gated Na channel through the cell. At the axon hillock, these subthreshold
in dendrite A, opening the channel, and causing a depolarizations add together, causing a suprathreshold
subthreshold depolarizing graded potential. At the same time, depolarization that triggers an action potential in the axon.
membrane potential becomes even more negative

Signals in the Axon than the resting membrane potential, and may ap-
Action potentials can be transmitted across long proach the K equilibrium potential. The duration
distances without degrading, and differ from and size of this after-hyperpolarization phase
graded potentials in many respects (Table 1). Ac- varies greatly among neurons, typically lasting be-
tion potentials typically have three phases (Figure tween 2 and 15 msec, at which point the membrane
10a). The depolarization phase of the action po- returns to the resting membrane potential.
tential is triggered when the membrane potential The ability of an axon to generate new action
at the axon hillock reaches threshold (as a result potentials varies during the phases of the action po-
of the net graded potential at the axon hillock). tential. During the absolute refractory period,
Once the axon hillock reaches threshold, the adja- which coincides with the depolarization and repo-
cent axonal membrane quickly depolarizes, larization phases, the axon is incapable of generat-
reaching a positive membrane potential of about ing a new action potential, no matter how strong the
30 mV. The depolarization phase is followed by stimulus. During the relative refractory period,
a repolarization phase, during which the mem- which coincides with the after-hyperpolarization
brane potential rapidly returns to the resting phase, a new action potential can be generated, but
membrane potential. Following repolarization, the only by very large stimuli.
179
Table 1 Differences between graded potentials and

–10 action potentials.
–30 Graded potentials Action potentials
–50 Threshold potential Vary in magnitude Always the same magnitude

(in a given cell type)
–70 E1 E2
Vary in duration Always the same duration (in
a given cell type)
–90 Resting membrane potential
Decay with distance Can be transmitted across
–110 long distances
Occur in dendrites Occur in axons
1 2 3 4 5 6 7 and cell body
Stimulus Stimulus Caused by opening Caused by opening and

Time (msec) and closing of many closing of voltage-gated ion
kinds of ion channels channels
(a) No summation
+30
+10 of voltage-gated ion channels, allowing ions to

Action potential
move across the membrane.
–10
Because there is some variation in the ion
–30 channels involved in the action potential in axons
Threshold potential
from different species, here we concentrate on the
–50
model of the action potential developed for the gi-
E2
–70 E1 ant axon of the squid. The squid giant axon, which
we discuss in more detail later in this chapter,
–90 Resting membrane potential
sends signals from the central nervous system to
the muscle of the squid’s mantle cavity, and thus is
1 2 3 4 5 6 7
part of an invertebrate motor neuron. Opening of
Stimulus Stimulus voltage-gated Na channels initiates the depolar-
Time (msec) ization phase of the action potential, and opening
(b) Temporal summation resulting in an action potential
of voltage-gated K channels initiates the repolar-
ization phase in the squid giant axon. When the
Figure 9 Temporal summation Graded potentials membrane potential at the axon hillock ap-
occurring at slightly different times can interact to influence
the net graded potential. (a) Subthreshold depolarizations (E1
proaches the threshold potential (typically around
and E2) of 10 mV that do not overlap in time do not trigger an 55 mV), voltage-gated Na channels in the axon
action potential. (b) Subthreshold depolarizations that occur at hillock begin to open, changing the permeability of
slightly different times may sum, if they overlap in time. If the the membrane to Na ions (Figure 10b), allowing
net change in membrane potential exceeds the threshold, they
will trigger an action potential.
Na ions to move across the membrane. The prob-
ability that a given voltage-gated Na channel will
be open (termed the open probability of the chan-
nel) depends on the size of the graded potential.
An excitatory graded potential that depolarizes
Voltage-gated channels shape the action the membrane toward the threshold potential in-
potential creases the probability that a voltage-gated Na
Opening and closing of voltage-gated ion chan- channel will be open. Thus, at the threshold poten-
nels cause the characteristic phases of the action tial, more voltage-gated Na channels will be open
potential. Just as the binding of a neurotransmitter than when the axon hillock is at the resting mem-
changes the shape of a ligand-gated ion channel, brane potential, increasing the permeability of the
changes in membrane potential change the shape membrane to Na.
180
Absolute Relative tion potentials generally occur in the axon, not in

refractory refractory the cell body or dendrites of a neuron.
period period
If voltage-gated Na channels remained open
indefinitely, Na ions would enter the cell until the
Depolarization
+30
phase of action membrane potential reached approximately 60 mV
potential (the equilibrium potential for Na). However,

+10
shortly before the membrane reaches this point,
–10 Repolarization the voltage-gated Na channels close, terminating
phase of action
potential
the depolarization phase of the action potential.
–30 Depolarizing
graded
In addition to increasing the open probability
–50 potential Threshold potential of voltage-gated Na channels, threshold depolar-
Resting membrane potential ization of the membrane at the axon hillock in-
–70
creases the probability that voltage-gated K
–90 K+ membrane potential channels will open. But voltage-gated K channels
After–hyperpolarization open more slowly than voltage-gated Na chan-
(a)
nels. In fact, voltage-gated K channels only begin
to open in substantial numbers shortly before the
Relative membrane ion
voltage-gated Na channels close. When voltage-

Na+ gated K channels open, the permeability of the
membrane to K ions increases (Figure 10b), and
permeability
K ions leave the cell in response to their electro-

K+ chemical driving force, making the intracellular
side of the membrane more negative, and caus-
ing the repolarization phase of the action poten-
0 1 2 3 4 tial. The difference in the time it takes for
voltage-gated Na channels and voltage-gated K
Stimulus
channels to open in response to a threshold de-
(b) Time (msec)
polarization explains why repolarization occurs
Figure 10 The phases of a typical action after depolarization.
potential (a) Changes in membrane potential during an Following the repolarization phase, the voltage-
action potential. (b) Changes in membrane permeability
gated K channels close slowly, and may stay open
during an action potential.
even after the membrane has reached the resting
membrane potential of approximately 70 mV.
Because the electrochemical potential for K is
The Na influx from the first voltage-gated 90 mV, K ions continue to move out of the cell
channels to open in response to the graded poten- until the membrane is slightly hyperpolarized, as
tial further depolarizes the local region of the long as the channels remain open, accounting for
membrane, further increasing the probability that the after-hyperpolarization phase of action poten-
voltage-gated Na channels will open, causing tials such as those in the squid giant axon.
even more voltage-gated Na channels to open,
further increasing the permeability of the mem-
brane, allowing even more Na ions to enter the
Voltage-gated Na channels have two
cell. This positive feedback loop of Na entry rein-
gates
forces itself, resulting in the extremely rapid Figure 11 summarizes a model of the changes in
change in membrane Na permeability shown in the conformation of voltage-gated Na channels
Figure 10b, and accounting for the rapid depolar- during the action potential. When the membrane of
ization phase of the action potential. The density the neuron is at the resting membrane potential
of voltage-gated Na channels in the membrane (step 1), there is a high probability that a given
must be high in order for the positive feedback voltage-gated Na channel will be closed, prevent-
mechanism of the action potential to function. ing movement of Na ions across the membrane.
Since voltage-gated Na channels are usually When the membrane potential at the axon hillock
present at high concentration only in the axon, ac- reaches the threshold potential, the probability that
181

Extracellular fluid +30 1 When the neuron is at the
Na+ Na+ Na+ resting membrane potential
the activation gate closes
voltage-gated Na+ channels,
preventing Na+ entry.
Activation –55
gate –70
Cytoplasm Inactivation gate
Time

+30 2 A suprathreshold depolarizing
Na+ graded potential causes the
activation gate to open,
allowing Na+ to enter the cell.
–55
–70
Time
+30 3 Increased Na+ entry further

Na+ Na + Na+ depolarizes the cell, opening
even more voltage-gated Na+
channels in a positive
feedback loop, causing the
rapid depolarization phase of
–55
the action potential.
–70
Time
+30 4 The inactivation gate of the

Na+ Na+ Na+ channel closes as the
membrane approaches
+30 mV, preventing Na+ entry.
–55
–70 5 Over time, in response to the

rapid repolarization of the
membrane, the channel
Time returns to its original state.
Figure 11 A model for the action of voltage-gated Na channels
the channel will open increases greatly. To open, the the equilibrium potential for Na, the electrochem-
Na channel undergoes a conformational change ical gradient that acts as a driving force for Na
that opens an activation gate, allowing Na ions to movement decreases and Na entry slows.
move across the membrane (step 2). The opening of Meanwhile, a time-dependent conformational
the activation gate increases the permeability of the change occurs in the channel, closing an
membrane to Na. As Na enters the cell, more and inactivation gate (step 4). With the inactivation
more voltage-gated Na channels open, and the ax- gate closed, no more Na can enter the cell, termi-
onal membrane potential rapidly becomes less neg- nating the depolarization phase of the action po-
ative (step 3), depolarizing the cell toward the tential. Over several milliseconds, in response to
equilibrium potential for Na ions (approximately changes in the membrane potential caused by the
60 mV). As the membrane potential approaches actions of the voltage-gated K channels, the inac-
182
tivation gate resets, and the chan-

Resting
nel returns to its initial conforma- membrane
tion (activation gate closed, potential
inactivation gate open), ready to
initiate another action potential. Suprathreshold Time
Stimulus graded potential
Figure 12 summarizes the rela- in axon hillock
tionship between the voltage-gated
Na and K channels and how they Depolarization of membrane
produce the action potential. When
the axon hillock depolarizes be- – +
yond the threshold potential, both Negative Positive
Activation gate
the Na and K channels receive a feedback of voltage-gated feedback
+ channels
signal to open. The voltage-gated Na
opens
Na channels open very quickly, al-
lowing Na to enter the cell, caus-
ing further depolarization. This
Depolarization
greater depolarization opens even phase Na+ enters cell

more Na channels, causing even
greater depolarization in a positive
feedback cycle. As the axon hillock Voltage-gated Inactivation gate
approaches the equilibrium poten- K+ channels of voltage-gated
open Na+ channels
tial for Na, ion entry slows, and closes
the voltage-gated Na channels
close, preventing further Na entry,
and terminating the positive feed- K+ leaves cell Na+ entry stops
back loop of the depolarization Repolarization
phase. At about the same time, the phase
voltage-gated K channels begin to
open, K leaves the cell, and the in-
tracellular side of the membrane After-
becomes more negative, initiating hyperpolarization Voltage-gated
phase K+ channels
the repolarization phase of the ac- close
tion potential.
At the end of an action poten- Figure 12 Relationship of voltage-gated Na and K channels
tial, some Na ions have entered during an action potential A suprathreshold graded potential stimulates both

the cell and some K ions have Na and K channels to open. Na channels open immediately, and the resulting
influx of Na causes even more Na channels to open, in a positive feedback loop.
moved out, leaving the cell in a K channels open more slowly, becoming fully opened around the time that the
slightly different state from the Na channels close and causing an efflux of K ions that repolarizes the membrane.
starting point. From the preceding K ions may continue to leave the cell and cause the membrane to hyperpolarize.

discussion, you might think that Repolarization and hyperpolarization remove the stimulus to open K channels,
causing them to close.
large numbers of ions must move
across the cell membrane during
an action potential. In fact, the number of ions sands of repeated action potentials would even-
moving across the membrane is extremely small tually cause the Na and K gradients of the rest-
compared to the total number of ions in the intra- ing cell membrane to dissipate, changing the
cellular and extracellular fluids. As a result, the resting membrane potential of the cell, unless ion
changes in membrane potential during the action gradients were restored. As you might expect
potential are not associated with any measurable from its role in establishing the resting mem-
changes in ion concentrations inside or outside brane potential, the Na/K ATPase, plays a pri-
the cell. However, even though only relatively mary role in restoring ion gradients following
small numbers of ions actually move across the repeated action potentials.
membrane during a single action potential, thou-
183
Action potentials transmit signals across an action potential along the axon represents a
long distances combination of action potentials occurring at spe-
cific points along the axon, and local flow of ions
Up to this point we have discussed how an action
and electrical current along the axon, which trig-
potential occurs at the axon hillock, but we have
gers action potentials further downstream. Be-
not considered how action potentials travel along
cause of the all-or-none nature of the action
the axon. One property of the action potential,
potential, each action potential that is generated
which is sometimes termed its “all-or-none” na-
along the axon is essentially identical to all the
ture, is crucial in allowing neurons to transmit
other action potentials along the axon. In this way,
electrical signals across long distances. Action po-
electrical signals can be transmitted across long
tentials are often described as all-or-none phe-
distances along the axon without degrading.
nomena because once an action potential has been
initiated (by the opening of a sufficient number of
voltage-gated Na channels), it always proceeds to Vertebrate motor neurons are myelinated
its conclusion; it never stops halfway through, or The axons of vertebrate motor neurons are wrapped
fails to reach its peak depolarization. But how in an insulating layer of myelin (Figure 14). Special-
does this property allow action potentials to travel ized lipid-rich cells called Schwann cells form the
along the axon, potentially across long distances? myelin sheath by wrapping in a spiral pattern
In fact, individual action potentials do not ac- around the axon of the neuron. Schwann cells are
tually travel along the axon. Instead, an action po- one of a large class of cells that are collectively
tential in one part of the axon triggers other action known as glial cells, which we discuss later in this
potentials in adjacent areas of the axonal mem- chapter. Several Schwann cells may wrap long ax-
brane. The transmission of an action potential is ons, separated by areas of exposed axonal mem-
similar to what happens when you knock over the brane called nodes of Ranvier that contain high
first in a long line of dominoes. The first domino densities of voltage-gated channels. In contrast, the
that is knocked over starts the next domino falling, myelinated regions of the axons are termed the in-
which starts the next domino, and so on down to ternodes. In myelinated axons, current spreads
the end of the line. In neurons, the first action po- electrotonically through internodes, while action
tential at the axon hillock causes another action potentials occur only in the nodes of Ranvier. This
potential farther down the axon, and so on down mode of action potential propagation is termed
to the axon terminal. Just as the last domino in a saltatory conduction from the Latin word saltare
series of falling dominoes is identical to the first (to leap or dance) because the action potential ap-
domino, the last action potential at the axon termi- pears to jump from node to node along the axon. As
nal is identical to the first action potential at the we discuss in more detail later in the chapter, all
axon hillock. Thus, action potentials can be con- else being equal, saltatory conduction along a
ducted across long distances without decaying. myelinated axon is more rapid than conduction
Figure 13 summarizes the mechanism of ac- along an unmyelinated axon. This is because elec-
tion potential conduction along the axon. During trotonic currents can travel farther with less degra-
an action potential, the Na ions entering via the dation through the internodes than through an
voltage-gated Na channels depolarize the section equivalent region of unmyelinated axon, and elec-
of the membrane immediately surrounding the trotonic current spread is much faster than gener-
channel. This depolarization can then spread along ating an action potential.
the axon by electrotonic current spread, just as the
depolarizations associated with graded potentials
can spread through the dendrites and cell body. Axons conduct action potentials
When the membrane in the adjacent region of the unidirectionally
axon reaches the threshold potential, voltage-gated If you electrically stimulate an axon halfway along
Na channels in this region open and trigger an- its length, action potentials will be generated in both
other action potential. The cycle of ion entry, cur- directions (toward the axon hillock and toward the
rent spread, and triggering of an action potential axon terminal). In a natural action potential, how-
continues along the axon from the axon hillock to ever, the stimulus always starts at the axon hillock
the axon terminal, causing a wave of depolariza- and travels toward the axon terminal, with little or
tion to spread along the axon. Thus, conduction of no conduction in the reverse direction. Since the de-
184
Extracellular fluid A B C 1 When an action potential

occurs at A on the membrane,
mV mV mV Na+ enters the axon through
opened voltage-gated Na+
Voltage-gated Na+ channels. This action potential
Na+ channel depolarizes the membrane at
– – – – – – – – + + + + + + + + + + + + + +
A to +30 mV.
+ + + + + + + + + – – – – – – – – – – – – – – – –
Cytoplasm
A B C 2 The depolarization due to the

action potential at A spreads
mV mV electrotonically by local
current flow through the axon,
+
Na depolarizing adjacent areas of
+ + + – – – – – – + + + + + + + + + + + + + + the membrane toward
threshold (–55 mV).
– – – + + + + + + – – – – – – – – – – – – – – – –
A B C 3 When the depolarization at

B reaches threshold,
mV mV voltage-gated Na+ channels at
B open, initiating an action
Na+ potential that depolarizes B
+ + + + + + + + + – – – – – – + + + + + + + + to +30 mV.
– – – – – – – – – + + + + + + + – – – – – – – – –
A B C 4 The depolarization due to the

action potential at B spreads
mV electrotonically by local current
flow through the axon,
Na+ depolarizing adjacent areas of
+ + + – – – – – – + + + + + + + + + the membrane toward threshold
(–55 mV), triggering
an action potential at C .
Voltage-gated Na+ channels at
– – – + + + + + + – – – – – – – – – – A are inactivated (and thus
refractory), so a new action
potential is not initiated at A .
Figure 13 Conduction of action potentials Na that enters the axon through
voltage-gated Na channels induces a local depolarization. This local depolarization spreads
along the axon via electrotonic conduction, triggering additional action potentials further down
the axon. This process of electrotonic current spread and new action potential initiation
continues down to the end of the axon. Each action potential is essentially the same as the
preceding ones, resulting in conduction without decrement.
polarization caused by the Na entering through tential (that started at the axon hillock and is being
voltage-gated Na channels spreads in all directions transmitted toward the axon terminal) at any point
along the axon, why do action potentials occur only along the membrane, the region just upstream of
in the downstream direction (toward the axon ter- the point you are observing must have recently pro-
minal) rather than also spreading backward toward duced an action potential (since action potentials
the axon hillock? If you examine a natural action po- are initiated at the axon hillock). As a result, the
185
Action potential frequency

carries information
How can an all-or-none signal like
the action potential carry informa-
tion about the strength of the graded
potential in the cell body? Action po-
tentials carry information by chang-
Nodes of Cell body ing frequency rather than amplitude.
Ranvier Internode As shown in Figure 15, a subthresh-
old stimulus does not trigger an ac-
tion potential, whereas a brief
stimulus at threshold might trigger a
Axon single action potential. If the thresh-
Myelinated old stimulus continues longer than
axon
the absolute and relative refractory
periods, additional action potentials
are generated. During the relative
refractory period, a new action po-
Nucleus Schwann cell Myelin sheath tential may be triggered if a large
(cross-section) stimulus causes the membrane po-
tential to reach threshold despite its
Figure 14 Structure of the myelin sheath Schwann cells wrap around
the axon many times, insulating the axon and forming the myelin sheath. The myelin initial hyperpolarized state. Thus, a
sheath is interrupted at regular intervals by the nodes of Ranvier, which are areas of suprathreshold stimulus may trigger
unmyelinated axon. more frequent action potentials by al-
lowing action potentials to occur dur-
voltage-gated Na channels in this upstream region ing the relative refractory period. Because action
of the axon are in a conformation in which they are potential frequency is related to the strength of the
unable to open in response to change in the mem- stimulus, neurons can use an all-or-none signal, the
brane potential (i.e., with their activation gate open action potential, to carry information about signal
and their inactivation gate closed, as illustrated in strength. The maximum frequency at which action
Figure 11, step 4). During this time, which corre- potentials can be generated is limited by the length
sponds to the absolute refractory period (Figure of the absolute refractory period, during which new
10), voltage-gated Na channels are incapable of action potentials cannot be generated regardless of
generating additional action potentials. This pre- the strength of the signal. In most mammalian neu-
vents backward (retrograde) transmission of action rons, the maximum frequency of action potential
potentials. The absolute refractory period also pre- generation is approximately 500–1000/sec.
vents summation of action potentials, because a
new action potential can only be triggered once the
absolute refractory period is completed.
Following the absolute refractory period, the
membrane enters the relative refractory period 5. Compare and contrast action potentials and
(Figure 10). During the relative refractory period, graded potentials.

the voltage-gated Na channels have reset and are 6. How do action potentials code information about
capable of initiating another action potential, but the intensity of the incoming signal?
new action potentials are more difficult to gener- 7. Why does the membrane potential become
ate because the membrane is hyperpolarized. As a positive during the depolarization phase of the
action potential?
result, a larger depolarization is required to reach
threshold. Only a very strong stimulus can cause 8. Why can action potentials be conducted across
long distances along the axon without degrading,
an action potential during the relative refractory when graded potentials die out within a few
period. Together, the absolute and relative refrac- millimeters?
tory periods prevent retrograde transmission of 9. What limits the frequency of action potentials?
action potentials.
186
kinds of postsynaptic cells, including muscle and

+30
Membrane potential (mV) endocrine cells. The synapse between a motor
One action Repeated
+10 potential action neuron and a skeletal muscle cell, which we dis-
–10 potentials cuss in detail in this part of the chapter, is termed
–30 Threshold the neuromuscular junction.
–50 potential
–70
Intracellular Ca2 regulates
–90
neurotransmitter release
Much of what we know about the biochemical
Subthreshold Brief Sustained events at the synapse has been learned from
stimulus threshold threshold
stimulus stimulus studying the neuromuscular junction. The mecha-
nism of synaptic transmission at the neuromuscu-
(a) A weak stimulus triggers a low frequency of action potentials
lar junction is outlined in Figure 16. When an
action potential reaches the membrane of the
presynaptic axon terminal of the neuromuscular
+30
junction, the resulting depolarization triggers the

+10
opening of voltage-gated Ca2 channels on the cell
–10 membrane of the axon terminal. The concentra-
–30 Threshold tion of Ca2 inside the neuron is much lower than
–50 potential the concentration of Ca2 outside the neuron, the
–70 equilibrium potential for Ca2 is 130 mV (as cal-
–90 culated using the Nernst equation), and the resting
membrane potential is 70 mV. Thus, both con-
centration and electrical gradients favor the move-
Sustained Sustained ment of Ca2 into the cell. The resulting increased
threshold suprathreshold
stimulus stimulus Ca2 concentration inside the axon terminal acts as
(b) A suprathreshold stimulus triggers a high frequency of
a signal to neurotransmitter-containing synaptic
action potentials vesicles. These vesicles are not randomly dis-
tributed within the synapse. Instead, they are
Figure 15 Frequency of action potentials Action
potential frequency relates to stimulus frequency. (a) A weak grouped into at least two distinct pools: a readily
stimulus triggers a low frequency of action potentials. (b) A releasable pool, and a storage pool. The readily
sustained suprathreshold stimulus triggers more frequent releasable pool of vesicles is located at the active
action potentials. A sufficiently large suprathreshold stimulus
zone of the synapse, bound to docking proteins
can trigger a new action potential during the relative
refractory period of the previous action potential. The at the synaptic membrane, ready to release their
maximum frequency of action potentials is limited by the contents by exocytosis. The storage pool, in con-
absolute refractory period of the voltage-gated Na channels. trast, consists of vesicles bound to the cytoskele-
ton, and not docked to the membrane. The Ca2
signal causes vesicles from the readily releasable
Signals Across the Synapse pool to fuse with the plasma membrane and re-
Once the action potential reaches the axon termi- lease their contents by regulated exocytosis, in a
nal, the fourth important functional zone of a neu- process similar to the release of other intercellu-
ron, the neuron must transmit the signal carried lar signaling molecules. The Ca2 signal also
by the action potential across the synapse to the causes vesicles from the storage pool to move to
target cell. The cell that transmits the signal is re- the active zone of the plasma membrane and
ferred to as the presynaptic cell, and the cell re- bind to docking proteins, ready for release fol-
ceiving the signal is called the postsynaptic cell. lowing subsequent action potentials.
The space between the presynaptic and post- Each vesicle contains many molecules of neu-
synaptic cell is referred to as the synaptic cleft. rotransmitter, and the number of molecules of
Together, these three components make up the neurotransmitter within a vesicle is similar for all
synapse. Neurons can form synapses with them- vesicles within a neuron. With increasing action
selves, with other neurons, and with many other
187
Plasma
Action membrane of 1 Action potentials arrive at axon terminal.
Presynaptic potential Axon terminal presynaptic cell
cell
2 Voltage-gated Ca2+ channels open.
1
Voltage-gated 3 Ca2+ enters the cell.
2 Ca2+ channel
Synaptic
vesicles
4 Ca2+ signals to vesicles.
Ca2+
3 4
5 Vesicles move to the membrane.
5
Neurotransmitter
6 Docked vesicles release neurotransmitter
6 by exocytosis.
7 Neurotransmitter diffuses across the

Synaptic Plasma membrane Neurotransmitter synaptic cleft and binds to receptors.
cleft of postsynaptic cell Docking bound to receptor
protein
7 8 Binding of neurotransmitter to receptor
Postsynaptic activates signal transduction pathways.
cell 8
Receptor Signal transduction pathways
Figure 16 Events of signal transmission at a chemical synapse
potential frequency, more and more vesicles move ter release? After the arrival of a single action po-
to the membrane and release their contents by tential at the axon terminal, Ca2 enters the cell
exocytosis. Because each vesicle contains many through activated voltage-gated Ca2 channels.
molecules of neurotransmitter, the amount of neu- This Ca2 is, however, quickly bound up by intra-
rotransmitter a neuron releases increases in a cellular buffers or removed from the cytoplasm by
steplike fashion, with each step corresponding to Ca2 ATPases, keeping intracellular Ca2 concen-
the contents of a vesicle, rather than increasing in tration low and limiting the release of neurotrans-
a smoothly graded fashion as would happen if mitter. In contrast, when action potentials arrive
neurotransmitter were released one molecule at a at the axon terminal at high frequency, the
time. This pattern of release is termed the quantal processes removing Ca2 from the cell cannot
release of neurotransmitter. However, under nor- keep up with the influx of Ca2 through the acti-
mal physiological conditions most neurons re- vated channels, and the intracellular Ca2 concen-
lease many synaptic vesicles when stimulated, so tration increases. This increased intracellular
the quantal release of transmitter is not generally Ca2 provides a stronger signal for exocytosis.
apparent. Thus, the signal intensity that was coded by action
potential frequency is translated into differences
in the amount of neurotransmitter released by the
Action potential frequency influences neuron.
neurotransmitter release
The amount of neurotransmitter released at a
synapse is related to the frequency of action poten- Acetylcholine is the primary
tials at the axon terminal. Weak signals, resulting neurotransmitter at the vertebrate
from low-frequency action potentials, cause fewer neuromuscular junction
synaptic vesicles to release their contents, whereas Although the motor neurons of invertebrates
strong signals, resulting from high-frequency ac- release other neurotransmitters, vertebrate
tion potentials, cause more synaptic vesicles to re- motor neurons release the neurotransmitter
lease their contents. But how is action potential acetylcholine (ACh) into the synapse. ACh is a
frequency coupled to the extent of neurotransmit- biogenic amine that is synthesized from the
188
amino acid choline. ACh synthesis occurs in the portant role in regulating the strength of the signal
axon terminal in a reaction catalyzed by the en- to the postsynaptic cell by regulating the concen-
zyme choline acetyl transferase: tration of neurotransmitter at the synapse.
Acetyl CoA choline → ACh CoA
Acetyl CoA from the mitochondria is combined Postsynaptic cells express specific
with the amino acid choline to form ACh and coen- receptors
zyme A. The ACh is packaged into synaptic vesi- The responses of postsynaptic cells to neurotrans-
cles and stored until an action potential arriving at
mitters are similar to the responses of target cells
the axon terminal triggers its release. ACh then
to hormones and other chemical messengers.
diffuses into the synapse and binds to receptors on
Postsynaptic cells detect neurotransmitters using
the postsynaptic cell membrane.
specific cell-surface receptors. When a neuro-
transmitter binds to its receptor, the receptor
changes shape. This change in shape of the re-
Signaling is terminated ceptor acts as a signal in the target cell. Skeletal
by acetylcholinesterase muscle cells express a class of receptor called
The signaling between a ligand such as a neuro- nicotinic ACh receptors, which were named
transmitter and its receptor must be terminated in because of their ability to bind to the drug nico-
order to be effective. A specific enzyme in the tine (the active ingredient in tobacco). Nicotinic
synapse, called acetylcholinesterase, removes ACh receptors are ligand-gated ion channels.
the ACh from its receptor, breaking the ACh down When ACh binds to a nicotinic receptor, the re-
into choline and acetate (Figure 17). The choline is ceptor changes shape, opening a pore in the mid-
taken up by the presynaptic neuron and reused to dle of the receptor that allows ions to cross the
form ACh, while the acetate diffuses out of the membrane. Nicotinic ACh receptors contain a
synaptic cleft. Acetylcholinesterase plays an im-
Plasma
Mitochondria membrane of 1 Acetyl CoA is synthesized in the
Presynaptic
presynaptic mitochondria.
cell
neuron
1 2 Choline acetyl transferase catalyzes the
conversion of choline and acetyl CoA
to acetylcholine (ACh).
Acetyl CoA 2
+ ACh 3 The ACh is packaged into synaptic
Choline
3 vesicles.
Choline acetyl
transferase
ACh 4 ACh is released into the synapse.
4 5 ACh binds to its receptor on the

postsynaptic cell.
Synaptic 6 Acetylcholinesterase (AChE) breaks

7 Choline
cleft down ACh into choline and acetate,
Acetate
AChE 5 terminating the signal in the
6 postsynaptic cell.
Postsynaptic
cell Plasma ACh receptor 7 The presynaptic cell takes up and
membrane of recycles the choline, and the acetate
postsynaptic Effects in
postsynaptic diffuses out of the synapse.
neuron
neuron
Figure 17 Synthesis and recycling of acetylcholine (ACh) at the synapse
189
relatively nonselective channel that is permeable the cell membrane. If there is a very low density of
to Na, K, and to a lesser extent Ca2; however, receptors on the postsynaptic membrane, neuro-
graded potentials in the postsynaptic cell caused transmitter will cause a weak response. If the den-
by these channels are dominated by Na ions be- sity of receptors on the postsynaptic membrane is
cause of the high driving force for Na influx rel- very high, the response will be larger. The density
ative to K efflux (as predicted by the Nernst of receptors on the postsynaptic cell can be regu-
equation). ACh binding to nicotinic receptors on lated by a variety of factors, including genetic vari-
skeletal muscle cells always causes a rapid exci- ation among individuals, the metabolic state of the
tatory postsynaptic potential because the result- postsynaptic cell, and specific drugs and disease
ing influx of Na depolarizes the postsynaptic states.
muscle cell. These excitatory potentials initiate The human disorder myasthenia gravis is an
muscle contraction. example of a disease state caused by alterations in
receptor number on muscle cells. People with
myasthenia gravis experience muscle weakness
Neurotransmitter amount and receptor and increased susceptibility to muscle fatigue, par-
activity influence signal strength ticularly in muscles that are used repeatedly. These
As in ligand-receptor interactions, both the symptoms are the result of an autoimmune condi-
amount of neurotransmitter present in the tion in which antibodies from a person’s immune
synapse and the number of receptors on the post- system destroy ACh receptors at the neuromuscu-
synaptic cell influence the strength of signal in the lar junction. The decrease in receptor number re-
target cell. Small amounts of neurotransmitter duces the intensity of the signal in the postsynaptic
provoke relatively small responses in the postsy- muscle cell at any given level of acetylcholine re-
naptic cell. As neurotransmitter concentration in- lease, which reduces the strength of muscle con-
creases, the response of the postsynaptic cell tractions and causes muscle weakness.
increases up to the point that all of the available The symptoms of myasthenia gravis can be
receptors are saturated. treated with a class of drugs called acetyl-
The concentration of neurotransmitter in the cholinesterase inhibitors. By partially inhibiting
synapse is a result of the balance between the rate the enzyme acetylcholinesterase, these drugs re-
of neurotransmitter release from the presynaptic duce the rate of removal of ACh from its recep-
cell and the rate of removal of the neurotransmit- tors, increasing the concentration of ACh in the
ter from the synapse. As we have already dis- synapse. This increase in ACh prolongs the ef-
cussed, the amount of neurotransmitter that is fects of this neurotransmitter, partially compen-
released from the presynaptic cell is largely a func- sating for the decreased number of ACh
tion of the frequency of action potentials at the receptors in patients with myasthenia gravis.
presynaptic axon terminal. In contrast, the removal Thus, these drugs can help to reduce the symp-
of neurotransmitter from the synapse depends on toms of muscle weakness and fatigue. However,
three main processes: (1) Neurotransmitters the dosage of acetylcholinesterase inhibitors
can simply diffuse passively out of the synapse. must be carefully controlled because at high lev-
(2) Surrounding cells, including presynaptic neu- els they can be deadly. Indeed, organophosphate
rons, can also take up neurotransmitter. These pesticides and chemical weapons such as the
cells act as important regulators of many neuro- nerve gas sarin are acetylcholinesterase in-
transmitters. (3) Enzymes present in the synapse hibitors. Like the drugs used to treat myasthenia
can degrade neurotransmitters. As we have al- gravis, these chemicals work by inhibiting the
ready discussed, at the neuromuscular junction, degradation of ACh by acetylcholinesterase. At
acetylcholinesterase activity is the most important high doses, these agents greatly increase the con-
determinant of ACh concentration. centration of ACh in the synapse. At the neuro-
At any given amount of neurotransmitter, the muscular junction, these large increases in ACh
response of the postsynaptic cell is also dependent lead to overexcitation of the muscle, causing
on the number of receptors present on the target twitching and other forms of uncoordinated mus-
cell. As you would expect, a postsynaptic cell can cle contraction, potentially leading to muscle fa-
only respond if it has the appropriate receptors in
190
tigue, paralysis, severe difficulty in breathing, form of neurotransmitters. Many chemical sub-
and ultimately death because of increasing fa- stances can act as neurotransmitters, and we dis-
tigue and paralysis of the respiratory muscles. cuss some of this diversity later in the chapter in
Lower doses of these agents also cause a range of our consideration of the diversity of synaptic
other symptoms because, as we discuss in the transmission. But neurons are also capable of de-
second half of the chapter, ACh acts as a neuro- tecting many kinds of incoming signals in addition
transmitter not just at the neuromuscular junc- to chemical signals in the form of neurotransmit-
tion but also at many other synapses, causing a ters. Some neurons are specialized to detect in-
wide variety of effects. coming signals such as temperature, pressure,
light, or environmental chemicals. The mecha-
nisms that neurons use to detect these signals are
extremely diverse, but they share one fundamen-
2 CO NC E P T C HE C K
tal characteristic. Whatever the incoming signal,
10. Describe the relationship between action membrane-bound receptors in the dendrites of
potential frequency and neurotransmitter the sensory neuron receive the signal and trans-
release.
duce it into an electrical signal in the form of a
11. What determines whether a neurotransmitter will change in the membrane potential. Because of the
depolarize or hyperpolarize a postsynaptic cell?
diversity and complexity of these processes, we do
12. Why does increasing the amount of
not consider them in detail here. In this chapter
neurotransmitter increase the response of the
postsynaptic cell? Why does the response reach a we focus on the diversity of signal conduction and
maximum, and not increase even when transmission, looking first at the diversity of the
additional neurotransmitter is added? action potential and the conduction velocity of ac-
tion potentials along the axon. Then we examine
some of the enormous diversity of synaptic trans-
Diversity of Neural Signaling mission. We conclude the chapter with a discus-
sion of the evolution of neurons.
Now that we have examined how signals travel
from one end of a motor neuron to the other, we
can begin to address some of the enormous diver-
sity in these processes among neurons from a sin-
Structural Diversity of Neurons
gle organism, and among neurons from different Although most neurons have dendrites, a cell body,
kinds of organisms. The diversity of neuron struc- and an axon, the details of neuron structure vary
ture and function allows neurons to play many greatly at the cellular level. Some neurons have rel-
roles. Some neurons (including the motor neurons atively simple structures, while others have com-
that we have already discussed) are specialized to plex, highly branched structures (Figure 18a).
transmit signals very rapidly across long dis- There is no clear correlation between the com-
tances, while other neurons are specialized to in- plexity of an organism and the complexity of its
tegrate many incoming signals and process them neurons. Instead, the structure of a neuron relates
to produce a response. We begin this section by to the function of that particular neuron. For ex-
examining the structural diversity of neurons, ample, neurons within the mammalian brain typ-
looking at how neuron structure relates to neuron ically have large numbers of dendrites, but may
function. We then look at some of the important lack an obvious axon. The many dendrites of these
processes performed by neurons to see how they neurons allow them to integrate an enormous
vary among neurons that perform different phys- number of incoming signals from other neurons.
iological roles in a variety of animal species. In contrast, the dendrites and axon of a motor
Neurons perform three distinct functions. neuron can easily be distinguished, as the axon is
They receive and integrate incoming signals, they typically much longer than the dendrites. These
conduct these signals through the cell, and they neurons are specialized for rapid, long-distance,
transmit these signals to other cells. In the first electrical signaling.
part of the chapter we discussed how vertebrate
motor neurons detect incoming signals in the
191
Cell
Cell body Cell
body body
Cell Cell
Cell body body
body
Cell
body
Neuron from
Purkinje cell of cnidarian
mammalian Vertebrate
cerebellum olfactory
neuron Insect
mechanoreceptor
Vertebrate neuron
motor Insect sensory
Vertebrate
neuron neuron
retinal
neuron
(a) Structural diversity of neurons
Dendrite
Reception Cell
body
Integration Dendrite
Axon
Cell Cell
body body
Conduction
Axon Axon
Axon
Transmission
Interneuron
Multipolar Bipolar Unipolar

Efferent neuron Sensory neuron neuron neuron neuron
(b) Functional classes of neurons (c) Structural classes of neurons
Figure 18 Variation in neuron structure and neurons convey signals from the nervous system to effector
function (a) Structural diversity of neurons. Neurons organs. (c) Structural classes of neurons. Multipolar neurons
always have a cell body, one axon, and at least one dendrite, have one obvious axon and multiple dendrites. Bipolar
but the number of dendrites, the position of the cell body, and neurons have a single branched dendrite and an obvious
the length of the axon can vary. (b) Functional classes of axon. Unipolar neurons have a single large axon that
neurons. Sensory neurons detect incoming signals. branches into two main processes. Note the variation in the
Interneurons form connections among neurons. Efferent location of the integrating center among these neurons.
located within the central nervous system, and

Neurons can be classified based convey signals from one neuron to another.
on their function Efferent neurons convey signals from the central
Neurons can be divided into one of three classes, nervous system to effector organs. The motor
depending on their functions (Figure 18b). neurons that we have already discussed are
Sensory (or afferent) neurons convey sensory in- one class of efferent neuron. In the case of
formation from the body to the central nervous motor neurons the effector is always a
system (which consists of the brain and spinal skeletal muscle, but other types of efferent neu-
cord in the vertebrates). Interneurons are
192
rons communicate with a variety of effector or- action potentials, which are conducted along the
gans including smooth muscles and endocrine axon to the axon terminal. This general scheme
glands. fits well for most multipolar neurons, although not
all multipolar neurons generate action potentials.
In some multipolar neurons with very short axons,
Neurons can be classified based electrotonic current spread is sufficient to convey
on their structure information along the axon.
Although there is substantial diversity in the struc- In a bipolar neuron, just as in a multipolar
ture of neurons, most of this diversity falls within neuron, receptors in the membrane at the end of
one of three major structural types (Figure 18c). one of the processes detect incoming signals and
The vertebrate motor neurons that we discussed transduce them into a graded potential. This
in the first part of this chapter are examples of graded potential spreads electrotonically to the
multipolar neurons. These neurons have many cell body, where it triggers action potentials in the
cellular extensions (or processes) leading from the second process, which acts as an axon. The exact
cell body. Only one of these processes is an axon, location of the trigger zone varies among bipolar
whereas the remaining processes are dendrites. neurons, and (like multipolar neurons) some kinds
Multipolar neurons are the most common type of of bipolar neurons do not use action potentials to
neuron in the vertebrates. Bipolar neurons have convey signals along the axon.
two main processes extending from the cell body, In a unipolar neuron, the dendrites detect in-
one of which is highly branched and conveys sig- coming signals and transduce them into graded po-
nals to the cell body, and thus is functionally simi- tentials, as in the other types of neurons. These
lar to a dendrite, and the other of which conveys graded potentials do not, however, travel directly to
signals away from the cell body, and thus acts as the cell body. Instead, they travel only as far as the
an axon. Some sensory neurons, such as retinal beginning (or initial segment) of the process that
cells and olfactory cells, are bipolar neurons. How- leads to the cell body. If the graded potential in this
ever, few other vertebrate neurons have this form, initial segment exceeds threshold, it will trigger an
and bipolar neurons are thus the least common action potential. These action potentials then travel
type of neuron in the vertebrate nervous system. A toward the cell body, and onward to the axon termi-
unipolar neuron has a single process from the nal. As a result of this arrangement, there has been
cell body. In most unipolar neurons, however, this some disagreement as to whether to call the first of
process splits into two main branches. As a result, these long extensions of a unipolar neuron an axon
these cells are sometimes termed pseudo- or a dendrite, because it is functionally similar to an
unipolar. One of these two branches conveys sig- axon in that it can generate action potentials, but it
nals toward the cell body, and the other conveys conducts impulses toward the cell body rather than
signals away from the cell body. Unipolar neurons away from the cell body and thus is functionally
are generally sensory neurons that are involved in similar to a dendrite. For the purposes of this text,
detecting environmental signals and conveying we will refer to both of the processes of a unipolar
this information to the rest of the nervous system. neuron as axons. The important point to keep in
From Figure 18c you can see that the cell body, mind, however, is that the integrating center is lo-
dendrites, and axon are arranged differently in cated in a very different position in a unipolar neu-
each of these types of neuron. This change in ron compared to a multipolar neuron.
arrangement has important implications for the Neurons from invertebrates can also be
functions of each of the zones of the neuron. In a grouped into these main structural classifications,
multipolar neuron, such as the vertebrate motor and are organized in ways similar to the verte-
neurons that we have already discussed, receptors brate neurons that we have discussed so far. In the
in the dendrites and cell body detect incoming sig- invertebrates, however, unipolar neurons are
nals and transduce them into an electrical signal more common than they are in the vertebrates. In-
in the form of a graded potential. Incoming graded deed, invertebrate motor neurons are often unipo-
potentials are conducted electrotonically to the lar, rather than multipolar. Whether in an
axon hillock, which acts as the integrating center invertebrate or a vertebrate, however, most neu-
for the neuron. If the graded potential at the axon rons share the common property of polarity. One
hillock exceeds the threshold potential, it triggers
193
end of the neuron receives incoming signals, and cently, these glial cells were believed to play a
the other end of the neuron transmits signals to rather passive role in the nervous system, and
other cells. Cnidarians, including sea anemones their name (which is derived from the Greek word
and jellyfish, provide an exception to this rule. glia glue) reflects this view. However, we now
Some cnidarian neurons lack polarity. That is, they know that glial cells play a wide variety of critically
are capable of sending and receiving signals at ei- important roles in the nervous system.
ther end and can conduct signals in either direc- In the vertebrates, there are five main types of
tion along the neuron. This difference has glial cells (Figure 19). Schwann cells, which form
important implications for the unique organiza- the myelin sheath, are associated with motor neu-
tion of the nervous system in cnidarians. rons and many sensory neurons. Schwann cells
play an important role in neural signaling by in-
creasing the conduction speed of action potentials
Neurons are associated with glial cells along the axon. They are also essential for the regen-
As we mentioned in the first half of this chapter, eration and regrowth of damaged sensory and mo-
vertebrate motor neurons are associated with a tor neurons. When a neuron is damaged, Schwann
type of glial cell called a Schwann cell. But cells digest the damaged axon and provide a path-
Schwann cells are not the only type of glial cell in way for neuronal regrowth. Oligodendrocytes
the vertebrates. In fact, glial cells far outnumber form a myelin sheath for neurons in the central ner-
neurons in most organisms. For example, 90% of vous system (CNS). A single oligodendrocyte may
the cells in the human brain are glia. Until re- wrap around the axons of several neurons, and
thus differs from a Schwann cell, which always en-
wraps a single neuron. Astrocytes have large stel-
Ventricle late (star-shaped) cell bodies and many processes.
They are located in the central nervous system and
Ependymal play a variety of roles including transporting nutri-
cell ents to neurons, removing debris, guiding neu-
ronal development, and regulating the contents of
the extracellular space around neurons (including
Capillary regulating synaptic neurotransmitter levels). In
fact, astrocytes in the brain often enwrap synapses
and may play an important role in regulating
synaptic communication by regulating neurotrans-
mitter levels. Microglia are involved in neuronal
maintenance. Microglia are the smallest glial cells.
Neuron
They are similar to the macrophages of the im-
Astrocyte mune system, and they function to remove debris
and dead cells from the central nervous system.
Microglia are most active following trauma or dur-
ing disease. Ependymal cells line the fluid-filled
cavities of the central nervous system. They often
have cilia, which they use to circulate the cere-
brospinal fluid that bathes the central nervous sys-
tem of vertebrates.
Although glial cells maintain a resting mem-
Oligodendrocyte
brane potential, they do not generate action po-
Microglial tentials, nor do they form obvious chemical
cell
CNS synapses. However, despite their lack of obvious
PNS chemical synapses, glial cells can take up and re-
lease neurotransmitters, and thus may have im-
Schwann
cell portant effects on neurons. In addition, some
glial cells in the central nervous system, such as
Figure 19 The primary glial cells of vertebrates
194
astrocytes, form connections with each other and to consider. Both the shape of the action potential
with neurons via gap junctions. Astrocytes actively and the speed of action potential conduction along
communicate with each other through these gap the axon vary among neurons. In the first half of the
junctions using intracellular Ca2 and other signal- chapter we considered the shape of an action po-
ing molecules. The presence of gap junctions sug- tential in a squid giant axon, and most action poten-
gests a complex interchange of signals between tials conform to this general form. However, the
neurons and glia, which may be important in reg- exact shape of the action potential can vary among
ulating the function of the nervous system. neurons from different organisms, between types of
Glial cells in invertebrates have a wide range neurons from the same organism, and even among
of morphologies, depending on their location in action potentials within the same neuron under dif-
the organism and the species being examined. In- ferent physiological conditions. The variations in
vertebrate glial cells are often termed gliocytes, the shapes of these action potentials are the result
and appear to be functionally similar to astrocytes, of the diversity of the molecular properties of the
as they intimately ensheathe synapses. Inverte- voltage-gated Na and K channels among these
brates lack a true myelin sheath, but axons of pe- neurons. In fact, some neurons entirely lack voltage-
ripheral neurons may still be wrapped in several gated K channels. In these neurons the repolariza-
layers of glial cell membrane. Box 2, Evolution and tion phase of the action potential is carried out by K
Diversity—The Evolution of Myelin Sheaths, pro- movements through K leak channels that are open
vides a comparison of the structure and function of at all times. As you might expect, neurons of this
the myelin sheaths in the vertebrates and the in- type do not exhibit an after-hyperpolarization phase
vertebrates. Overall, the functions of glial cells are following the action potential.
thought to be similar in both vertebrates and in-
vertebrates.
From the preceding discussion, it is clear that
Voltage-gated ion channels are encoded
neurons are structurally diverse, and can form
by multiple genes
complex associations with each other and with the Many ion channels exist as multiple isoforms:
surrounding glial cells. Neurons are also diverse in slightly different molecular variants of the same
their functions. In the next sections of the chapter protein, encoded by different genes. Sequence
we revisit the primary functions of the neuron that variation among the isoforms of voltage-gated ion
we discussed in the context of a typical vertebrate channels can lead to functional differences that
motor neuron, examining the diversity of signal change the way neurons work. In mammals at least
conduction and signal transmission in neurons. 18 separate genes encode voltage-gated K chan-
nels, and over 50 distinct types of voltage-gated K
channels have been characterized among all ani-
mal species. Voltage-gated K channels cause the
2 CO NC E P T C HE C K repolarizing phase of the action potential in most
13. Is a typical vertebrate efferent (motor) neuron (as neurons. Thus, their diverse isoforms result in a di-
shown in Figure 18b) multipolar, bipolar, or versity of shapes during the repolarizing phase of
unipolar? the action potential in different cells, tissues, and
14. Answer the same question for vertebrate organisms. Voltage-gated K channels also have a
interneurons and sensory neurons. strong influence on the excitability of the cell, action
15. Describe the primary types of glial cells in the potential duration, and action potential rate. For
vertebrates. What are their functions? example, voltage-gated K channels that open
extremely quickly in response to depolarization
tend to make action potentials more difficult to
generate, because K ions leave the cell at the same
Diversity of Signal Conduction time that Na ions are entering, countering the
We have already seen that axons can conduct sig- depolarization due to voltage-gated Na channels.
nals either electrotonically or using a combination In contrast, some voltage-gated K channels are
of electrotonic current spread and regenerating ac- referred to as delayed rectifiers, because they
tion potentials, but there is additional diversity in respond relatively slowly to changes in membrane
signal conduction among neurons that we have yet potential, increasing the length of the action
195

The Evolution of Myelin Sheaths
Certain invertebrate neurons, including example, certain proteins are known to be critically im-
giant nerve fibers in the ventral nerve cord of portant for the function of the vertebrate myelin sheath.
earthworms, crabs, and shrimp, are wrapped in multi- If these proteins are defective or present in reduced lev-
ple layers of cell membranes, in a pattern that looks su- els, the rate of action potential conduction decreases.
perficially like the myelin sheaths that are wrapped None of these proteins are found in invertebrates. This
around the axons of neurons in the vertebrates. Protein observation suggests that the molecular machinery in-
complexes termed septate junctions hold together the volved in invertebrate wrappings is fundamentally dif-
cells that wrap around axons with these myelin-like ferent from that of the myelin sheath of vertebrates, and
structures in the invertebrates. Septate junctions form likely evolved independently.
a tight seal between the cells that enwrap the neuron, Recently, however, it has been shown that some of
and these septate junctions function to isolate the nerve the proteins involved in the interaction between the
from the extracellular fluid. This observation suggests myelin sheath and the axon are found in both verte-
that invertebrate wrappings may play a role that is sim- brates and invertebrates. For example, in the fruit fly
ilar to the insulating function of myelin. There are, how- Drosophila (an invertebrate), proteins called neurexins
ever, a number of differences between the myelin are found at high concentrations in the septate junctions
sheaths of vertebrates and the wrappings of inverte- of the cells that ensheathe axons. A similar protein in
brates. For example, note in the figure that the location mammals is found in the myelin sheath near the nodes
of the nucleus of the ensheathing cell is generally next of Ranvier. This part of the myelin sheath forms junc-
to the axon, rather than in the outer layer of the sheath tions similar to the septate junctions found in inverte-
as in the vertebrates. brates. Taken together, these observations suggest that
Although there is substantial diversity among inver- there are underappreciated similarities between the
tebrates in the morphology of these neuronal wrap- myelin sheath of the vertebrates and the wrappings sur-
pings, in general the layers of membrane in rounding invertebrate neurons.
invertebrate wrapping are not as closely stacked as they Other similarities between the neurons of inverte-
are in a vertebrate myelin sheath. Also, the proteins in- brates and vertebrates may provide some insight into
volved in the structure of the myelin sheath of verte- the evolution of the vertebrate myelin sheath. For exam-
brates and the wrappings of invertebrates differ. For ple, in the invertebrate sea slug Aplysia, voltage-gated
Na channels are clustered at distinct locations along
the axon. Similarly, voltage-gated Na channels in ver-
Nucleus of tebrates are clustered in the nodes of Ranvier in a
ensheathing
cell myelinated neuron. Clustering of voltage-gated chan-
nels is likely important to optimize action potential con-
duction, even in unmyelinated axons. At present,
however, it is not clear whether these similarities be-
tween invertebrate wrappings and vertebrate myelina-
Axon tion are independent evolutionary events that represent
convergence to an optimal design, or were instead pres-
ent in the common ancestors of all animals.
References
q Waehneldt, T. V. 1990. Phylogeny of myelin proteins. Annals of the
New York Academy of Sciences 605: 15–28.
Myelin-like
wrapping q Weatherby, T. M., A. D. Davis, D. K. Hartline, and P. H. Lenz. 2000.
The need for speed. II. Myelin in calanoid copepods. Journal of
Comparative Physiology. A. 186: 347–357.
Myelin-like wrappings in invertebrates.
196
potential. Table 2 lists some examples of the diver- channels can also influence the length of the rela-
sity of K channels. The significance of this diver- tive refractory period. Neurons with higher densi-
sity for the functioning of the whole organism is ties of voltage-gated Na channels tend to have
not yet fully understood, but it clearly influences shorter relative refractory periods because of the
the functional diversity of neurons. decrease in the threshold potential.
Compared to voltage-gated K channels, The many isoforms of voltage-gated channels
voltage-gated Na channels are much less di- have only recently been identified, and neurobiolo-
verse. Mammals express at least 11 isoforms of gists still do not entirely understand the role that
the voltage-gated Na channel, but the functional these isoforms play in generating functional diver-
differences among these Na channel isoforms are sity in the nervous system. In general, there is a cor-
rather minor. There are measurable differences in relation between the complexity of the nervous
the exact time required for them to open, the system and the total number of isoforms of voltage-
length of time they stay open, and their inactivation gated ion channels, which suggests (but does not
characteristics, but the importance of these differ- prove) that more diverse voltage-gated channels are
ences is not yet understood. Only two voltage-gated required to build a highly complex nervous system.
Na channel genes have been identified in Variants in ion channels can be mixed and matched
Drosophila and squid, compared to the 11 iso- to generate even larger numbers of combinations.
forms in mammals. The significance of the in- There are millions of possible combinations of iso-
crease in isoform number as the complexity of the forms of voltage-gated channels, neurotransmit-
nervous system increases is also poorly under- ters, and receptors, and thus millions of possible
stood, but it may be important in the functioning types of neuron. The human nervous system, one of
of complex mammalian nervous systems. the most complex nervous systems of any animal,
The density of voltage-gated Na channels also contains billions of individual neurons, many with
has a profound effect on the function of a neuron. unique properties and functions. Biologists are only
All else being equal, neurons that have a higher just beginning to probe the complexities of these in-
density of voltage-gated Na channels will have a teractions, and many important questions have yet
lower threshold than neurons with a lower density to be addressed. The role of isoforms in generating
of voltage-gated Na channels. A higher density diversity in neural signaling is thus an area of inten-
means more Na channels are available to open at sive current research.
a given stimulus intensity, and more Na will en-
ter the cell. As a result, the balance point between
Voltage-gated Ca2 channels can also
the dissipation and influx of Na ions is more eas-
be involved in action potentials
ily reached at a lower level of depolarization.
Thus, a smaller graded potential can excite a neu- In some neurons, voltage-gated Ca2 channels are
ron with high densities of voltage-gated Na chan- involved in the action potential. In neurons that
nels. Similarly, the density of voltage-gated Na have voltage-gated Ca2 channels in the axon,
Table 2 Diversity of K channels.
Channel type Function

Delayed rectifier Opens slowly in response to changes in membrane potential, closes slowly,
responsible for repolarizing axonal membrane following an action potential
A channel (KA channel) Opens when membrane is depolarized, closes rapidly, influences neuron
excitability
Inward rectifier (KIR channel) Opens when membrane is hyperpolarized, influences duration of action
potential
Ca2 activated (KCa channel) Opens in the presence of Ca2, influences excitability of neuron
M channel (KM channel) Opens when membrane is depolarized, closes slowly, regulated by
neurotransmitters
ACh channel (KACh channel) Opens when membrane is exposed to ACh, involved in regulating heartbeat
197
these channels open at the same time as (or in- tions we examine how the properties of the axon
stead of) voltage-gated Na channels. This results influence conduction speed, and see how these
in Ca2 entry into the cell, causing a depolariza- properties are modified in giant axons and myeli-
tion. Generally, the depolarization caused by Ca2 nated axons.
influx is slower and more sustained than the depo-
larization from Na influx. A sustained depolariza-
tion phase slows down the rate at which action The cable properties of the axon influence
potentials can be generated by prolonging the re- current flow
fractory period. For example, the action potentials
To understand how the properties of the axon in-
that control rhythmic swimming in jellyfish have a fluence the speed of action potential conduction,
sustained depolarization phase due to Ca2 influx, we need to review some basic physics and take a
and last about 10 times longer than a typical ver-
closer look at electrical currents in the axon. The
tebrate action potential. Voltage-gated Ca2 chan-
physical principles that govern the extent of cur-
nels are also important in establishing the shape
rent flow along an axon are similar to the physical
of action potentials in excitable tissues other than
principles governing the transmission of electrical
neurons, including cardiac muscle. current through transatlantic telephone cables.
Thus, the properties of the axon that dictate cur-
Conduction speed varies among axons rent flow along the axon are often called the cable
properties of the axon. Current, whether in an
In addition to differences in the shape of the ac- electrical wire or in an axon, is simply a measure
tion potential, the speed of action potential con- of the amount of charge moving past a point in a
duction along the axon varies greatly among given amount of time, and is a function of the drop
neurons (Table 3). Some neurons conduct action in voltage across the circuit and the resistance of
potentials very quickly, while action potentials in the circuit. Ohm’s law (a principle that you should
other neurons are conducted rather slowly. Ani- be familiar with from introductory physics courses)
mals use two main strategies for increasing the describes this relationship between current and
speed of action potential conduction: myelination voltage. Ohm’s law is often written in the form
and increasing the diameter of the axon. The ax-
ons of some neurons, including the vertebrate V IR
motor neurons that we have already mentioned, where I is the current, V is the voltage drop across
are myelinated. Other neurons with high conduc- the circuit, and R is the resistance of the circuit.
tion velocity have unusually large-diameter ax- Voltage is a measure of the energy carried by a
ons termed giant axons. The fastest nerve unit of charge. Thus, the difference in voltage be-
conduction is always observed in either large-di- tween two points is a measure of the energy avail-
ameter or myelinated neurons. In the next sec-
Table 3 Conduction velocities in axons from various species.
Organism/nerve Diameter (µm) Myelination Speed of propagation (m/sec)

Squid/giant axon 50–1000 No 30 (at 15°C)
Crayfish/leg 36 No 8 (at 20°C)
Lumbricus (worm) lateral 60 No 11.3 (at 20°C)
Frog/sciatic nerve, A fibers 18 Yes 42 (at 20°C)
Frog/sciatic nerve, B fibers 2 Yes 4 (at 20°C)
Frog/sciatic nerve, C fibers 2.5 No 0.3 (at 20°C)
Cat/saphenous nerve, A fibers 22 Yes 120 (at 37°C)
Cat/saphenous nerve, B fibers 3 Yes 15 (at 37°C)
Cat/saphenous nerve, C fibers 1 No 2 (at 37°C)
198
able to move charge from one point to the other,

just as potential energy is a measure of the energy Extracellular
Na+
available to move an object from one point to an- + + + + – – – – + + + + +
fluid
other. In contrast, resistance is a measure of the – – – – + + + + – – – – –
Membrane
force opposing the flow of electrical current.
Thus, by rearranging the equation, you can see Cytoplasm
that current is proportional to the voltage drop
across a circuit, and inversely proportional to the – – – – + + + + – – – – –
Membrane
resistance. + + + + – – – – + + + + +
Current flows through an electrical circuit only Na+ Extracellular

fluid
when the circuit is complete. You can think of an
axon as behaving like a simple electrical circuit in (a) Current flow in axon
which current flows as shown in Figure 20a. Ions
moving through voltage-gated channels cause a
current across the membrane. This introduced Re
Extracellular fluid
current spreads electrotonically along the axon.
Some of this current leaks out of the axon, and a Rm Cm Membrane
current flows “backward” along the outside of the
axon, completing the circuit. Each compartment of Cytoplasm
Ri
the axon has an associated resistance, which im-
pedes the flow of the current. Thus, we can think (b) An electrical circuit model for a patch of membrane
of each small area of the axon as consisting of an
electrical circuit with three resistors (the extracel-
Extracellular
lular fluid, the membrane, and the cytoplasm) as fluid
shown in Figure 20b. Membrane
Notice that in addition to the membrane resis-
tance (designated Rm), intracellular resistance Cytoplasm
(designated Ri), and extracellular resistance (des-
ignated Re), there is an additional element in this Membrane
circuit diagram, designated Cm. The parallel bar
Extracellular
symbol in the circuit diagram indicates the pres- fluid
ence of a capacitor. Thus, the part of the circuit (c) An electrical circuit model for the axon
that crosses the membrane is actually represented
by a resistor and a capacitor arranged in parallel. Figure 20 Model of the current flow in an axon
(a) Electrotonic current spread. Introduced current (for
Capacitors are devices for storing electrical charge example, due to Na influx) spreads electrotonically through
that consist of two conducting materials separated the axon, but some of this current leaks out through the
by an insulating layer. In the case of the cell mem- membrane and flows “backward” along the outside of
the axon. (b) An electrical circuit model for a patch of mem-
brane, the intracellular fluid and extracellular fluid
brane. The axon consists of three compartments: the extra-
are the conducting layers of the capacitor, while cellular fluid, the membrane, and the cytoplasm with an
the phospholipids of the cell membrane are the in- associated electrical resistance. The cell membrane also
sulating layer. acts as a capacitor, and can be modeled as a resistor and
The circuit shown in Figure 20b describes capacitor arranged in parallel. (c) An electrical circuit model
for a segment of an axon. An actual axon can be modeled as
what is happening in a small patch of the axon, but a series of smaller circuits connected together.
recall that axons can be very long. In order to fully
model the axon, we need to think about the axon
as a series of these small circuits connected to-
gether to form a much larger electrical circuit Intracellular and membrane resistance
along the axon (Figure 20c). With this simplified influence conduction speed
model of the axon as an electrical circuit in mind, When you depolarize a region of the membrane,
we can begin to see how these circuit elements af- the inside of the membrane becomes more posi-
fect the speed of action potential conduction along tively charged than adjacent regions of membrane,
the axon. while the outside of the membrane becomes more
199
negatively charged than adjacent regions. As a re-

sult, current spreads along the axon (on both the in-
Membrane potential (% of maximum)

ner and outer surfaces) by electrotonic conduction.
As this electrotonic current spreads along the axon, 100 Vmax
it depolarizes these adjacent regions of the mem-

brane. However, as we mentioned in the first part –x/λ
V = Vmaxe
of the chapter, the change in membrane potential
(measured as the voltage drop across the mem-
brane) decreases with distance, a phenomenon
37
called conduction with decrement. But why does
voltage decrease with distance? Recall that resis-
tance is a force that impedes current flow. Thus, in
a simple electrical conductor the decrease in volt- 0
1 2 3 4 5
age is a direct result of the resistance of the mate- λA λB
rial. Since resistance is cumulative with distance, Distance from initial stimulus (mm)
we would expect to see the voltage drop with dis-
Figure 21 The relationship between membrane
tance, according to Ohm’s law. For electrotonic cur- potential, distance along the axon, and the
rent spread we need to consider the resistance of length constant When the length constant is large, the
both the extracellular and intracellular fluids. If the change in membrane potential as a result of an introduced
current decays slowly with the distance traveled by
resistance of these materials is high, voltage will
electrotonic current spread. When the length constant is
drop quickly with distance. small, the membrane potential decays rapidly with distance.
However, an axon is not just a simple conduc- Vmax maximum change in membrane potential at the
tor, and we need to consider more than just the in- stimulus point. x distance from the initial stimulus.
tracellular and extracellular resistances. Most V change in membrane potential at a distance (x) from the
initial stimulus. λ length constant of the membrane.
membranes contain K leak channels, which, un-
like voltage-gated channels, are essentially always
degrades quickly with distance. The length con-
open. Thus, as current travels along the axon,
stant can be calculated as follows:
some positive charge leaks out through these
channels, decreasing the current as it flows along l 2rm> 1ri ro 2
the axon. The extent of loss of this positive charge where rm membrane resistance, ri intracellu-
depends upon the resistance of the membrane. lar resistance, and ro extracellular resistance.
When membrane resistance is high, current flow The extracellular resistance is usually assumed to
across the membrane will be low, and less charge be low and constant, and is often neglected in these
will be lost. When membrane resistance is low, calculations, so the equation can be rewritten as
l 2rm>ri
current flow across the membrane will be large,
and more charge will be lost, resulting in greater
dissipation of the axonal current with distance. From this equation, it is easy to see that the length
The effects of membrane resistance, extracel- constant of the membrane will be largest when
lular resistance, and intracellular resistance on membrane resistance is high and intracellular re-
the distance an electrical signal can travel are sistance is low.
summarized by a parameter termed the length So why does the length constant of a membrane
constant (l) of the membrane. The length constant influence the speed of conduction along the axon?
is defined as the distance over which a change in Recall that conduction along an axon represents a
membrane potential will decrease to 37% of its combination of electrotonic conduction along the
original value. This may seem to be an arbitrary axon and action potential generation at specific
value, but it is a consequence of the fact that a points on the axon. Electrotonic conduction is very
change in membrane potential decreases expo- rapid compared to the speed of opening and closing
nentially with distance (37% is equivalent to 1/e). voltage-gated channels during an action potential;
As shown in Figure 21, when the length constant in fact, for our purposes electrotonic currents can
is large, the change in membrane potential de- be considered to spread essentially instantaneously
grades less with distance, whereas if the length along the axon. A neuron that used only electro-
constant is small, change in membrane potential tonic current flow would transmit signals very rap-
200
idly. In fact, neurons with very short axons often use

only electrotonic conduction to carry electrical sig-
nals, but electrotonic current spread is effective

only up to a distance of 2 or 3 mm in most organ-
isms. In longer axons, action potentials must be
generated to “boost” the signal before it dies out be-
cause of the decrease in voltage with distance. How-
ever, the ability to signal over long distances using
the action potential comes with a cost—a reduced
speed of signal transmission. Since electrotonic cur-
rents spread along the axon extremely rapidly, the
farther a threshold depolarization can spread along
the axon, the shorter the length of time it will take
for an impulse to reach the end of the axon. Thus,
Stimulus intensity (mV)

increasing the length constant of the axon increases
the velocity of action potential conduction.
Membrane capacitance influences

the speed of conduction
As we have already mentioned, biological mem-
branes act as electrical capacitors. You can observe
the presence of the membrane capacitor by exam- 0 10 20 30 40 50 60
ining what happens when you inject current into a Time (msec)
neuron (Figure 22). A rectangular pulse of current
Figure 22 Response of a membrane to a
does not result in an immediate change in the rectangular pulse of introduced current When
membrane potential of the cell. Instead, there is a a neuronal membrane is exposed to a rectangular pulse
lag caused by the presence of the membrane ca- of current, the membrane potential does not change
pacitor. When a capacitor is present in an electrical instantaneously. Instead, due to the capacitance of the
membrane, membrane potential increases gradually with
circuit (whether in a manufactured electrical cir- injected current, and then decreases gradually when the
cuit or a biological membrane), it will accumulate a stimulus is removed.
charge difference across its insulating surface. For
example, consider a simple electrical circuit that
consists of a switch, a battery, a capacitor, and a re- As more and more charges build up on the ca-
sistor arranged in series. When we close the switch pacitor, they increasingly repel each other, and it
on the circuit, the voltage difference between the becomes more and more difficult for additional
poles of the battery causes electrons to try to flow charges to be deposited on the capacitor. Eventu-
from the negative pole (cathode) of the battery to the ally, the charge on the capacitor will equal the
positive pole (anode) of the battery. But the capaci- driving force coming from the voltage drop across
tor acts as an insulator, so negative charges cannot the battery, and no more current will flow. The
flow across the capacitor and instead “pile up” on point at which current stops flowing across a par-
one side. Recall from basic physics that like charges ticular capacitor is determined by a parameter
repel and opposite charges attract. As a result of called capacitance. You can think of capacitance
this attraction (which occurs across the thin insulat- as the quantity of charge needed to create a poten-
ing layer of the capacitor), the negative charges on tial difference between the two surfaces of the ca-
one side of the capacitor “pull” positive charges to- pacitor. Thus, a capacitor with high capacitance is
ward the capacitor and repel negative charges, able to store large amounts of charge, and a ca-
causing current to flow through the circuit. Note pacitor with low capacitance is only able to store
that current does not actually flow across the insu- relatively small amounts of charge. Capacitance
lating layer of the capacitor. Instead, electrostatic depends on three features of the capacitor: the
forces acting across the insulating layer of the ca- material properties of the capacitor, the area of
pacitor induce a current in the circuit. the two conducting surfaces, and the thickness of
201
the insulating layer. The electrical properties of bi- brane potential to decay to 37% of its original
ological membranes don’t change that much from value (or to reach 63% of its maximal value). As
one cell to another, so we only need to consider the was the case with the length constant of the mem-
area and thickness of the membrane. The larger brane, these numbers are not arbitrary, but in-
the area of the capacitor, the greater the capaci- stead reflect the observation that there is an
tance, while the thicker the insulating layer, the exponential increase in membrane potential. The
lower the capacitance. relationship between electrical properties of the
So why is the membrane capacitor important membrane and the time constant of the mem-
for the function of an axon? In the case of the ax- brane is described as follows:
onal membrane, which we can model as a resistor
t rm cm
and a capacitor arranged in parallel as shown in
Figure 20, when you introduce an electrical current where rm membrane resistance and cm mem-
into an axon (for example, by opening voltage- brane capacitance. Increases in either membrane
gated Na channels), the membrane voltage will resistance or membrane capacitance will increase
change, but more slowly than expected because ini- the time constant of the membrane, delaying cur-
tially most of the current flows into the membrane rent flow across the membrane.
capacitor. As the capacitor becomes fully charged, The time constant of the membrane has im-
it becomes more difficult for current to flow into the portant consequences for temporal summation in
capacitor, and once the membrane capacitor is neuronal cell bodies. Imagine two graded poten-
charged, current will not flow into this portion of tials occurring at the same time in a presynaptic
the circuit at all. At this point, current will begin to cell that sum to provide a suprathreshold poten-
flow through the resistor, changing the membrane tial. What will happen if these two graded poten-
potential. Thus, there is a balance between current tials occur at slightly different times? The time
flowing through the membrane resistors and cur- constant of the membrane helps us to determine
rent flowing into the membrane capacitor. the answer to this question. If the time constant is
The time needed for the membrane capacitor small, these potentials will decay rapidly, and they
to charge can be described by the time constant (t) are less likely to be able to sum to provide a
of the membrane. The larger the time constant, suprathreshold potential. In contrast, if the time
the longer it will take for the membrane to reach a constant is large, these potentials will decay
given membrane potential (Figure 23). The time slowly, making them more likely to overlap in time,
constant is defined as the time taken for the mem- and thus to sum to a suprathreshold potential.
It is clear that the time constant of the mem-
brane is important in temporal summation, but
how does changing the time constant of the mem-
Membrane potential (% of maximum)
Applied voltage brane affect the speed of conduction along the

100 axon? As current spreads electrotonically along
A the axon, some of the voltage must first be used in
B order to charge the membrane capacitor. Only
cm of B > cm of A
once the capacitor is fully charged does current
63
begin to flow across the membrane and alter
membrane potential. As a result, electrotonic cur-
rent spread is delayed. The smaller the time con-
stant of the membrane, the faster the membrane
can depolarize by a given amount, and the greater
0 the rate of electrotonic current spread and action
τA τB potential propagation.
Time (msec)
To summarize our discussion so far, three main
Figure 23 The time constant of the membrane factors influence the speed of action potential prop-
When the time constant (τ) of the membrane is large, it takes agation. The first factor is the kinetics of the voltage-
longer for the membrane to reach the maximum potential
gated channels. For example, all things being
difference. The time constant (τ) is a reflection of the
capacitance (cm). When capacitance is large, the time equal, action potentials typically propagate faster at
constant will be large. higher temperatures than at lower temperatures
202
(within physiological limits) because the channels tebrates, although they are absent in mammals. Gi-
open faster at warmer temperatures. This obser- ant axons are easily visible to the naked eye and can
vation suggests that the speed of opening of the be up to a millimeter in diameter, much larger than
voltage-gated channels sets limits on the speed of most mammalian axons, which are typically less
action potential propagation. In fact, voltage-gated than 5 µm in diameter. In squid, for example, giant
channels open and close very slowly compared to axons are found in the neurons that stimulate
the speed of electrotonic current spread, so any muscle contraction around the mantle cavity (Fig-
factors that can increase the speed or distance of ure 24). A squid can expand and contract its man-
electrotonic current spread will increase the speed tle, drawing water into the mantle cavity and
of conduction. Electrotonic current spread is, in rapidly expelling it through the siphon, providing a
turn, dependent on the length constant and the kind of jet propulsion. Jet propulsion allows the
time constant of the axon. In the next sections we squid to move very fast, but for the jet propulsion to
address how myelination and increasing the diam- work properly, muscle fibers throughout the entire
eter of the axon, as in giant axons, alter these prop- mantle must contract at almost the same time.
erties of the axon and thus conduction velocity. Some parts of the mantle are much farther away
from the central nervous system of the squid than
others. In order to reach all parts of the mantle at
Giant axons have high conduction speed the same time, action potentials must be con-
Giant axons have evolved independently many ducted faster in the neurons that innervate the
times, and are found in both vertebrates and inver- distant parts of the mantle than in neurons with
The mantle cavity fills with water.
The brain sends a signal to the stellate

ganglia, which send signals along axons of
different diameters in the mantle.
Nerve impulses reach the muscle at many

points in the mantle cavity.
The muscles of the mantle contract

synchronously, rapidly closing the mantle,
forcing water out the siphon, producing
rapid jet propulsion.
Figure 24 Schematic diagram of part of the nervous system of the squid

Loligo pealei When squid want to move rapidly, they expel water out of their siphon by
rapidly contracting the mantle muscles. To ensure that the entire mantle contracts rapidly in a
coordinated way, axons of neurons that innervate distant parts of the mantle have much larger-
diameter axons than neurons that innervate parts of the mantle close to the stellate ganglion.
These giant axons conduct action potentials much more rapidly than smaller-diameter axons.
203
short axons. Axons that activate muscles at the far channels, allowing greater ion flow across the mem-
end of the mantle cavity have very large diameters, brane so that membrane resistance decreases. As-
while axons that activate muscles in the region of the suming that the axon is roughly cylindrical in shape,
mantle cavity closest to the central nervous system the surface area of the membrane is related to the
have smaller diameters. Combining axons of varying diameter of the axon via the following formula:
diameters allows the near-simultaneous contraction
Surface area 2rh
of the entire mantle by speeding up transmission to
the most distant part of the body. Because of its large where r is the radius of the axon, and h is the
size, the squid giant axon has been an important length. Thus, the membrane resistance is propor-
model system for neurobiology (Box 3, Methods and tional to the radius of the axon. As axon diameter
Model Systems: The Squid Giant Axon). increases, membrane resistance decreases.
The effects of membrane resistance and intra- Intracellular resistance, however, is related to
cellular resistance on the length constant of the the volume of the axon. As volume increases, in-
membrane explain why large-diameter axons, such tracellular resistance decreases. The volume of the
as giant axons, conduct signals more rapidly than axon can be approximated with the formula for
small axons. Recall that the length constant of the the volume of a cylinder:
membrane increases as membrane resistance in-
Volume r2h
creases, but decreases as intracellular resistance in-
creases. So what happens to membrane resistance Thus, intracellular resistance decreases in propor-
and intracellular resistance as axon diameter in- tion to the radius of the axon squared. So what are
creases? Membrane resistance is inversely propor- the effects of membrane resistance and intracellu-
tional to the surface area of the membrane. As lar resistance on the length constant of the mem-
surface area increases so does the number of leak brane? As axon radius increases, both membrane

The Squid Giant Axon
More than half a century ago, Alan terms of known electrical theory. In 1963, they received
Hodgkin and Andrew Huxley first showed that the Nobel Prize for Medicine for this work.
neurons send electrical signals by selectively allowing Their research highlights the importance of selecting
ions to cross the cell membrane in a voltage-dependent the right model system to address an experimental ques-
fashion. The Hodgkin-Huxley theory of the action poten- tion. Hodgkin and Huxley chose the giant axon because
tial is the basis for our current understanding of neuro- its size allowed them to make recordings of the action po-
physiology. When Hodgkin and Huxley were performing tential that would not have been possible using any other
their groundbreaking experiments in 1939, while Huxley animal. In addition, the action potential in the squid giant
was still an undergraduate student, the only available axon is a relatively simple one, shaped by only two ion
recording electrodes were far too large to fit into a typi- channels: a voltage-gated K channel and a voltage-
cal mammalian axon. Instead, Hodgkin and Huxley used gated Na channel, with no complexities resulting from
the giant axon of the squid Loligo pealei as a model sys- the presence of multiple isoforms. This property of the
tem to make electrical recordings from the inside of a squid giant axon allowed Hodgkin and Huxley to develop
single axon. The squid giant axon is the largest known their elegant mathematical model of the action potential,
axon in any animal. It is hundreds of times larger in di- which would have been more difficult had the ion dynam-
ameter than a typical mammalian axon, and as much as ics of the system been more complex. They could never
50 times larger than giant axons from other inverte- have anticipated this property of the squid giant axon, so
brates. Only through detailed experimental work using serendipity as well as planning played an important part
the squid giant axon were Hodgkin and Huxley able to in the success of their experiments.
obtain the data that allowed them to formulate the References
mathematical models to describe the action potential. q Hodgkin, A. L., and A. F. Huxley. 1952. A quantitative description
In 1952 they published a paper containing a mathemat- of membrane current and its application to conduction and exci-
ical model that could explain the action potential in tation in nerve. Journal of Physiology (London) 117: 500–544.
204
resistance and intracellular resistance decrease. The capacitance of the membrane also
From the definition of the length constant changes as axon diameter increases, but this has
( l 2rm>ri ), we can see that decreasing the intra- only a marginal effect on the time constant of the
cellular resistance will increase the length constant membrane. We have already seen that membrane
of the membrane, increasing conduction speed. resistance decreases as membrane area increases.
However, decreasing membrane resistance will In contrast, membrane capacitance increases with
tend to decrease the length constant, slowing con- membrane area. Thus, the effects of membrane
duction speed. So why do these two effects not sim- resistance and membrane capacitance on the time
ply cancel each other out? Remember that the constant of the membrane have a tendency to
intracellular resistance decreases in proportion to cancel each other out. Therefore, changes in the
the radius of the axon squared, while membrane re- time constant of the membrane have a relatively
sistance decreases in direct proportion to the radius small effect on local current flow as axon diame-
of the axon. Thus, increasing the radius of an axon ter increases.
has a much greater effect on the intracellular resis-
tance than on the membrane resistance. Therefore,
the net effect of increasing the radius of an axon is Myelinated neurons evolved
to increase the speed of conduction (Figure 25). in the vertebrates
Although increasing axon diameter provides sub-
λ = rm /ri stantial increases in conduction velocity, there are
two main disadvantages to using large axons to
1
rm ∝ ––––– increase conduction velocity. Large axons take up
2πrh
more space, and this may limit the number of neu-
1
ri ∝ ––––– rons that can be packed into the nervous system.
πr 2h
Organisms such as mammals, with very complex
nervous systems, do not have giant axons. In-
stead, they use myelination to increase the speed
r=1 h=5 r=5 of action potential conduction. Large-diameter ax-
h=5 ons also have a much larger volume of cytoplasm
per unit length, making them energetically expen-
sive to produce and maintain. As a result, you
would expect that giant axons would be used only
1 1 1 1
rm ∝ –––––––––– = –––– rm ∝ –––––––––– = –––– when extremely high-speed conduction is a neces-
2π15 10 π 2π55 50 π
sity for survival. In squid, giant axons are present
1 1 1 1
ri ∝ –––––––––––– = ––– ri ∝ –––––––––––– = ––––– only in the neurons controlling escape and prey-
π115 5π π555 125 π
capture behaviors. Similarly, giant axons are as-
λ∝ 5π
–––– λ∝ 125 π
–––––
10 π 50 π sociated with startle and escape responses in
other organisms (including both vertebrates and
λ∝ 1
–– λ∝ 2.5
2 invertebrates).
Myelinated neurons are found in most verte-
λ ∝ 0 .7 λ ∝ 1.6
brates. Only lampreys and hagfish (jawless verte-
brates) lack multilayered myelin sheaths. As we
Figure 25 Why giant axons conduct action
potentials rapidly The geometry of the axon influences have already discussed, certain invertebrate neu-
the length constant (λ) of the membrane and explains why rons also have axons that are wrapped in multiple
larger-diameter axons conduct signals more rapidly than layers of cell membrane, although these wrap-
small-diameter axons. The length constant of the membrane pings differ in structure from the true myelin
is directly proportional to the membrane resistance (rm), and
inversely proportional to the intracellular resistance (ri). The sheath found in vertebrates, and may not be as ef-
membrane resistance is inversely proportional to axon fective in increasing the rate of signal conduction.
radius, whereas intracellular resistance is inversely The myelin sheath is an important evolutionary
proportional to axon radius squared. An axon with radius 1 innovation, allowing rapid signal conduction in a
will have a length constant proportional to 0.7, while an axon
with radius 5 will have a length constant proportional to 1.6.
compact space, which may have provided the con-
A longer length constant means that local currents can flow ditions necessary for the evolution of the complex
farther without degrading, so signal conduction will be faster. nervous systems of the vertebrates.
205
Myelination increases conduction speed Diversity of Synaptic Transmission

All else being equal, myelinated neurons conduct Once the wave of depolarization reaches the axon
signals more rapidly than unmyelinated neurons terminal, this electrical signal must be transferred
because the myelin sheath acts as insulation for to the postsynaptic cell. In the first half of the chap-
the axon, reducing current loss through leak chan- ter, we saw how vertebrate motor neurons release
nels and thus increasing membrane resistance. the neurotransmitter acetylcholine to send signals
Reducing ion leak increases the length constant of across the synapse. But synaptic transmission is in-
the membrane, increasing the distance that local credibly diverse, and can be accomplished via a va-
current can travel before degrading. Thus, reduc- riety of mechanisms. For example, unlike the
ing ion leak increases conduction velocity. The vertebrate motor neurons that we discussed in the
presence of the myelin sheath also decreases the first half of the chapter, some neurons do not re-
capacitance of the membrane, because capaci- lease chemical neurotransmitters onto their target
tance is inversely proportional to the thickness of cells. Instead, these neurons have gap junctions
the insulating layer in a capacitor. The many lay- that directly connect them to their target cells (Fig-
ers of cell membrane of the myelin sheath act to- ure 26). Gap junctions are composed of a series of
gether as a single insulator. Thus, although each proteins that form small pores in the membranes of
membrane alone has the same thickness, the ef- two adjacent cells, allowing ions and other small
fective thickness of the many-layered myelin molecules to travel directly from cell to cell.
sheath is much greater. The increase in the thick- Synapses in which the presynaptic and postsynap-
ness of the membrane decreases the capacitance, tic cells are connected via gap junctions are termed
reducing the time constant of the membrane and electrical synapses, because the electrical signal
thus increasing the speed of electrotonic conduc- in the presynaptic cell is directly transferred to the
tion in the internodes. postsynaptic cell through the gap junctions. Most
Note that the placement of the nodes of Ranvier neurons, however, do not form gap junctions with
is critical for the function of a myelinated axon. The their target cells. Instead, these neurons form
nodes cannot be placed too far apart or the signal chemical synapses. As we saw in the case of a ver-
will not be sufficient to depolarize the neuron be- tebrate motor neuron, at a chemical synapse the
yond threshold at the next node, because current presynaptic neuron converts its electrical signal to
inevitably decreases with distance, although less a chemical signal in the form of a neurotransmitter,
so in a myelinated axon than in an unmyelinated which diffuses across the synapse to the postsynap-
axon. Typically, the length of the internodes is tic cell and binds to receptors on the postsynaptic
about 100 times the diameter of the axon, ranging membrane.
from about 200 µm to 2 mm. Indeed, in some neu-
rons, electrotonic spread can carry a suprathresh-
old depolarization past several nodes of Ranvier, Electrical and chemical synapses play
which then appear to fire “simultaneously.” different roles
Electrical and chemical synapses differ in a num-
ber of respects. In a chemical synapse, the primary
flow of information is from the presynaptic cell to
the postsynaptic cell, and not in the reverse direc-
16. What causes the shape of action potentials to tion. Transmission across a chemical synapse is
vary among neurons? also relatively slow compared to the speed of prop-
17. What sets the speed of action potential agation of an action potential because of the need
conduction, and why? for docking and fusion of synaptic vesicles, diffu-
18. Compare and contrast giant axons and sion across the synapse, and signal transduction in
myelinated axons as strategies for increasing the the postsynaptic cell. Thus, transmission across a
speed of signal conduction.
chemical synapse is associated with a synaptic de-
19. What factors would you expect to be important in
lay of several milliseconds. In contrast, transmis-
determining the maximum spacing between nodes
of Ranvier in a myelinated neuron, and why? sion across an electrical synapse is essentially
instantaneous, since it occurs via electrotonic cur-
206
Presynaptic Presynaptic
Electrical neuron Electrical neuron
signal signal
Electrical Chemical
Gap Neurotransmitter
signal signal
junction
Electrical Electrical Receptor

signal signal
Postsynaptic neuron Postsynaptic neuron
(a) Electrical synapse (b) Chemical synapse
Figure 26 Electrical and chemical synapses (a) In an electrical synapse, the

electrical signal is directly transmitted from the presynaptic cell to the postsynaptic cell via gap
junctions. (b) In a chemical synapse, the electrical signal in the presynaptic cell is converted to
a chemical signal, in the form of a neurotransmitter, which crosses the synaptic cleft and binds
to a receptor on the postsynaptic cell membrane. The receptor converts the chemical signal to
an electrical signal in the postsynaptic cell.
rent spread, and thus is not associated with any involved in the escape response of crayfish are
significant synaptic delay. In addition, electrical connected via electrical synapses.
synapses can easily convey information in either The proportion of electrical to chemical
direction, because electrical currents or ions can synapses in the nervous system also varies among
move freely in either direction through the gap organisms. For example, organisms with rela-
junctions connecting the cells (although some gap tively simple nervous systems, such as cnidarians
junctions have specialized structures that ensure (jellyfish, sea anemones, and related animals), of-
unidirectional signal transmission). ten have electrical synapses between their neu-
Although signal transmission across an elec- rons, whereas organisms with more complex
trical synapse is much more rapid than across a neural pathways generally make more use of
chemical synapse, chemical synapses have one chemical synapses. From these more complex
substantial advantage over electrical synapses. In neural pathways and networks emerge more so-
an electrical synapse, the signal in the postsynap- phisticated and plastic animal behaviors. How-
tic cell is always similar to the signal sent by the ever, electrical synapses also play an important
presynaptic cell, because direct transfer of ions or role in organisms with more complex nervous sys-
current causes the postsynaptic signal. In a chem- tems. In the mammalian brain, for example, elec-
ical synapse, the signal in the postsynaptic cell is trical synapses among neurons may be important
not necessarily the same as in the presynaptic cell. in synchronizing brain function.
For example, a series of action potentials in a
presynaptic cell could result in the release of a
neurotransmitter that causes the postsynaptic cell
Chemical synapses have diverse
to hyperpolarize, inhibiting it from firing action
structures
potentials. Chemical synapses provide an addi- There is substantial diversity in the morphology of
tional level of regulation for the nervous system; in chemical synapses (Figure 27a). We have already
comparison, direct electrical coupling across an examined the morphology of the neuromuscular
electrical synapse limits the diversity of the signal junction, the chemical synapse between a motor
in the postsynaptic cell. neuron and a muscle. The axon of a motor neuron
Electrical synapses are present in neural path- splits into several terminal branches, and each
ways involved in escape behaviors in some organ- branch terminates in a swelling called the axon
isms, presumably because they increase the speed terminal (or sometimes the terminal bouton
of the escape response. For example, the neurons
207
Mitochondrion Mitochondrion
Mitochondrion Vesicle Vesicle

Vesicle
Mitochondrion
Receptor
Receptor
Receptor
Vesicle
Axon terminal Axon varicosities En passant synapse Spine synapse
(a) Types of synapses
Axosomatic
synapse Axodendritic synapse
Axoaxonic synapse
Dendrodendritic
synapse
(b) Locations of neuron-to-neuron synapses
Figure 27 Variation in the structure and location of synapses

(a) Structural diversity of chemical synapses. There are four main types of chemical synapses.
(b) Diversity in the location of neuron-to-neuron synapses. Synapses can be axodendritic,
axosomatic, dendrodendritic, or axoaxonic.
or synaptic knob). The synapses formed at axon ter- membrane at the junction is not specialized, and
minals are highly structured, and the postsynaptic does not contain a high concentration of receptors.
cell membrane contains increased densities of neu- Instead, neurotransmitter diffuses broadly and
rotransmitter receptors in close proximity to the contacts receptors located across large areas of
axon terminal. Axon terminals are found at the the target organ. Neurons in the central nervous
ends of many types of neurons, in addition to the system can form a similar type of synapse, called
motor neurons that we have already encountered. an en passant synapse, that consists of a swelling
Alternatively, some neurons form synapses at along the axon of the presynaptic neuron. These
axon varicosities, or swellings along the axon synapses differ from neuroeffector junctions in
that can be arranged like beads on a string. Each that the postsynaptic membrane may be special-
of these swellings contains vesicles filled with ized and contain high densities of receptors. An-
neurotransmitter, which are released onto the other common type of synapse in the central
target cell. Certain types of neurons in the periph- nervous system is termed a spine synapse. In
eral nervous system, called autonomic neurons, these synapses, the presynaptic cell connects with
form synapses with their effector organs at axon a specialized structure, termed a dendritic spine,
varicosities. These neuroeffector junctions differ on the dendrite of the postsynaptic cell.
from true synapses in that the postsynaptic cell
208
Neuron-to-neuron synapses can form at a va- mate, aspartate, and glycine are also used for pro-
riety of locations (Figure 27b). Axodendritic tein synthesis; GABA is a derivative of glutamate.
synapses form between the axon terminal of one Animals can synthesize all four of the amino acids
neuron and the dendrite of another, while that act as chemical messengers, although they
axosomatic synapses form between the axon ter- may also obtain these amino acids from food. Once
minal of one neuron and the cell body of another. synthesized, amino acid neurotransmitters are
Axodendritic and axosomatic synapses are the packaged into vesicles, and stored until they are
most common types of neuron-to-neuron synapses. released by exocytosis.
Dendrodendritic synapses form between the den- The neuropeptides, also called neuroactive
drites of two neurons, and are often electrical peptides or peptide neurotransmitters, are com-
synapses that allow communication of information posed of short chains of amino acids. Neuropep-
in both directions between neurons. Axoaxonic tides are synthesized in the rough endoplasmic
synapses form between an axon terminal of a reticulum, which synthesizes all secreted pep-
presynaptic neuron and the axon of a postsynaptic tides. In neurons, the rough endoplasmic reticu-
neuron. Axoaxonic synapses most commonly occur lum is generally found in the cell body. Vesicles
near the axon terminal of the postsynaptic neuron, containing peptide neurotransmitters are then
and play a role in regulating neurotransmitter re- transported from the cell body to the axon termi-
lease from the postsynaptic neuron, often by alter- nal along a complex network of microtubules, via
ing Ca2 influx. By modulating the release of a process called fast axonal transport. However,
neurotransmitter from neurons within the nervous neurobiologists have recently discovered that
system, these axoaxonic synapses play a role in reg- some neurons in the brains of invertebrates such
ulating learned behaviors. as snails can synthesize peptide neurotransmit-
ters in both the axon and axon terminal, suggest-
ing an additional layer of functional complexity.
There are many types Acetylcholine and the biogenic amines play
of neurotransmitters particularly important roles in integrating physio-
Neurons that form chemical synapses with their tar- logical functions because they are important neu-
get cells can communicate in diverse ways in part rotransmitters that communicate with many kinds
because of the large number of different chemical of tissues. You will encounter these neurotransmit-
substances that act as neurotransmitters. Neurobi- ters again and again as you read this text, since
ologists have discovered more than 50 substances they are involved in the homeostatic regulation of
that act as neurotransmitters (Table 4), and these many physiological systems. We have already dis-
neurotransmitters have diverse effects on postsy- cussed the role of acetylcholine at the neuromus-
naptic cells. cular junction, but this neurotransmitter plays
To be classified as a neurotransmitter, a sub- many other roles in the nervous system. Because
stance must meet several criteria. It must be syn- of their physiological importance, we discuss
thesized in neurons. It must be released at the acetylcholine and the biogenic amines in more de-
presynaptic cell membrane following depolariza- tail in later sections.
tion, and it must bind to a postsynaptic receptor Some neurotransmitters do not fit into any
and cause a detectable effect. Neurobiologists simple chemical class. These neurotransmitters
often group neurotransmitters into five major include purines such as ATP, which is important
classes: amino acids, neuropeptides, biogenic in energy metabolism, and the gas nitric oxide.
amines, acetylcholine, and a grab-bag class con- The gaseous neurotransmitters, such as nitric
sisting of neurotransmitters that do not fit into any oxide (NO), are not packaged into vesicles. In-
of the other groups. Many of these classes of mol- stead, after they are synthesized at the axon ter-
ecules can also act as hormones or paracrine sig- minal, they diffuse freely out of the presynaptic
nals, and thus neurotransmission is part of a neuron in all directions into every nearby cell.
continuum of chemical communication systems in Because NO diffuses freely across membranes, it
animals. cannot be stored, and must be synthesized as
Four amino acids have been shown to act as needed.
neurotransmitters: glutamate, aspartate, glycine,
and gamma-aminobutyric acid (GABA). Gluta-
209
Table 4 A summary of neurotransmitters.
Neurotransmitter Receptor Receptor type Receptor location Effect

Acetylcholine Nicotinic Ionotropic Skeletal muscles, Excitatory
autonomic neurons, CNS
(central nervous system)
Muscarinic Metabotropic Smooth and cardiac Excitatory or
muscle, endocrine and inhibitory
exocrine glands, CNS
Amino acids
Glycine Glycine Ionotropic CNS Inhibitory
Aspartate Aspartate Ionotropic CNS Excitatory
Glutamate AMPA Ionotropic CNS Excitatory
NMDA Ionotropic CNS Excitatory
mGlu1-8 Metabotropic CNS Excitatory or
inhibitory
GABA GABA-A Ionotropic CNS Inhibitory
GABA-B Metabotropic CNS Generally
inhibitory
Biogenic amines
Dopamine Dopamine Metabotropic CNS Excitatory or
inhibitory
Norepinephrine and adrenergic Metabotropic CNS and peripheral Excitatory or
nervous system (PNS), inhibitory
cardiac muscle, smooth
muscle
Epinephrine and adrenergic Metabotropic Cardiac muscle, smooth Excitatory or
muscle, CNS inhibitory
Peptides
Endorphins Opiate Metabotropic CNS Generally
inhibitory
Neuropeptide Y NPY Metabotropic CNS Excitatory or
inhibitory
Other
Adenosine Purine Metabotropic CNS Generally
inhibitory
Nitric oxide None N/A N/A N/A
cell less likely to generate an action potential. The

Neurotransmitters can be excitatory resulting changes in membrane potential are often
or inhibitory referred to as inhibitory postsynaptic poten-
The response of a target cell depends on the type of tials (IPSPs). Excitatory neurotransmitters gen-
receptors it expresses. Thus, depending on the na- erally cause depolarization, making the
ture of its receptor, a neurotransmitter can cause postsynaptic cell more likely to generate an action
the postsynaptic cell to either depolarize or hyper- potential. These depolarizations are termed exc-
polarize. Inhibitory neurotransmitters generally itatory postsynaptic potentials (EPSPs).
cause hyperpolarization, making the postsynaptic
210
Neurotransmitter receptors can be Extracellular fluid

ionotropic or metabotropic Ions cannot cross Neurotransmitter
the membrane
The binding of a neurotransmitter to its receptor
Neurotransmitter 1 Neurotransmitter
can cause either a fast or a slow response within binding site binds to receptor
the postsynaptic cell, depending on the signal
transduction cascade associated with the receptor.
Neurotransmitter receptors are often classified as
Ionotropic
either ionotropic or metabotropic. Ionotropic re- receptor 2 Ions cross membrane
ceptors are ligand-gated ion channels. When a
neurotransmitter or other chemical signaling 3 Rapid change in
Cytoplasm membrane potential
molecule binds to an ionotropic receptor, the
conformation of the protein changes, opening a (a) Ionotropic receptors
pore within the receptor protein that allows ions
to move across the cell membrane (Figure 28a).
Neurotransmitter
Because binding of the neurotransmitter directly
causes changes in the shape of the protein to re-
1 Neurotransmitter
sult in ion movement, ionotropic receptors initi- binds to receptor
ate rapid changes in the membrane potential of
the postsynaptic cell. The nicotinic ACh recep-
tors that we have already encountered are an ex-
Metabotropic
ample of an ionotropic receptor. receptor 3 Opens ion
When a neurotransmitter binds to a 2 Activates signal channels,
metabotropic receptor, there is a change in the transduction pathway ions enter cell
conformation of the receptor (Figure 28b) that

sends a signal via a second messenger, initiating a 4 Modifies existing proteins,
activates or releases gene
signaling cascade within the postsynaptic cell. We expression
have already discussed the organization and func-
tion of various signal transduction pathways, and 5 Coordinated cellular response
metabotropic receptors work through similar
pathways. A signaling cascade activated by a (b) Metabotropic receptors
metabotropic receptor ultimately sends a message Figure 28 Ionotropic and metabotropic

to ion channel proteins, modulating the activity of receptors (a) Structure and function of an ionotropic
ion channels on the postsynaptic cell membrane receptor. When there is no neurotransmitter bound to an
ionotropic receptor, the ion channel within the protein is
and thus altering membrane potential. closed, and ions cannot cross the cell membrane. When
Metabotropic receptors tend to cause slower-act- neurotransmitter binds to an ionotropic receptor, the gated
ing changes in the postsynaptic cell than ion channel opens, which allows ions to cross the membrane
ionotropic receptors because of the complex sig- and cause a response in the postsynaptic cell. (b) Structure
and function of a metabotropic receptor. When
naling pathways between binding of the neuro- neurotransmitter binds to a metabotropic receptor, the
transmitter to the receptor and the opening of ion receptor changes shape, sending a signal that activates a
channels. Metabotropic receptors often also cause signal transduction pathway. The signal transduction
long-term changes in the postsynaptic cell by af- pathway can open or close ion channels, modify existing ion
channel proteins, or activate or repress gene expression,
fecting the transcription or translation of recep-
causing a coordinated cellular response.
tors and ion channels.
the brain in vertebrates. Receptors for acetyl-

Acetylcholine receptors can be ionotropic choline are termed the cholinergic receptors.
or metabotropic There are two major classes of cholinergic
We have already discussed the role of acetyl- receptors: the nicotinic and the muscarinic recep-
choline (ACh) in carrying signals across the neuro- tors. As we have already discussed, nicotinic
muscular junction, but acetylcholine is also a receptors are ionotropic receptors that cause a
neurotransmitter at many other synapses, includ-
ing synapses in the autonomic nervous system and
211
rapid response in the target cell, whereas mus-

Top view
carinic receptors are metabotropic receptors that
β δ
cause slower responses in the target cell. β δ
The nicotinic receptor is made up of a variety α γ α
of combinations of the five possible subunits: , , α α

γ, ε, and , each of which is encoded by several iso-
γ
forms. The nicotinic acetylcholine receptor was
first studied intensively in the electric organ of the ACh binding sites on
ray Torpedo californica, which generates a strong nicotinic ACh receptor
electrical current that these rays use to stun their Nicotinic Plasma
prey. The electric organ is a modified muscle that ACh receptor membrane
has high levels of the nicotinic acetylcholine recep- Figure 29 A schematic diagram of a nicotinic
tor. Figure 29 shows the combination of subunits ACh receptor from the electric organ of Torpedo
of the ACh receptor expressed in the Torpedo elec- The nicotinic ACh receptor is an ionotropic receptor made up
tric organ. These subunits are arranged like the of five subunits arranged around a central pore that forms a
Na channel. Each receptor has two binding sites for ACh,
staves of a barrel around a central pore. This formed by the subunit at the junction of the γ or subunits.
muscle-type nicotinic ACh receptor has two bind-
ing sites for ACh that are located on the subunit
at the - and -γ subunit interfaces. The subunit named because the drug muscarine binds to them
composition of nicotinic receptors differs between and not to nicotinic receptors. They are found on
skeletal muscle, the autonomic nervous system, a variety of tissues, including the brain, the heart,
and the brain. The nicotinic receptors in the auto- the gut, and the bronchial passages. Stimulation
nomic nervous system are made up of an 3 sub- of muscarinic receptors causes a slower response
unit, an 5 subunit, an 7 subunit, a 2 subunit, in the postsynaptic cell than do nicotinic recep-
and a 4 subunit, while the receptors in the brain tors, and the response can be either excitatory or
are predominantly composed of combinations of inhibitory, depending on the cell type. Thus, al-
4 and 2 subunits. These different subunit and though metabotropic receptors (such as the mus-
isoform combinations confer differing properties, carinic receptors) cause slower responses than
adding to the complexity of the vertebrate nervous ionotropic receptors (such as the nicotinic recep-
system. tors), they are capable of generating more diverse
Muscarinic ACh receptors are metabotropic responses. Table 5 summarizes some of the simi-
receptors that are indirectly coupled to ion chan- larities and differences between types of choliner-
nels through G proteins. Muscarinic receptors are gic receptors.
Table 5 Cholinergic receptor subtypes.
Second
Receptor Effect of messenger
subtype Location binding pathway Agonists Antagonists
Nicotinic Neuromuscular junctions, Excitation Ion influx ACh, Curare
ganglionic neurons, nicotine,
adrenal medulla carbachol
Muscarinic Gut Excitation G-protein ACh, Atropine,
coupled muscarine, scopolamine
carbachol
Heart Inhibition
Bronchioles (lung) Excitation
Sweat glands Activation
Blood vessels of skeletal Inhibition
muscle
212
The biogenic amines play diverse COOH

physiological roles HO CH2 C NH2
Amines are chemicals that possess an amino (–NH2) H
group; those that can act as chemical messengers Tyrosine
are referred to as the biogenic amines. Several bio-
genic amines act as neurotransmitters, including Tyrosine β -hydroxylase
the catecholamines (dopamine, norepinephrine, HO
and epinephrine), and serotonin. All of these bio- COOH
genic amines are synthesized in the axon terminal HO CH2 C NH2
using an amino acid as a precursor. Acetylcholine
H
also contains an NH2 group, and thus potentially
L-Dihydroxyphenylalanine (L-dopa)
could be considered a biogenic amine. But be-
cause ACh is not synthesized from an amino acid
Dopa decarboxylase
precursor, and because the NH2 group is in the
HO
center of the molecule rather than at one end, ACh
is usually classified separately from the biogenic
HO CH2 CH2 NH2
amines.
The catecholamines are synthesized via a
Dopamine (DOPA)
common pathway from the amino acid tyrosine
(Figure 30). Serotonin is synthesized from the Dopamine β -hydroxylase
amino acid tryptophan via a common pathway
HO
with the hormone melatonin. Dopamine and sero-
tonin are primarily involved in signaling within
HO CH CH2 NH2
the central nervous system. Epinephrine and nor-
epinephrine (also called adrenaline and noradren- OH
aline) play an important role in the peripheral Norepinephrine (NE)
nervous system and are involved in regulating

Phenylethanolamine N-methyltransferase (PNMT)
many important physiological processes, includ-
ing heart rate and breathing. HO
Receptors for norepinephrine and epinephrine
are termed the adrenergic receptors (derived HO CH CH2 NH CH3
from the word adrenaline). There are two major OH
classes of adrenergic receptors: alpha () and beta Epinephrine (E)
(). Both norepinephrine and epinephrine bind to
Figure 30 The synthetic pathway for the
receptors, although epinephrine binding to re- catecholamines The catecholamines norepinephrine
ceptors is weak. In contrast, receptors bind (NE) and epinephrine (E) are synthesized via a common
strongly to both neurotransmitters. In mammals, pathway with dopamine from the amino acid tyrosine.
several variants of each receptor type are present L-Dopa, DOPA, NE, and E are biogenic amines: chemical
messengers containing an amine group (NH2).
(1, 2; 1, 2, etc.). The great diversity of receptor
types allows norepinephrine and epinephrine to
have opposing effects on different tissues, depend- pressure. The diversity of adrenergic receptors ac-
ing on the particular receptor that is present. For counts for the opposing effects of norepinephrine
example, when norepinephrine binds to 2 recep- and epinephrine on different tissues.
tors on the smooth muscles surrounding the bron- Isoforms of the same class of receptor may ac-
chioles (passages leading to the lungs), the muscle tivate very different signal transduction cascades
relaxes. Muscle relaxation increases the diameter of within a target cell. Figure 31 summarizes the ma-
the bronchiole, making it easier to breathe. In con- jor postsynaptic effects of norepinephrine binding
trast, when norepinephrine binds to 2 receptors to several classes of adrenergic receptor.
on the smooth muscles surrounding blood vessels, The binding of the neurotransmitter to 1
the muscles contract. Muscle contraction decreases adrenergic receptors activates a signal transduction
the diameter of the blood vessel, increasing blood
213
Binding of NE Extracellular fluid

cascade involving a G protein that ac-
NE
to α1 receptor tivates phospholipase C, which in
Activates Ca2+
α1 adrenergic receptor channel
turn breaks down the molecule phos-
phoinositol-phosphate (PIP) into a
Plasma molecule of diacylglycerol (DAG) and
DAG membrane
PLC PIP + PKC inositol triphosphate (IP3). The IP3
Breaks IP3
Activates
down
P causes release of Ca2 from intracel-
Activates Phosphorylates lular stores and, with DAG, activates
Activates the enzyme protein kinase C, which
G protein Cytoplasm
phosphorylates voltage-gated Ca2
channels, placing them in an acti-
(a) Binding of NE to α1 adrenergic receptors
vated conformation. So ultimately,
the signal transduction cascade acti-
Binding of NE
NE
to α2 receptor vates the target tissue by making Ca2
Inactivates Ca2+ channels easier to open. In contrast,
α2 adrenergic receptor channel the binding of the neurotransmitter
to 2 adrenergic receptors activates a
AC
PKA different G protein, which inactivates
Inactivates the enzyme adenylate cyclase, which
Inactivates causes cyclic AMP (cAMP) levels to
ATP cAMP Dephosphorylates
Activates levels decrease. This decrease in cAMP in-
G protein decrease activates the enyzme protein kinase A,
inactivating voltage-gated Ca2 chan-
(b) Binding of NE to α2 adrenergic receptors
nels. Ultimately, this signal transduc-
tion cascade tends to inactivate the
NE Binding of NE target tissue by making Ca2 chan-
to β receptor
nels more difficult to open. The
Activates Ca2+
β2 receptor channel binding of the neurotransmitter to
adrenergic receptors activates a
AC different G protein, which activates
PKA
Activates adenylate cyclase, causing cAMP to
P
Activates increase. The increased cAMP acti-
ATP cAMP Phosphorylates vates protein kinase A, which acti-
Activates levels
G protein increase vates voltage-gated Ca2 channels.
This signal transduction pathway
(c) Binding of NE to β receptors tends to activate target tissues by
Figure 31 Binding of norepinephrine to different receptor subtypes making voltage-gated Ca2 channels
Norepinephrine can bind to several types of receptor, causing opposing responses in easier to open. Thus, the effects of a
the target cell. (a) When norepinephrine binds to an 1 adrenergic receptor, the single neurotransmitter can vary de-
receptor changes shape and activates a G protein, signaling to the enzyme pending on the particular receptor
phospholipase C (PLC), which catalyzes the breakdown of phosphatidylinositol-
phosphate (PIP) into diacylglycerol (DAG) and inositol triphosphate (IP3). The IP3 that is present on the target tissue.
activates the enzyme protein kinase C, which then phosphorylates and activates Ca2 Table 6 summarizes some of the
channels. (b) When norepinephrine binds to an 2 adrenergic receptor, the receptor characteristics of the major adrener-
activates a G protein that inactivates the enzyme adenylate cyclase (AC). This reduces gic receptors in humans.
the production of cAMP from ATP, reducing intracellular cAMP levels. The reduced
cAMP inactivates protein kinase A (PKA), dephosphorylating Ca2 channels and
inactivating them. (c) When norepinephrine binds to a receptor, the change in shape
of the receptor activates a G protein, which activates adenylate cyclase (AC), which
Neurons can synthesize more
increases the conversion of ATP to cAMP, increasing intracellular cAMP. The cAMP than one kind of
signals to protein kinase A, which then phosphorylates and activates Ca2 channels. neurotransmitter
Thus, the same neurotransmitter can have opposing effects in different postsynaptic
cells, depending on the type of receptor that is present. For many years it was believed that
a neuron could secrete only a single
kind of neurotransmitter, but now it
214
Table 6 Summary of some major adrenergic receptor subtypes.
Receptor Location Effect Second messenger

subtype (in humans) (in humans) system Sensitivity
␣1 Blood vessels of skin, Vasoconstriction G protein activates NE > E
gut, kidneys, salivary phospholipase C
glands
␣2 Membrane of Inhibits release G protein inactivates adenylate NE > E
adrenergic axon of NE cyclase, inhibits cAMP
terminals production
␤1 Heart Increases heart G protein activates adenylate NE E
rate and strength cyclase, activates cAMP
production
␤2 Lungs Dilates bronchial G protein activates adenylate E > NE
passages cyclase, activates cAMP
production
is known that a single neuron can secrete several Figure 32 illustrates some features of synaptic
different neurotransmitters. For example, many plasticity at the neuromuscular junction. An in-
neurons synthesize both a small molecule neuro- crease in neurotransmitter release in response to
transmitter (like ACh or norepinephrine) and one repeated action potentials is termed synaptic fa-
or more neuropeptides. It is still not entirely clear cilitation. Synaptic facilitation occurs because the
how a neuron controls which neurotransmitter it accumulation of intracellular Ca2 following each
releases, but different neurotransmitters appear action potential allows more neurotransmitter to
to be released from a single axon terminal at dif- be released by subsequent action potentials. In
ferent stimulus frequencies. For example, low- contrast, synaptic depression, which is a de-
frequency stimulation might release ACh, whereas crease in neurotransmitter release with repeated
high-frequency stimulation might release a neu-
ropeptide. It is likely that separate groups of
synaptic vesicles reside in a single neuron, each
containing a different neurotransmitter, and each
Membrane potential of
postsynaptic cell (mV)
releasing its contents in response to different stim- Facilitation

ulus frequencies. Depression Post–tetanic
potentiation
Neurotransmitter release varies

depending on physiological state
In addition to its substantial diversity among neu-
10 20 30 40 50 60 70 80 90 100 Minutes later
rons and across species, synaptic transmission also
varies within a single neuron, depending on the Stimulus Stimulus Single
physiological state of that neuron. We have already begins ends stimulus
discussed how action potential frequency relates to Time (msec)
neurotransmitter release, but most neurons have Figure 32 Synaptic plasticity If a motor neuron is
another layer of functional complexity because stimulated several times in succession, the membrane
neurotransmitter release can vary depending on potential change in the postsynaptic cell may increase in
amplitude with each succeeding stimulus, a process called
the past history of action potentials at that axon ter- synaptic facilitation. After a long period of high-frequency
minal. This synaptic plasticity, or the ability of a stimulation, the amplitude of the change in membrane
synapse to change its function in response to pat- potential in the postsynaptic cell will eventually decrease,
terns of use, underlies many important brain func- a process called synaptic depression. If the stimulus is
removed, and the neuron is allowed a brief interval (up to
tions including learning and memory. The vast
several minutes) without stimulation, the amplitude of the
majority of neurons exhibit at least some degree of potential evoked by the next stimulus is increased, a process
synaptic plasticity. called post-tetanic potentiation.
215
action potentials, occurs because of the progres- fashion, but is conducted about 1000 times more
sive depletion of the readily accessible pool of slowly than a typical vertebrate action potential.
synaptic vesicles that is available for fusion and Green plants, from tomatoes to trees, can also
exocytosis of neurotransmitter. produce action potentials, although they do not
Post-tetanic potentiation (PTP) occurs after have a specialized tissue for conducting these sig-
a train of high-frequency action potentials in the nals to specific locations over long distances. The
presynaptic neuron. For several seconds or min- action potential in plants appears to travel through
utes following a burst of action potentials, a subse- the xylem or phloem vessels, and is a means of rap-
quent action potential will result in increased idly transmitting a signal to the entire plant. Most
release of neurotransmitter. The mechanisms un- of the work on action potentials in plants has con-
derlying PTP differ from those involved in synap- centrated on the response to wounding, but even a
tic facilitation, and are thought to involve a stimulus as simple as turning on a light can pro-
Ca2-dependent increase in the available pool of voke an action potential in plants such as a tomato.
neurotransmitter-containing vesicles. Synaptic fa- The nature and ionic basis of the plant action po-
cilitation and post-tetanic potentiation result in tential is not yet well understood because plant
only brief changes in the activity of the synapse, cells are more difficult to work with than animal
but neurons have other mechanisms that allow cells, since they have a rigid cell wall and multiple
them to undergo long-term changes in synaptic intracellular compartments with varying ionic
activity. composition. However, it is known that action po-
tentials are conducted without decrement in plants,
and that the action potential may involve Ca2 ions.
Evolution of neurons Similarly, voltage-gated channels are present in
Only the metazoans have neurons, but electrical many unicellular organisms, including protists and
signaling in other organisms can provide clues as prokaryotes. Paramecium, a ciliate protist, swims
to the evolution of the metazoan neuron. Plants, via the coordinated beating of the cilia that cover its
which do not have neurons, do express voltage- exterior. If a Paramecium makes contact with a
gated channels, and use them for electrical com- solid object while swimming, it will back up by re-
munication. For example, algae from the family versing the direction in which the cilia beat. This re-
Characeae have giant cells that are capable of gen- versal is the result of opening of voltage-gated Ca2
erating action potentials. Single cells in this channels, which causes an action potential. Mutant
species can be up to a millimeter in diameter and Paramecium that do not contain a functional copy
several centimeters in length. Early neurobiolo- of this voltage-gated Ca2 channel can only swim
gists sometimes used this species as an experi- forward. In general, action potentials in protists ap-
mental model when squid were not available, pear to be Ca2 dependent; a single species,
since these algae produce an action potential that Actinocoryne contractilis, has been demonstrated
has a shape similar to those observed in the squid to have both Ca2- and Na-dependent action
giant axon. However, at a molecular level the ac- potentials.
tion potential in Chara is very different from the
action potential in animals. It results from ion
movements through Cl channels that are acti-
Only animals have voltage-gated
vated in a Ca2-dependent manner. An increase in
Na channels
Ca2 influx through a voltage-gated ion channel Only metazoans have voltage-gated Na channels,
takes place at the beginning of the action potential, and essentially all metazoans have at least one gene
which initiates a signal transduction pathway that that codes for a voltage-gated Na channel.1 In fact,
opens Cl channels, causing Cl ions to leave the as we have already discussed, many metazoan
cell. The efflux of Cl depolarizes the cell, resulting genomes contain multiple genes that code for
in an action potential. Therefore, the action poten-
tial in Chara is not due to a voltage-gated channel, 1
C. elegans provides one known exception to this rule. The
although a voltage-gated channel triggers it. The C. elegans genome lacks voltage-gated Na+ channels, and these
action potential in Chara shares some features animals do not produce action potentials. C. elegans is thought
to have lost the ancestral voltage-gated Na+ channels present in
with metazoan action potentials, although it dif- other animals. Graded potentials are sufficient to transmit in-
fers in many respects. It acts in an all-or-none formation along the neurons of these small animals.
216
slightly different isoforms of voltage-gated Na in bacteria, algae, protozoans, and plants (organ-
channels. The DNA sequences of voltage-gated Na isms that do not have nervous systems). So it is ap-
channel genes from all metazoans share many fea- parent that most neurotransmitters did not
tures, suggesting that the voltage-gated Na chan- originally evolve to perform their neural signaling
nel arose only once, in a common ancestor of the role. Metazoans appear to have taken ancient mol-
metazoans. Current evidence suggests that the ecules and used them for a new function: cell-to-
most likely ancestor of the voltage-gated Na chan- cell signaling in the nervous system.
nel was a voltage-gated channel that generated both As nervous systems have become more elabo-
Na- and Ca2-dependent signals (perhaps a chan- rate, the number and complexity of neurotransmit-
nel similar to the one discovered in Actinocoryne ter-receptor interactions has increased. For
contractilis, previously discussed). This observa- example, Bracheostoma lanceolatum—the am-
tion suggests that the separation of electrical con- phioxus—a cephalochordate (the sister group to
duction as a Na-based process may have been a the vertebrates), has only one catecholamine re-
key innovation in the evolution of multicellular an- ceptor gene, and uses dopamine but not norepi-
imals. Ca2 plays an important role in intracellular nephrine as a neurotransmitter. Lampreys and
signaling in many cell types, and it is possible that hagfish have two catecholamine receptor genes,
this limits its utility as an ion that can be used to and both dopamine and norepinephrine are used
carry long-distance electrical signals. as neurotransmitters. In contrast, in mammals
there are five different dopamine receptors, nine
adrenergic receptors, and three adrenergic re-
Most organisms use chemicals ceptors. The increased complexity of neurotrans-
for cell-to-cell communication mitter-receptor interactions may be involved in the
Although synaptic transmission shares many evolution of increasing complexity in vertebrate
features with other modes of cell-to-cell communi- nervous systems.
cation, such as endocrine and paracrine commu-
nication, current evidence suggests that synaptic
transmission arose only once, since all living ani-
mals have similar mechanisms for converting 20. Compare and contrast electrical and chemical
electrical signals to chemical signals at the synapses.
synapse. For example, jellyfish, which are very 21. Compare and contrast ionotropic and
distantly related to vertebrates, have mechanisms metabotropic receptors.
of Ca2-induced neurotransmitter release from 22. Compare and contrast the effect of
presynaptic neurons very similar to the mecha- norepinephrine binding to the different types of
adrenergic receptors.
nisms used by mammalian neurons.
23. What are the fundamental evolutionary
Many neurotransmitters are simple mole-
innovations that allow neural signaling in
cules, such as amino acids, that are found in all liv- animals?
ing things. Even acetylcholine has been detected
Summary
Signaling in a Vertebrate Motor Neuron k Graded potentials travel across short distances
k Neurons are excitable cells that use a combina- through the cell body to the axon hillock where
tion of electrical and chemical signals to rapidly they are integrated, either by spatial summa-
transmit information throughout the body. tion or temporal summation, to alter the mem-
brane potential of the axon hillock.
k Vertebrate motor neurons consist of dendrites,
a cell body, an axon, and several axon terminals. k When the axon hillock depolarizes beyond the
threshold potential, the graded potentials can
k Membrane-bound receptors in the dendrites
trigger action potentials in the axon.
and cell body receive incoming signals that
stimulate gated ion channels, which open or k Action potentials occur only in axons, and differ
close, causing graded potentials. from graded potentials in that they occur in an
217
“all-or-none” fashion, and can be conducted ences in the properties or density of voltage-
across long distances without degrading. gated Na and K channels.
k Action potentials have three main phases: a de- k The cable properties of the axon influence the
polarization phase, a repolarization phase, and speed at which action potentials are conducted
an after-hyperpolarization phase. along the axon.
k The depolarization phase of the action potential k Large-diameter axons and myelinated axons con-
is the result of the opening of voltage-gated Na duct signals more rapidly than small-diameter
channels, which open in response to threshold or or unmyelinated axons.
suprathreshold depolarization of the membrane.
k Over 50 different substances are known to act
k Opening of voltage-gated K channels causes as neurotransmitters.
the repolarization phase.
k Some neurotransmitters bind to several differ-
k An action potential in one part of the axon trig- ent receptors, and are thus able to have oppo-
gers other action potentials in adjacent areas of site effects on different postsynaptic cells.
the axonal membrane, allowing conduction
k Only metazoans have nervous systems, but
without decrement.
many other organisms use changes in mem-
k When an action potential reaches the axon ter- brane potential as signals to convey information.
minal, the signal must be transmitted to other
k Voltage-gated channels are present in plants,
cells across the synapse.
algae, and protozoans, and are used to generate
k At electrical synapses, signals are transmitted signals that can modify behavior or convey in-
directly from cell to cell via gap junctions. formation between distant tissues. Voltage-
gated Na channels, however, are found only in
k At chemical synapses, the electrical signal en-
animals.
coded by the action potential is converted to a
chemical signal, in the form of a neurotransmitter. k Over the course of evolution, the number and
diversity of ion channels in metazoans appears
k The binding of a neurotransmitter to its recep-
to have increased with increasing complexity of
tor generates a signal in the postsynaptic cell.
the nervous system.
Diversity of Neural Signaling k The number and complexity of neurotransmitter-
k The structure and function of neurons is di-
receptor interactions have also increased greatly
verse, and can vary among animals and among
in the metazoans.
different neurons within a single animal.
k Action potentials can vary in length and shape
among different neurons, as a result of differ-
Review Questions
1. What are the four main functional zones of a 6. Draw a diagram to illustrate the relationship
neuron? between the states of the various voltage-
2. Why does the opening of a Na channel cause gated ion channels, membrane permeability,
a neuron to depolarize? and the phases and refractory periods of the
action potential.
3. Why do only the ions Na, K and Cl appear
in the Goldman equation as formulated for a 7. Explain in your own words why increasing the
neuron at rest? density of voltage-gated Na channels de-
creases the threshold potential of a neuron.
4. Why can’t graded potentials be propagated
across long distances in neurons? 8. What molecular properties of the ion channels
involved in action potentials cause unidirec-
5. What is the difference between temporal and
tional propagation of action potentials along
spatial summation? Can spatial summation
the axon, and why?
occur without temporal summation?
218
9. Why are acetylcholinesterase inhibitors effec- similar between the neurons. Explain the rea-
tive in the treatment of myasthenia gravis? soning behind any differences that you indicate
10. Which type of neuron would you expect to have in shape between the two action potentials.
more dendrites, an afferent (sensory) neuron 12. Explain why a myelinated neuron conducts
or an interneuron? Justify your answer. signals more rapidly than an equivalent un-
11. Draw a diagram of the shape of an action po- myelinated neuron.
tential in a neuron that expresses voltage-gated 13. Compare and contrast the signal transduc-
K channels compared to the action potential tion pathways initiated by binding of norepi-
in a neuron that does not express voltage-gated nephrine to the various types of adrenergic
K channels, assuming that all other factors are receptors.
Synthesis Questions
1. Ouabain is a poison that selectively binds to 5. What would happen if you experimentally
the Na/K ATPase and inhibits it. What stimulated an axon close to both the axon
would happen over the course of a few hours hillock and the axon terminal at the same time?
to the resting membrane potential of a neuron 6. What would happen to action potential gener-
that was poisoned with ouabain? ation in an axon if you applied a drug that
2. Immediately after the application of ouabain, caused voltage-gated K channels to remain
would the neuron in question 1 still be able to open constantly?
generate an action potential? Why or why not? 7. Imagine a postsynaptic neuron that is contacted
3. A student is eating at the lab bench (in clear vi- by two different excitatory presynaptic neurons.
olation of laboratory policy), and mistakenly One of these presynaptic neurons (neuron A)
sprinkles tetrodotoxin on his fries. Given that contacts the cell body of the postsynaptic cell
this substance inhibits voltage-gated Na next to the axon hillock, whereas the other
channels, indicate whether the following presynaptic neuron (B) contacts a dendrite of
statements concerning this student are true or the postsynaptic cell on the side of the cell body
false. Explain your answers, and consider the farthest away from the axon hillock. Explain
time course of the response. why repeated firing of neuron A at slightly be-
• It will be more difficult for the student’s neu- low the threshold potential could cause the
rons to generate action potentials. postsynaptic neuron to initiate an action poten-
tial, while firing of neuron B at exactly the same
• The student’s neurons will fire more fre-
intensity and frequency might not.
quently, since membrane potential will be
brought closer to threshold. 8. You have discovered a drug that blocks voltage-
gated Ca2 channels. What are the likely effects
• The effect on the membrane potential of the
of this drug at the synapse?
student’s neurons could be predicted by the
Nernst equation, which factors in the effects of 9. Drugs called selective serotonin reuptake in-
both ion concentration and ion permeability. hibitors (SSRIs), which affect the reuptake of
neurotransmitter by presynaptic cells, are
4. Describe the relationship between the after-
used for the treatment of depression. Sero-
hyperpolarization phase of the action poten-
tonin normally causes an excitatory post-
tial and the relative refractory period. Why is
synaptic potential. What effect would the
the relative refractory period important for
administration of an SSRI have on the re-
neural signaling?
sponse of these postsynaptic cells, and why?
1. Use the table to the right and the Goldman Intracellular Extracellular Membrane
equation to calculate the resting membrane concentration concentration permeability
Ion (mM) (mM) at rest
potential of a neuron at 37°C. (Temperature in
K 140 4 1
Kelvin Temperature in °C 273.15). Please
report your answer in millivolts. Na 15 145 0.05

Cl 4 110 0.1
Ca2 0.0001 5 0
219
2. The neuron described in question 1 contains Twelve neurons synapse on one postsynaptic
ligand-gated Ca2 channels. What will happen neuron. At the axon hillock of the postsynaptic
to the membrane potential of this neuron if neuron, 10 of the presynaptic neurons pro-
neurotransmitter binds to these channels? Be duce EPSPs of 2 mV each and the other two
quantitative in your answer; what is the maxi- produce IPSPs of 4 mV each. The threshold
mum possible change in membrane potential? potential of the postsynaptic cell is 60 mV
3. (a) During extreme dehydration, plasma K (resting membrane potential is 70 mV). Will
can increase to as high as 10 mM. What would an action potential be produced? Justify your
the membrane potential of this neuron be un- answer.
der these conditions? (Assume there are no 5. Calculate the relative conduction velocities in
other changes in ion concentrations.) (b) What two different axons, one with a diameter of
would happen to the ability of this neuron to 2 µm and another with a diameter of 50 µm,
generate action potentials during extreme de- assuming that all other factors are the same
hydration? Why might this be problematic? between the two axons.
For Further Reading

See the Additional References section at the end excitation in nerve. Journal of Physiology,
of the chapter for more readings related to the London 117: 500–544.
topics in this chapter.
This autobiography provides a personal glimpse
into the research that initiated the modern era of
Signaling in a Vertebrate Motor Neuron neurobiology.
These excellent neurobiology textbooks provide a Hodgkin, A. L. 1992. Chance and design:
detailed look at the structure and function of Reminiscences of science in peace and war.
neurons. New York: Cambridge University Press.
Kandel, E. R. 2000. Principles of neural science.
New York: McGraw-Hill. This review outlines some of the shortcomings of
the Hodgkin and Huxley model for the action
Levitan, I. B., and L. K. Kaczmarek. 2001. The potential, particularly for neurons with very
Neuron: Cell and molecular biology. New York: complex sets of voltage-gated ion channels.
Oxford University Press.
Meunier, C., and I. Segev. 2002. Playing the
Matthews, G. 2001. Neurobiology: Molecules, devil’s advocate: Is the Hodgkin-Huxley model
cells and systems. New York: Blackwell useful? Trends in Neuroscience 25: 558–563.
Science.
Neher and Sakmann shared the Nobel Prize in
This extremely informative book is an excellent part for their development of the patch clamp
reference for learning more about the molecular technique. Using the patch clamp technique,
biology and physiology of ion channels. Neher and Sakmann were able to demonstrate
Hille, B. 2001. Ion channels of excitable that ion channels actually exist, and to determine
membranes, 3rd ed. Sunderland, MA: Sinauer how they function. This discovery is one of the
Associates. fundamental underpinnings of modern
neurophysiology.
In these classic papers, Hodgkin and Huxley Neher, E., and B. Sakmann. 1976. Single-channel
demonstrated the features of the action potential, currents recorded from membrane of
and presented their theory of the underlying denervated frog muscle fibres. Nature 260:
mechanism. 799–802.
Hodgkin, A. L., and A. F. Huxley. 1939. Action Neher, E., and B. Sakmann. 1992. The patch
potentials from inside a nerve fibre. Nature clamp technique. Scientific American 266:
144: 710–712. 44–51.
Hodgkin, A. L., and A. F. Huxley. 1952. A
quantitative description of membrane current This review highlights the properties of the nodes
and its application to conduction and of Ranvier, and summarizes some of the current
220
literature demonstrating that different ion Sakmann, B. 1992. Elementary steps in synaptic
channels are localized at specific sites along the transmission revealed by currents through
axon. single ion channels. Science 256: 503–512.
Salzer, J. L. 2002. Nodes of Ranvier come of age. Diversity of Neural Signaling
Trends in Neuroscience 25: 2–5.
This paper summarizes the diversity and
This paper demonstrates for the first time that evolution of the voltage-gated sodium channels
action potentials may not actually be initiated at that are the fundamental basis of neuronal action
the axon hillock, but rather a little bit further potentials.
down the axon, at least in pyramidal neurons. Goldin, A. L. 2002. The evolution of voltage-gated
The authors are also able to demonstrate that Na channels. Journal of Experimental
differences in the properties of voltage-gated Na Biology 205: 575–584.
channels, not just differences in their
concentration, may be important for the These papers provide a discussion of the
occurrence of action potentials in axons and not evolution of myelin and its role in increasing the
the cell body. speed of action potential conduction.
Colbert, C. M., and E. Pan. 2002. Ion channel Waehneldt, T. V. 1990. Phylogeny of myelin
properties underlying axonal action potential proteins. Annals of the New York Academy of
initiation in pyramidal neurons. Nature Sciences 605: 15–28.
Neuroscience 5: 533–538. Weatherby, T. M., A. D. Davis, D. K. Hartline, and
P. H. Lenz. 2000. The need for speed. II.
The paper below is an excellent overview of Myelin in calanoid copepods. Journal of
synaptic transmission. Comparative Physiology, Part A: Sensory,
Jessell, T. M., and E. R. Kandel. 1993. Synaptic Neural, and Behavioral Physiology 186:
transmission: A bidirectional and self- 347–357.
modifiable form of cell-cell communication.
Cell 72 Suppl: 1–30.
In this review of his Nobel Prize–winning work,

Bert Sakmann describes some of his experiments
on the neuromuscular junction.
Barnard, E. A. 1992. Receptor classes and the transmitter- Robertson, B. 1997. The real life of voltage-gated K
gated ion channels. Trends in Biochemical Science 17: channels: More than model behaviour. Trends in
368–374. Pharmacological Sciences 18: 474–483.
Blumenthal, K. M., and A. L. Siebert. 2003. Voltage-gated Rosenthal, J. J., and W. F. Gilly. 2003. Identified ion channels
sodium channel toxins: Poisons, probes, and future in the squid nervous system. Neurosignals 12: 126–141.
promise. Cell Biochemistry and Biophysics 38: 215–238. Shepherd, G. M., and S. D. Erulkar. 1997. Centenary of the
Catterall, W. A. 2000. From ionic currents to molecular synapse: From Sherrington to the molecular biology of the
mechanisms: The structure and function of voltage-gated synapse and beyond. Trends in Neuroscience 20: 385–392.
sodium channels. Neuron 26: 13–25. Yu, F. H., and W. A. Catterall. 2003. Overview of the voltage-
Doyle, D. A. 2004. Structural changes during ion channel gated sodium channel family. Genome Biology 4(3) no.
gating. Trends in Neuroscience 27: 298–302. 207. http://genomebiology.com/ 2003/4/3/207.
Jiang, Y., A. Lee, J. Chen, V. Ruta, M. Cadene, B. T. Chait, and
R. Mackinnon. 2003. X-ray structure of a voltage-
dependent K channel. Nature 423: 33–41.
Credits
142 Shin Kuang, Courtesy of S. Kuang and J.R. Sanes
143 Stephen Dalton/Nature Picture Library.
221
Cellular Movement and Muscles
More than 300 years ago a Dutch dry-goods merchant lowing them to see organelles move rapidly throughout large
named Anton van Leeuwenhoek became one of the earliest algal cells. Even the cytoplasm itself seemed to flow beneath
cell biologists. Utilizing his flair for glasswork, van Leeuwen- the margins of the plasma membrane.
hoek created a homemade lens that allowed him to discover We now realize that all eukaryotic organisms show
the microscopic organisms inhabiting pond water. He was some form of movement, either within cells, by cells, or by
struck by how these small creatures swam forward and organisms. However, animals are the only group of multicel-
backward through the water. Even then, movement was syn- lular organisms that are able to actively move from place to
onymous with life, and he recognized that these microscopic place, courtesy of a distinctive cell type found only in ani-
“animalcules,” as he called them, were alive. Over the next mals: the muscle cell. A study of the evolutionary and devel-
200 years, the quality of microscopes improved. By the late opmental origins of muscles reveals a paradox of unity and
1800s, microscopists were able to look inside living cells, al- diversity. At the molecular level, most muscle proteins have
222
Antelope.
One of the most important factors driving the diversity of

muscle types in more complex animals was the trend toward
larger bodies. While small animals can survive using simple
diffusion of respiratory gases, large animals have low surface
area to volume ratios, and simple diffusion cannot meet their
Sperm. metabolic demands. Thus, the genes for muscle proteins
evolved in combination with primitive respiratory and circula-
homologues in fungi, plants, and other eukaryotes. Although tory systems. For example, molluscs possess well-developed
muscles are constructed from the same cytoskeletal ele- muscular hearts, and their multiple types of muscle are used
ments shared by all organisms, the distinct features of the in locomotion and feeding. Likewise, arthropods have com-
homologues in animals enable them to construct muscle. plex muscles that control ventilation and movement.
By looking at the anatomical, physiological, and ge- The greatest diversity in muscle types, however, occurs in
netic properties of living animals, we can gain insight into the vertebrates. More than 300 million years ago, the early
the evolutionary origins of muscle. The simplest animals vertebrate ancestors experienced two rounds of genome du-
lack true muscles, although they do have specialized cells plications. The extra copies of genes for critical muscle pro-
that contract. For example, sponges (phylum Porifera), the teins allowed for the evolution of highly specialized muscle
earliest multicellular animals, have pores that allow sea- types. Instead of only having single genes for important mus-
water to penetrate their bodies. Specialized contractile cle proteins, as found in the invertebrates and protochordates,
cells surround pores, controlling their diameter. genome duplication and later gene duplications in ancestors
Musclelike cells first arose in cnidarians, such as the of more complex animals created extra copies of these genes,
familiar Hydra. Myoepithelial cells combined to form fibers providing fertile ground for the evolution of specialized mus-
that worked in conjunction with their internal hydrostatic cle protein isoforms. Whereas simple invertebrates must em-
skeleton to extend the body stalk. True muscle first ap- ploy only one or two muscle myosin genes to build all
peared in a related group of animals called ctenophores. muscles, vertebrates possess at least 15 different myosin
These animals, which include sea walnuts and sea goose- genes. With the transition to land and the challenges of move-
berries, have true smooth muscle cells in the body wall. ment under the full weight of gravity, muscle genes rapidly
The animals within the various worm phyla, including evolved, allowing muscle specialization and diversification.
flatworms, nematodes, and annelids, have more elaborate While this remarkable diversity in locomotor muscles
muscle systems. Worms use complex longitudinal and cir- is impressive, remember that muscles are built from the
cular smooth muscles for locomotion, nematodes have pha- same components that enable intracellular movements in
ryngeal muscles used for feeding, and annelids have other eukaryotes. When you marvel at the athleticism of a
thickened regions of blood vessels that act as pumping cheetah sprinting, a tuna swimming, or a hummingbird
hearts. Although these ancient animals have several dis- hovering, remember that these impressive capacities de-
crete types of muscle, more complex recent animals display pend upon cellular machinery not unlike that found in the
much greater diversity in muscle anatomy and physiology. fungus growing on your shower curtain.2
223
Overview
Every physiological process, be it intracellular trans-
port, changes in cell shape, cell motility, or muscle-
dependent animal locomotion, depends in some
way on movement. Regardless of the type of move-
ment, the same intracellular machinery underlies
each one: the cytoskeleton and its motor proteins.
Recall that eukaryotic cells possess a cytoskeleton
composed of microtubules, microfilaments, and in-
(a)
termediate filaments. Of these, only microtubules
and microfilaments have important roles in cellular
movement. Microtubules work in conjunction with
the motor proteins kinesin and dynein. Myosin, in
contrast, is the actin-dependent motor protein. The
diversity in cellular movement is possible because
these basic elements can be arranged and used in
countless combinations.
There are three general ways that cells use
these elements to move (Figure 1). Most com-
monly, cells use the cytoskeleton as a roadway,
where motor proteins act as trucks carrying cargo (b)
over the complex cytoskeletal networks. Just as
the highway route controls traffic, cells mediate
intracellular traffic by controlling where the roads
go, which vehicles ride the road, and the nature of
the cargo. For example, the precision of cell sig-
naling pathways depends on motor proteins being
able to carry secretory vesicles from sites of syn-
thesis to the plasma membrane for exocytosis. If a (c)
vesicle is carried to the wrong place or released at
Figure 1 Three ways to use the cytoskeleton
the wrong time, dangerous miscommunications for movement (a) Cells can use their cytoskeleton as
can result. a road on which motor proteins move, often carrying
A second class of movement is driven by active intracellular cargo. (b) Some cells move by pushing the
reorganization of the cytoskeletal network. Rather cytoskeleton forward, much like a bulldozer pushes earth
ahead. (c) Movement sometimes resembles a tug-of-war,
than acting as a road, in this case the cytoskeletal
where motor proteins, depicted as people, can pull the
fibers act as bulldozers that push the cellular con- cytoskeleton, symbolized by the rope.
tents forward. This type of movement, often called
amoeboid movement, is most common in protists.
Many metazoan cell types, such as leukocytes and tures are the foundation of cilia, flagella, and mus-
macrophages, also use amoeboid movement. Mo- cle. Cells primarily regulate this type of movement
tor proteins may or may not be involved in the by controlling the activity of the motor protein.
process. Cells regulate this type of movement by
controlling the rate and direction of growth of cy-
toskeletal fibers. Cytoskeleton and Motor
The third type of movement is analogous to a Proteins
group of people pulling a rope. In this case, the mo-
tor protein pulls on the cytoskeletal rope. Cells then The cytoskeleton and motor proteins work in con-
organize the cytoskeleton in a way that translates junction to enable animals to mediate intracellular
this tugging action into movement. As you will see trafficking, changes in cell shape, and cellular
later in this chapter, these cytoskeletal superstruc- movement. Three general explanations exist for
224
the variations seen in the cellular movement in an- traffic, as motor proteins can move either toward
imal cells. First, most animals possess multiple iso- the central MTOC or to the periphery of the cell.
forms of critical cytoskeletal and motor proteins. Cells use their microtubule network to control
This arsenal of genetic variation allows metazoans the movement of subcellular components, such as
to build specialized types of cells. Second, animal vesicles and organelles. Microtubule systems also
cells can use a single set of building blocks to orga- mediate the rapid changes in skin color seen in
nize the cytoskeleton in different ways. Third, an- some animals that use cryptic coloration, such as
imals can regulate an existing suite of proteins in the African claw-toed frog, Xenopus laevis (Figure
real time; hormones bind to receptors, triggering 3). Skin color is determined by the distribution of
regulatory cascades that alter enzyme activity that dark pigment granules within cells called
modifies the properties of the cytoskeleton and melanophores. When the pigment granules are
motor proteins. These three aspects of diversity concentrated near the MTOC, the skin is pale in
account for the distinct ways animal cells build and color. When the granules are dispersed through-
use the cytoskeleton and motor proteins for move- out the cell, the skin darkens. Changes in the di-
ment. The capacity to be different at a cellular level rectional movement of pigment granules along
is central to the animals’ ability to generate specific microtubule tracks within the melanophore, con-
types of cells, as well as to adapt to evolutionary trolled and triggered by hormones, create adap-
challenges. As we proceed through this textbook, tive coloration in animals. A closer look at how
you will see that these cellular processes underlie microtubules are built will lay the foundation for
many important physiological systems. understanding the role they play in vesicle traffic,
pigment dispersal, and other types of intracellular
and cellular movements that are central to physi-
Microtubules ological function.
Cells can organize microtubules in many arrange-
ments. Most cells gather the ends of microtubules
near the nucleus of the cell at the microtubule- Microtubules are composed of ␣-tubulin
organizing center (MTOC) (Figure 2). The micro- and ␤-tubulin
tubules radiate from the MTOC like spokes of a Microtubules, so named because of their tubelike
wheel that extend to all margins of the cell. The out- appearance, are composed of long strings of the
ward ends of microtubules are anchored to integral protein tubulin, itself a dimer of two closely related
proteins embedded within the plasma membrane. proteins: ␣-tubulin and ␤-tubulin. The evolution-
This microtubule network is vital to intracellular ary history of tubulin is intriguing and rich in
paradoxes. For example, tubulin genes have
changed very little since the earliest eukaryotes.
(+) (+)
The ␣-tubulin of yeast is very similar to your own;
even ␣-tubulin and ␤-tubulin are nearly 40% iden-
Microtubule tical in most species. Many animals have multiple
tubulin isoforms that are expressed in different tis-
Nucleus sues. Because of the similarity in the structures of
(–) different isoforms, they were believed to be inter-
(+) (–) (–) (+) changeable: for example, one ␣-tubulin isoform
(–) could be replaced with another ␣-tubulin isoform
without obvious consequences. The importance of
MTOC the subtle differences in tubulin structure between
(+) species, as well as within a species, has only re-
cently been appreciated. In one instance, when ne-
(+) matodes (C. elegans) were genetically modified to
express a different isoform of ␤-tubulin in their
touch neurons, the mutant worms had sensory
Figure 2 Microtubule network of cells Many
cells organize microtubules into a network, with the minus
dysfunction. These studies showed that even sub-
ends gathered near the center of the cell at the tle differences in the structure of tubulin isoforms
microtubule-organizing center (MTOC). have important consequences for cellular function.
225
Pigment
granules Microtubules
Aggregate
pigment
granules
Melanophore Plasma
+ MSH membrane
+ Melatonin
Figure 3 Movement of pigment granules Melanophores from the African claw-

toed frog Xenopus allow rapid changes in color. Arrays of microtubules radiating from the
central MTOC carry pigment granules throughout the cell. Actin filaments, not shown here, also
play a role in controlling local pigment distribution. Pigment granules aggregate in response to
the hormone melatonin, and disperse in response to melanophore stimulating hormone, MSH.
(Micrographs courtesy of V. Gelfand, University of Illinois)
Unlike many large, complex proteins, micro- The next step in microtubule assembly occurs
tubules form spontaneously within cells, a feature when multiple tubulins assemble end-to-end. Like
that is central to microtubule function. The first step a line of magnets, the plus end of the growing
of assembly (Figure 4) occurs when ␣-tubulin and chain attracts the minus end of a free dimer. The
␤-tubulin combine to form tubulin. Prior to dimer- chain, or protofilament, grows until it reaches a
ization, both subunits bind to a single molecule critical length. The protofilaments then line up
of GTP. When tubulin forms, the GTP bound by side by side to form a sheet that eventually rolls
␤-tubulin may be hydrolyzed into GDP and phos- into a tube to form the microtubule. Because the
phate. In contrast, the GTP bound by ␣-tubulin re- angle between adjacent protofilaments is about
mains intact and bound within the tubulin 28°, 13 protofilaments are required to form a com-
structure. The ␣-tubulin, with its GTP intact, is on plete circular tube. Once the microtubule is
one end of the dimer; the ␤-tubulin, with its hy- formed, it can continue to grow by incorporating
drolyzed GTP, is on the other end of the dimer. The more dimers, or it may shrink by shedding them.
difference between the two monomers creates
structural asymmetries within tubulin, known as
polarity. The ␣-tubulin subunit is at the so-called
Microtubules show dynamic instability
minus end (⫺) of the tubulin dimer, whereas ␤- Microtubule dynamics, such as the rates of growth
tubulin is at the plus end (⫹). The polarity of tubu- and shrinkage, regulate many cellular functions.
lin has important ramifications in the subsequent Any chemical that disrupts microtubule dynamics
steps of microtubule assembly. can become a potent poison. Some plants use mi-
226
GTP GTP crotubule poisons as part of their defense against

α–tubulin + β–tubulin animal grazing; for example, the Pacific yew tree
(Taxus) produces taxol, the periwinkle plant
1 α–tubulin and β–tubulin (Vinca) produces vinblastine, and the autumn cro-
GDP+P combine to form
dimer, tubulin. cus (Crocus) produces colchicine. Animals that
Minus (–) end Plus (+) end
graze on these plants are sickened as a result of
the effects of these alkaloids on their own micro-
2 Multiple dimers tubule dynamics. Many of these plant defense
Tubulin
assemble end-to-end agents have been developed as anticancer drugs
to form a protofilament.
because of their ability to kill rapidly dividing cells.
These compounds are also very useful tools in the
(–) (+)
laboratory, as they allow researchers to dissect the
processes that control microtubule dynamics.
(–) (+) The balance between growth and shrinkage
Protofilament determines the length of the microtubule (Figure
3 Protofilaments line up
to form sheet. 5). Many factors influence microtubule dynamics,
but the most important is the local concentration
of tubulin. If the end of the microtubule is exposed
to a high concentration of tubulin, it will tend to
grow. At low tubulin concentrations, however,
(–) (+)
microtubules tend to lose tubulin dimers and
shrink. At a specific critical concentration (Cc),
Sheet of
protofilaments
growth and shrinkage are in balance and there is
no net change in length. However, several factors
4 Sheet of protofilaments complicate this simple pattern of concentration-
roll up to form a tube. dependent regulation. First, the Cc value at the
plus end is lower than at the minus end. This
(–) (+) Treadmilling range
(+) end
Microtubule
5 Microtubule grows by
monomer addition to
+ end and shrinks by
Growth
monomer removal from

– end.
(–) end
Shrinkage
(–) (+)
0
(–) (+)
Shrinkage Growth
Figure 4 Microtubule assembly Microtubules are

composed of repeating units of the protein tubulin, a dimer of Cc(+) Cc(–)
two GTP-binding proteins, ␣-tubulin and ␤-tubulin. Tubulin [Tubulin]
dimers connect end-to-end to begin the construction of a
protofilament. The protofilaments join side by side to start Figure 5 Microtubule dynamics Whether
the formation of a sheet. Once the sheet reaches a critical a microtubule grows or shrinks depends on tubulin
width, it rolls into a tube to form the microtubules. concentration. Below a critical concentration (Cc) the
Microtubules grow by adding tubulin and shrink by losing microtubule is more likely to shrink. Above Cc it will likely
tubulin. grow. While both ends can add or lose tubulin, the plus
end has a lower Cc. This means at any particular tubulin
concentration, the plus end is more likely to grow than
is the minus end.
227
means that if both ends are exposed to the same

tubulin concentration, the plus end is more likely
to grow and the minus end is more likely to shrink. MAPs
Colchicine and vinblastine are toxic because they
prevent microtubule growth. Colchicine binds to
free tubulin and prevents it from incorporating
into microtubules, while vinblastine prevents mi-
crotubule formation by causing free tubulin dimers
to aggregate. This reduces the concentration of Microtubule
free tubulin, curtailing microtubule assembly.
The second feature that distinguishes micro- Nucleus
tubule growth is known as dynamic instability.
Even when the tubulin concentration exceeds Cc,
the microtubule will grow for a few seconds, then
spontaneously shrink for a few seconds. This
concentration-independent transition is due to a MTOC
change in the GTP bound by ␤-tubulin. Once incor-
porated into a microtubule, the ␤-tubulin subunit
may or may not hydrolyze GTP. As long as the GTP
in ␤-tubulin remains intact, the microtubule tends
to grow. Alternatively, if the GTP is hydrolyzed, the
microtubule will tend to shrink. Microtubules
maintain their constant length by balancing
growth and shrinkage, while hydrolyzing a lot of MAP
GTP in the process. This may at first seem to be a
waste of the cell’s energy, but it is a necessary cost. Plasma
Dynamic instability, despite its energetic costs, en- membrane
hances the ability of the cell to regulate microtubule Figure 6 Microtubule-associated proteins
growth in space and time. Systems in motion are Microtubules are connected to each other and to membrane
much easier to alter than static systems. proteins by microtubule-associated proteins, or MAPs.
Microtubule dynamics are also regulated by
microtubule-associated proteins, or MAPs (Fig-
ure 6). These proteins bind to the surface of mi-
crotubules, stabilizing or destabilizing the
microtubule structure. Some MAPs bind to the sociating impairs many cellular processes, includ-
plus end of microtubules and prevent the transi- ing cell division.
tion from growth to shrinkage. A group of MAPs The activities of MAPs are regulated by protein
called stable-tubule only polypeptides, or STOPs, kinases and protein phosphatases. Changes in MAP
are used by many cell types that need long, stable phosphorylation can alter its subcellular location,
microtubules. For instance, STOPs are abundant change its ability to bind a microtubule, or alter its
in nerves where microtubules are important for functional properties. Many signaling pathways
the development of long axons and dendrites. target MAPs to alter microtubule structure. For ex-
Other MAPs act as protein cross-linkers. MAPs can ample, the hormones that regulate cell division,
join microtubules together into bundles, or link the known as cytokines, induce changes in microtubule
microtubules to other cellular structures, such as structure by regulating the MAP structure and ac-
membrane receptors. Taxol is a potent toxin be- tivity. The subsequent changes in the microtubule
cause it stabilizes microtubules. However, not all network ensure that cellular constituents are
MAPs stabilize microtubules. For example, katanin equally divided between daughter cells.
(Japanese for “sword”) is a MAP that severs micro- Temperature is another parameter that affects
tubules. Normal cell function depends on the microtubule dynamics. Early experiments showed
regulation of both assembly and disassembly of that isolated microtubules could assemble and dis-
microtubules. Preventing microtubules from disassemble spontaneously in test tubes. When micro-
228

Thermal Adaptation in Microtubules
The thermal instability of microtubules yeast in which the ␤-tubulin gene was subtly mutated; a
presents a conundrum. If mammalian micro- single cysteine was mutated to alanine. This simple mu-
tubules spontaneously disassemble at 25°C, what is dif- tation made the microtubules cold-stable. Unfortu-
ferent about the microtubules of animals that live at even nately for the yeast, the structural changes that
colder temperatures? Many mammalian tissues can increased cold-stability also dramatically impaired
stabilize microtubules using a number of microtubule- processes that depend on microtubule dynamic insta-
binding proteins, such as STOPs (stable-tubule only pro- bility, such as growth and cell replication. These studies
teins), MAPs, and capping proteins. Do cold-dwelling illustrate two important aspects of microtubules. First,
organisms use these same proteins to prevent thermal microtubule function is critically dependent upon main-
instability, or is there something different about tubulin it- taining a dynamic balance between assembly and disas-
self? Insight into this question comes from studies using sembly, or stability and instability. Second, even modest
models in which differences arise from both natural se- changes in microtubule structure, arising through evo-
lection and genetic engineering approaches. lution or genetic engineering, can produce a micro-
For many cold-dwelling organisms, microtubule sta- tubule with very different properties. Whether these
bility can be traced to the structure of tubulin itself. subtle mutations are adaptive or lethal depends on how
When first discovered, this was a bit surprising because the specific mutation affects the proteins, and how the
the sequence of tubulin is extraordinarily conserved structural change influences function in the context of
across animals. Isolated microtubule proteins from environmental conditions.
cold-water fish spontaneously assemble at lower tem-
peratures than do those proteins from mammals.
Antarctic fish have been isolated in Polar Seas for more References
than 10 million years. Over this time, the sequences of q Detrich, H. W., III, S. K. Parker, R. C. Williams Jr., E. Nogales, and
␣-tubulins and ␤-tubulins have accumulated only a few K. H. Downing. 2000. Cold adaptation of microtubule assembly
amino acid variations, yet the microtubules from these and dynamics. Structural interpretation of primary sequence
changes present in the alpha- and beta-tubulins of Antarctic
fish are much more stable than microtubules from
fishes. Journal of Biological Chemistry 275: 37038–37047.
warm-water fish. When the genes for ␤-tubulin from a
q Modig, C., M. Wallin, and P. E. Olsson. 2000. Expression of cold-
cold-tolerant cod were transfected into cultured human
adapted beta-tubulins confer cold-tolerance to human cellular
cells, the microtubules from the transgenic cells were microtubules. Biochemical and Biophysical Research Communica-
stable in the cold. These studies show that very subtle tions 269: 787–791.
differences in tubulin structure, even one or two amino q Sidell, B. D. 2000. Life at body temperatures below 0 degrees C:
acids, can result in profound differences in cold stabil- The physiology and biochemistry of Antarctic fishes. Gravity and
ity. Researchers studied microtubules produced by Space Biological Bulletin 13: 25–34.
tubules were cooled to 25°C, for example, they dis- Microtubule polarity determines the
assembled. Although this is a useful laboratory direction of movement
technique to study microtubule dynamics, what The extensive microtubule networks within cells
does it mean for the animals? Temperature-induced provide a complex roadway for the motor pro-
disassembly is not physiologically relevant for most teins. But how do motor proteins identify which
endothermic animals, such as mammals and birds, road to ride? Once on the road, how do they decide
because they maintain body temperatures well which way to go? Recall that the orientation of the
above the threshold temperature. However, many dimers endows a microtubule with a structural po-
ectothermic animals must endure temperatures low larity, where microtubules have a plus end and a
enough to disrupt the microtubules of a mammal. In minus end. Since cells organize microtubules by
that case, how do animals that live in the cold avoid collecting the minus ends at the MTOC, the plus
spontaneous disassembly of their microtubules? ends are found at the periphery. Motor proteins
See Box 1, Evolution and Diversity: Thermal Adap- recognize microtubule polarity, and each motor
tation in Microtubules for an explanation. protein moves in a characteristic direction; kinesin
229
Vesicle grab a tubulin dimer, then bend to pull themselves

(filled) along the microtubule. Likewise, in both, the
structural changes in the motor protein are fueled
Kinesin
Nucleus in cell by ATP hydrolysis, the rate of movement of kinesin
body of neuron Microtubule and dynein along the microtubule is determined
primarily by the ATPase domain of the proteins,
MTOC and regulatory proteins that associate with the
(+) motor protein control the rate of movement. De-
(+) spite these similarities, kinesin and dynein have
(+) important differences that affect how cells use
Axon them to move along microtubules.
Let’s first consider the structure and function of
Vesicle (empty)
kinesin. Each kinesin molecule has a long neck, a
Accessory proteins
fanlike tail, and a globular head that possesses
Dynein ATPase activity. The tail is responsible for attaching
Microtubule to cargo, whereas the head attaches to the micro-
tubule. Phylogenetic analyses have revealed a very
Figure 7 Vesicle traffic in a neuron Vesicle traffic large and diverse family of kinesins. Some members
depends on the polarity of the microtubules. Kinesin carries of the kinesin superfamily are active as monomers.
vesicles of neurotransmitters to the synapse, whereas dynein
Other kinesins assemble into dimers, either homo-
carries empty vesicles back to the MTOC.
dimers or heterodimers. These kinesin dimers
may in turn interact with regulatory proteins
moves along the microtubule in the plus direction,
called kinesin-associated proteins. Some kinesin-
whereas dynein moves in the minus direction.
associated proteins can alter the kinetics of move-
The polarity of the microtubules and the direc-
ment, such as the rate of ATP hydrolysis, while some
tional movement of the motor proteins allow cells to
influence the type of cargo kinesin binds. Many of
transport cargo to the right place. Consider how a
these kinesin-associated proteins are themselves
neuron uses this network to transport neurotrans-
members of multigene families, which enable cells
mitter vesicles (Figure 7). Kinesin can pick up vesicles
to fine-tune microtubule-based movements.
filled with neurotransmitters in the cell body, and
Like kinesin, dynein has a globular head, a
walk along microtubules toward the plus ends at the
neck, and a tail. Dynein is larger than kinesin, and
synapse. Once the vesicles release their neurotrans-
can move along microtubules about five times
mitters, endocytosis returns empty vesicles to the
faster. The many isoforms of dyneins fall into two
cell. Dynein then carries the endocytic vesicle to the
classes: cytoplasmic and axonemal. Cytoplasmic
cell body, moving along the microtubule toward the
dyneins are dimers of two identical subunits (heavy
minus end. This simple example illustrates why di-
chains) with a number of associated smaller pro-
rectional movements of neurosecretory vesicles are
teins. The dynein heavy chains possess the ATPase
necessary for nerve function. Most cells possess
activity, and mediate binding to the microtubule.
countless types of vesicles that need to be transported
Unlike kinesin, dynein does not attach directly to
to many locations. How do cells ensure that each of
vesicles. Instead, large multiprotein complexes of
these diverse vesicles goes to the correct location? At
accessory proteins link dynein to its cargo, provid-
least part of the answer lies in the structural diversity
ing another layer of regulation of microtubule
of motor proteins themselves. Large gene families en-
movement. Axonemal dyneins are the driving force
code multiple isoforms of kinesin, dynein, and their
behind movements generated by cilia and flagella.
respective regulatory proteins. Each combination of
isoforms imparts different transport characteristics.
Cilia and flagella are composed
Kinesin and dynein move along of microtubules
microtubules Cilia and flagella are similar structures with diverse
Although kinesin and dynein are unrelated pro- roles in animal physiology. For example, flagella
teins, they work in similar ways. Both undergo propel sperm toward the egg, while cilia allow ep-
conformational changes, where they stretch out to
230
ithelial cells to push mucus over the cell surface.

Cilia differ from flagella in their arrangement and
the way they move. Flagella normally occur singly
or in pairs, whereas cilia are more abundant. In ad-
dition, flagella move in a whiplike manner, whereas
cilia move with a wavelike motion. Microtubules in
cilia and flagella are arranged into a structure
called an axoneme, which is wrapped in an exten-
sion of the plasma membrane in the form of a mem-
branous sheath.
A cross-section through a flagellum reveals a
structure that resembles a wagon wheel (Figure
8). At the hub of the wheel are two single micro-
tubules interconnected by a protein bridge.
Around the edge are nine pairs of microtubules or
Plasma
doublets, connected to each other by the protein membrane
nexin. Protein spokes then radiate from the two
singlets toward the nine doublets. Almost 10 years
before microtubules were first identified, this
“nine ⫹ two” arrangement in axonemes was seen (a) Longitudinal view of an axoneme
to underlie the structure of flagella and cilia.

Microtubule singlets
How does dynein power microtubule move-
ment in cilia and flagella? Each doublet has a series Nexin
of dynein motors that extend toward the neighbor-
ing doublet. At rest, the dynein sits inactive in this
Microtubule
structure. When the cell receives a signal, protein doublet
kinases phosphorylate critical proteins associated
Inner
with dynein to activate the ATPase. Once activated, sheath
dynein walks along the neighboring microtubule
toward the minus end of the microtubule located at Dynein
the base of the axoneme. The waving of cilia and outer arms
whipping of flagella result from asymmetric activa-

tion of dyneins on opposing sides of the axoneme. Dynein
inner arms
When dyneins on one side of the axoneme are ac-
tivated, the tip of the flagellum bends in that direc-
tion. These cycles of activation and inactivation of Spoke
dynein along the entire length of the axoneme gen- (b) Enlarged cross-section of an axoneme
erate movement. If all of the dyneins were acti-
vated simultaneously, no movement would occur. Figure 8 Structure of the flagellum The tail of a
sperm is constructed from microtubules arranged into a
Table 1 summarizes some of the important complex network called an axoneme. The core structure is
roles microtubules play in diverse physiological composed of nine doublets of microtubules, connected by the
functions. linker protein nexin. Radial spokes extend from this outer
ring toward a central pair of single microtubules. Dynein
arms extend from one doublet to the adjacent doublet.
Microfilaments
Microfilaments are the other type of cytoskeletal tor protein myosin, are found in all eukaryotic cells;
fiber used in movement. Like microtubules, micro- the organization of these elements enables diverse
filaments play important roles in the transport of types of cellular movement. In some cases, cellular
vesicles throughout cells. In addition, microfilament- movement arises simply from the polymerization of
based movement also allows cells to change shape actin. More often, however, actin-based movement
and move from place to place. The elements of involves myosin. Let’s look at the many ways in
microfilament-based movement, actin and its mo- which microfilaments drive movement.
231
Table 1 Microtubules and animal physiology.
Cellular process Physiological function

Cytokinesis Development and growth: All cells need to divide, and microtubules ensure that
chromosomes are equally divided after mitosis.
Axon structure Nervous system: Microtubules support the long axons.
Vesicle transport Hormones and cell signaling: Microtubules carry hormones from sites of synthesis to sites
of release.
Pigment dispersion Adaptive coloration: Microtubules control the distribution of pigment granules throughout
the cell to affect animal color.
Flagellar movement Reproduction: Flagella allow sperm to swim toward the egg.
Ciliary movement Respiration, digestion: Cilia propel mucus and other fluids over the epithelial surface.
Microfilaments are polymers of actin can spontaneously assemble and disassemble with-
out an energy investment. It polymerizes sponta-
Microfilaments are composed of long strings of the
neously when its concentration is above a threshold
protein actin. These actin monomers are called
Cc. Each actin filament can grow from both plus and
G-actin, because of the globular structure of the
minus ends, but growth is six to ten times faster at
protein. When G-actin assembles into filaments,
the plus end. If the growth at the plus end exactly
however, it is referred to as F-actin (Figure 9). Actin
balances the shrinkage at the minus end, the total
length of the microfilament is con-
stant. However, if you were to follow
G-actin
the position of an individual actin
monomer, you would see it move
Nucleation progressively from the plus end to-
ward the minus end. This process is
called treadmilling. As with micro-
tubules, accessory proteins can mod-
Elongation
ulate the rate of microfilament
growth. One way that a cell increases
(–) (+) the length of a microfilament is by
stabilizing the minus end, preventing
F-actin
it from disassembling. To do that,
cells use capping proteins that bind
on the end of microfilaments to sta-
Capping bilize the structure.
protein Cells can arrange microfilaments
in many ways, often with the help of
actin-binding proteins that cross-link
microfilaments (Figure 10). Microfil-
aments can be arranged in tangled
networks, linked together by long,
Actin treadmilling Actin growth flexible actin-binding proteins such
Figure 9 Structure of actin and microfilaments G-actin monomers join as filamin, or aligned in parallel into
together to initiate the formation of F-actin. After this process of nucleation, the stiff bundles, cross-linked by short
microfilament elongates by incorporating more G-actin into the plus end. Growth is actin-binding proteins such as fascin.
more favorable at the plus end, and the minus end is more likely to lose monomers. Actin bundles run throughout the
This pattern results in the process called treadmilling, where an individual monomer
(shown in blue) travels down the length of the filament, even if the total length remains
cell, providing support. In some in-
constant. If the minus end of the microfilament is stabilized, by a capping protein for stances, these stiff actin fibers push
instance, the microfilaments can lengthen. the margins of the cell outward. For
232
G-actin
Cross-linker
Plasma (e.g., fascin)
membrane (+)
F-actin
Plasma
F-actin
membrane
Actin assembly Actin bundles
F-actin
Cross-linker
Plasma
(e.g., filamin)
membrane
Nucleus Plasma
Cross-linker F-actin
membrane
(e.g., dystrophin)
Integral protein
Membrane attachment Actin network
Figure 10 Actin networks Actin microfilaments can be arranged in many different

conformations, often using cross-linking proteins for stabilization. Microfilaments can grow
from their plus ends, causing cellular extensions. Actin bundles form when parallel arrays are
cross-linked together. The microfilaments can be attached to integral membrane proteins by
cross-linking proteins such as dystrophin. Actin can also be arranged into complex networks
stabilized by cross-linking proteins such as filamin and fascin.
example, they provide the foundation for microvilli, protists, but they are thinner and more sheetlike.
the fingerlike extensions of digestive epithelia. The The nature of the amoeboid protrusions in ani-
bundles and networks of microfilaments compris- mals depends upon how the newly synthesized
ing the actin cytoskeleton are connected to the microfilaments are integrated into fibers. Filapo-
plasma membrane by specific anchoring proteins dia result when the microfilaments are limited to
such as dystrophin. simple fibers. Lamellipodia arise from sheetlike
networks of microfilaments.
In a stationary cell, the actin network extends
Actin polymerization can generate around the cell’s periphery, attached at many
movement points to plasma membrane receptors. When this
Although most types of microfilament-based cell is induced to move, it protrudes a region of the
movement rely on myosin, the actual polymeriza- membrane forward. Underneath the plasma
tion of actin can mediate some forms of move- membrane, the plus ends of the microfilaments
ment. While biologists do not yet fully understand rapidly incorporate G-actin, pushing the mem-
how it works, actin polymerization is important in brane forward. At the trailing edge of the cell, the
two kinds of amoeboid movement in animals. Fil- minus ends lose G-actin monomers. Actin-binding
apodia are thin rodlike extensions of cells formed proteins regulate actin polymerization, and conse-
by actin fibers. Cells build filapodia for many pur- quently amoeboid movement. At the leading edge,
poses. For example, nerve cells use filapodia to the protein profilin binds to free G-actin monomers,
make physical contact with neighboring cells, helping them integrate into the plus end of the mi-
which is an important step in the embryonic devel- crofilament. Another protein, cofilin, however,
opment of the nervous system. Digestive epithelia breaks microfilaments at the trailing edge to trigger
use filapodia to build microvilli, protrusions that disassembly.
increase the surface area of the plasma mem- Sperm also use actin polymerization during
brane. In contrast, some metazoan cells move us- fertilization (Figure 11). The process of fertiliza-
ing actin-based extensions called lamellipodia. tion depends on the sperm’s ability to control the
Lamellipodia resemble the pseudopodia found in growth of its actin cytoskeleton toward the egg.
233
When a sperm encounters an egg, it uses surface

Jelly coat
receptors to form a tight bond with the egg’s outer
Egg surface. Activation of these receptors triggers the
Sperm formation of a structure called an acrosome.
Within the acrosome, a vesicle full of hydrolytic
enzymes is pushed to the cell surface. When it
binds to the sperm plasma membrane, exocytosis
Nucleus Acrosomal Jelly coat
vesicle
of the acrosomal vesicle helps break down the
egg’s jelly coat. The sperm then uses actin poly-
merization to push an extension of the sperm
Egg
Release of plasma plasma membrane through the softened jelly coat.
acrosomal membrane Once the sperm plasma membrane fuses with the
vesicle egg plasma membrane, the nuclear DNA of the
Receptor contents Egg
Sperm cytoplasm sperm can be transferred into the egg.
Actin uses myosin as a motor protein

Although some cells use actin polymerization to
generate movement, in most situations microfila-
(+) ments are used in combination with myosin. Dif-
ferent arrangements of actin and myosin enable
Actin cells to transport vesicles and organelles, change
polymerization
shape, and even move from place to place. As was
the case with microtubule-based movements, di-
versity in both the motor protein and associated
regulatory proteins provides cells with the regula-
tory precision needed to control intracellular traf-
fic. Many aspects of actin- and myosin-based
movement are similar throughout eukaryotes. For
(+) example, muscle uses a unique arrangement of
actin and myosin, in combination with novel iso-
Fusion
Actin forms of myosin and its regulatory proteins. Let’s
polymerization
begin by examining myosin structure and con-
sider how it controls movement.
The myosin gene family of eukaryotes is very
large, with at least 17 different classes of myosins
(I–XVII) distinguished by differences in their struc-
tural properties. The most common myosins stud-
Transfer ied in animals are in classes I, II, and IV. Myosin II
of sperm is sometimes called muscle myosin, although it
DNA
also occurs in nonmuscle tissues. Myosins I and V
are most important in intracellular traffic. Most
animals possess multiple isoforms of myosins
within each class, adding to the repertoire of
myosin functions available in animal cells.
Figure 11 Acrosome of sperm Once the sperm find
the egg, activation of membrane receptors in the sperm
Despite their structural differences, each
triggers the exocytosis of the acrosomal vesicle and the myosin isoform shares a general organization,
polymerization of microfilaments. The acrosomal enzymes with a head, a tail, and a neck (Figure 12). The
help dissolve the physical barriers around the egg. The head possesses ATPase activity, which provides
growing microfilaments push the sperm membrane through
the jelly coat into contact with the egg plasma membrane.
the energy for movement. The tail allows myosin to
After membrane fusion, the sperm DNA moves into the egg bind cargo, such as vesicles, organelles, or even
to complete fertilization. the plasma membrane. In addition, the tail struc-
234
Head Neck Tail this process we must consider both the chemical
events associated with the enzymatic head of the
Myosin I myosin, as well as the structural changes through-
out the myosin that culminate in movement. The
Calmodulin light chains
two processes are integrated in the sliding fila-
ment model. This general model, first proposed
Myosin V almost 60 years ago by Hugh Huxley, shows how
a myosin head walks along an actin polymer. This
model can be used to explain all the different types
of movement mediated by myosin. For example, a
Regulatory light chain model involving a single myosin can be used to de-
Myosin II scribe vesicular transport. The sliding filament
model can also be used to describe how myosin
Essential light chain and actin interact during muscle contraction, dis-
130 nm cussed later in this chapter.
Many of the principles explained by the sliding
Figure 12 Myosin structures Each myosin isoform
possesses a catalytic head, a regulatory neck, and a tail
filament model can be illustrated through the fol-
region that interacts with other proteins. Regulatory lowing analogy. Imagine a rope stretching across
proteins, such as light chains and calmodulin, can bind the the floor of a room. Now think about how you
neck region. Differences in structures of myosin and its would pull yourself across the room using your
regulatory proteins account for the specific properties of
each isoform. Myosins I and V are used primarily in
arm. You start by extending your arm forward to
intracellular traffic. Myosin II is involved in cytokinesis and grasp the rope, then bend your extended arm,
muscle contraction. pulling yourself forward. Next, you release the
rope, extend your arm, grasp the rope again, and
ture of some myosin isoforms can cause the indi- bend your arm. As you make your way across the
vidual myosin proteins to assemble into dimers. room, your arm undergoes cycles of extension,
Whereas myosin I remains as a monomer, both grasping, and bending. Although each part of the
myosin II and myosin V normally dimerize. The cycle costs energy, the most demanding step in the
neck regulates the activity of the myosin head di- cycle is when you bend your arm to pull yourself
rectly, and also mediates the effects of proteins that forward. In the sliding filament model, myosin
associate with the neck, known as myosin light acts very much like your arm, and actin is the
chains. Myosin II, for example, has two different equivalent of the rope. The myosin molecule ex-
myosin light chains: essential light chain and tends by straightening its neck, pushing the head
regulatory light chain. Myosin light chains are reg- forward. The myosin head then forms a bond with
ulated by reversible phosphorylation. Phosphory- actin, just as your hand grasps the rope. This
lation by myosin light chain kinase (MLCK) may strong interaction between myosin and actin is
alter the catalytic activity of the myosin head or in- called a cross-bridge. Myosin bends, pulling the
duce a structural change that permits myosin to in- actin toward its tail. This step is called the power
teract with actin. Many of the hormones that stroke. The cross-bridge cycle includes the for-
regulate myosin function either target MLCK or mation of the cross-bridge, the power stroke, and
myosin light chain phosphatase (MLCP), which the return to the resting, unattached position.
dephosphorylates the myosin light chain. The mechanical changes in the cross-bridge
cycle are driven by chemical and structural
changes occurring within the myosin catalytic
The sliding filament model describes head (Figure 13). As previously discussed, myosin
actino-myosin activity is an ATPase; the breakdown of ATP provides the
Despite the great diversity in myosin, the basic energy for the mechanical changes. At the
mechanism that defines its interaction with micro- beginning of the cycle, myosin is tightly bound to
filaments is shared by all isoforms. Myosin, like all actin and the ATP binding site is empty. If no ATP
the motor proteins we have discussed, is an ATPase is available, the myosin remains firmly attached.
that converts the energy released from ATP hy- However, once ATP binds, myosin loses its
drolysis into mechanical energy. To understand affinity for actin, and the cross-bridge is broken.
235
if the rope is not attached to the

1 ATP binds,
causing wall, your arm actions move the
myosin to rope. Within the cell, actino-myosin
Actin detach.
movement depends on which of the
(+) (–)
elements, actin or myosin, is immo-
Myosin ATP bilized. If the actin microfilament is
head
immobile, then myosin walks along
ATP
2 Myosin head the microfilament. This is analogous
4 ADP is ADP
extends and
released.
to myosin carrying a vesicle through-
attaches to
P ADP + Pi adjacent actin. out the cell. Conversely, if myosin is
Actin moves immobile, the actin filament moves.
In some cases, myosin is attached to
ADP 3 Release of ADP
the plasma membrane; in this situa-
ATP
phosphate tion, cross-bridge cycling pulls the
promotes actin microfilament over the surface
power stroke.
of the plasma membrane. This
Figure 13 Sliding filament model In this figure, we follow a single myosin arrangement allows cells to change
head as it progresses through a cross-bridge cycle. In the absence of ATP, the myosin shape. We will consider a third sce-
head remains attached to the microfilament. Once ATP binds (step 1), myosin releases nario later in this chapter when we
the microfilament. ATP hydrolysis induces myosin to extend toward the plus end of the
discuss how the sliding filament
microfilament (step 2), although the energy remains trapped in the myosin head. Upon
release of the phosphate, the stored energy is used to bend myosin, pulling the model applies in muscle, where
filament back in the power stroke (step 3). Once the movement is complete, ADP is both the actin and myosin are or-
released (step 4) and the ATP binding site remains vacant until ATP binds to initiate ganized into a three-dimensional
another cross-bridge cycle.
superstructure.
Release of actin activates the myosin ATPase to

break ATP down to ADP and phosphate. The hy-
Myosin activity is influenced by unitary
drolysis of ATP causes myosin to extend forward
displacement and duty cycle
to grasp further up the actin microfilament. (Al- The sliding filament model provides the context
though the ATP molecule within the myosin head for understanding two features of actino-
has been chemically changed to ADP and phos- myosin–based movement: duty cycle and unitary
phate, the energy that had been stored within the displacement. These properties are most easily
ATP remains stored within the myosin head as an understood using the myosins involved in intracel-
energy-rich conformation.) Once myosin binds lular trafficking as an example.
again, it first releases phosphate and then ADP. Unitary displacement corresponds to the dis-
Upon phosphate release, myosin uses the stored tance myosin steps during each cross-bridge cycle.
energy to pull the actin microfilament in the Returning to our rope-climbing analogy, the uni-
power stroke. The myosin head remains attached tary displacement is the distance you are able to
to the actin until another ATP molecule finds its move with each cycle of release, extend, grasp, and
empty nucleotide-binding site and the cycle re- pull. In this analogy, the unitary displacement de-
peats. If no ATP is available, myosin remains pends on the length of one’s arm. With myosin, the
firmly attached to actin, creating a condition step size depends on the length of the neck. Opti-
known as rigor. When an animal dies, the ATP cal studies show that the actual distance moved
levels decline and muscles become locked in rigor with each step is not fixed; for example, the unitary
mortis. displacement of a myosin V monomer may range
The actual movement that happens within the anywhere from 5 nm to a maximum distance of
cell during a cross-bridge cycle depends upon the about 20 nm. The myosin V dimer uses both of its
structural arrangements of actin and myosin, monomers in tandem, walking along actin with an
specifically which of the two is free to move. Return- average unitary displacement of about 36 nm. This
ing to our earlier analogy, if the rope is tied to the distance is related to an important structural char-
wall, your arms pull you across the room. However, acteristic of the actin microfilament.
236
To understand the relationship between uni- actin. Most nonmuscle myosins have duty cycles of
tary displacement and actin structure, consider about 0.5. This means that myosin is tightly bound
the following analogy. Think of the actin filament to actin for only half of each cross-bridge cycle.
as a spiral staircase, with each step representing Why is duty cycle significant? Imagine climbing
an actin monomer. You, acting as myosin, have the that spiral staircase using only one arm. If you re-
challenge of climbing the stairs from the outside of leased your grasp to reach the next step, you’d fall.
the staircase. You can only use your two arms to Likewise, if vesicles were carried along microfila-
climb. If you climbed the staircase one step at a ments using only a single myosin head, they would
time, your travels would carry you up the staircase float away from the actin track when the myosin
in a spiral. How would your strategy change if you reached the point in the cross-bridge cycle where
needed to stay on the same side of the staircase as it released actin.
you ascended? You would have to reach straight Vesicles and organelles avoid falling off the mi-
up as high as the stair directly above. This dis- crofilament in two ways. First, vesicles use dimers
tance reflects the period of the spiral. Like the spi- of myosin. When one myosin head attaches, the
ral staircase, microfilaments are spirals, twisted other can detach and extend forward, functioning
into a helix with a period of 36 nm (Figure 14). Be- much like you did when you climbed the staircase
cause myosin walks with an average unitary dis- with two arms. The duty cycle of 0.5 would mean
placement of 36 nm, it remains on the same side that each arm could only hold the stair half the
of the spiral as it travels along the microfilament. time. Clearly, climbing the stairs or walking along
If it had a shorter or longer unitary displacement, a microfilament this way requires exquisite coor-
it would spiral around the microfilament, creating dination, with the two myosins working in perfect
a problem for myosin carrying a large vesicle or synchrony. If at any point neither of the heads was
organelle, as its spiral trajectory would complicate attached, the vesicle would fall off the microfila-
movement through the dense cytoskeletal net- ment. In reality, the two heads are not perfectly co-
work. As you will see later in this chapter, muscle ordinated and a second mechanism is required to
myosins do not have this 36-nm unitary displace- ensure that the vesicle remains attached. Vesicles
ment; nonetheless, they avoid these problems in further reduce the risk of falling off the microfila-
other ways. ment by engaging multiple myosin dimers. Imag-
The second parameter that describes myosin ine how much easier it would be to climb that
activity is duty cycle, the proportion of time in spiral staircase if you could use two arms as well
each cross-bridge cycle that myosin is attached to as two legs.
The sliding filament model was an important
advancement in our understanding of how
36 nm 36 nm
myosin moves along actin. Its general features
apply to most types of actino-myosin activity in all
eukaryotes. However, the exact values of duty
cycle, unitary displacement, and other kinetic fea-
tures of actino-myosin change in different situa-
tions. For example, the kinetics differ depending
on whether myosin and actin are immobilized or
free to move. The mechanical properties of actino-
myosin influence the enzymatic features, and vice
versa.
Actin and myosin perform diverse and impor-
tant functions in animal cells (Table 2). Many of
their responsibilities in animal cells are little dif-
ferent from their roles in other eukaryotes. Over
hundreds of millions of years, animals evolved
Figure 14 Unitary displacement Myosin V walks novel isoforms of myosin, and arranged actin and
along the actin filament in steps of about 36 nm, which myosin in different ways, providing the foundation
corresponds to the period of the actin filament. for a specialized contractile tissue: muscle.
237
Table 2 Actin and myosin function in animal physiology.
Cellular process Physiological function

Vesicle transport Hormones and cell signaling: Microfilaments carry hormones from sites of synthesis to
sites of release.
Microvilli Digestion: Actin supports the fingerlike extensions of the cells of the intestinal
epithelium.
Amoeboid movement Cardiovascular physiology: Blood cells use amoeboid movement to invade damaged
tissue.
Skeletal muscle contraction Locomotion: Muscles provide the contractile force for movement.
Respiratory physiology: Trunk muscles help move air over the respiratory surface.
Cardiac muscle contraction Circulatory physiology: Cardiac muscles pump blood.
Smooth muscle contraction Circulatory physiology: Vascular smooth muscle controls the diameter of blood vessels.
Digestion: Visceral smooth muscle forces food down the intestinal lumen.
2 CO N CEP T C HE C K Muscles provide the contractile force needed

in many multicellular tissues and physiological
1. Compare and contrast microtubules and systems. We are most familiar with their role in
microfilaments in terms of primary, secondary, animal locomotion, where skeletal muscles move
tertiary, and quaternary structural levels.
the body trunk and appendages. However, mus-
2. What factors influence the assembly and
cles play many roles in animal physiology beyond
disassembly of the cytoskeleton?
locomotion. In the circulatory system, for exam-
3. What is meant by polarity with respect to
microfilaments and microtubules? Why is it
ple, muscles provide the pumping power of the
important to structure and function? heart and give blood vessels control over their di-
4. Which plant alkaloids disrupt animal ameter.
cytoskeleton function? What do they do for the The remainder of this chapter focuses on the
plants? Why might they have no effect on the cellular aspects of muscle function: how muscle
cytoskeleton in the plants? cells are built, how they are controlled, and how
the elements have been fine-tuned at the cellular
level to achieve diversity in function. Although
Muscle Structure and there is extraordinary diversity in the way muscles
Regulation of Contraction are constructed and used, some features are
shared among all muscle types and species. First
Earlier in this chapter we discussed how the cy- and foremost, the contractile elements of all mus-
toskeleton and motor proteins mediate diverse cles are polymers of myosin and actin. The myosin
types of intracellular and cellular movement. Ani- polymer forms the backbone of a multiprotein
mals use these same elements to build muscle complex known as the thick filament. Analagous
cells, or myocytes. A “muscle,” such as skeletal to the microfilaments of the cytoskeleton, muscle
muscle or heart muscle, is composed of many cells possess a thin filament, composed primarily
types of cells, each of which contributes to muscle of polymerized actin (Figure 15).
structure and function. In addition to the myo- In most areas of cell biology, “myosin” refers to
cytes, which confer the contractile properties of the motor protein itself. When physiologists discuss
muscle, there are also endothelial cells that make muscle, however, “myosin” refers to a hexamer
up capillaries, immune cells for defense, pluripo- consisting of two myosin II motor proteins, or
tent stem cells to rebuild damaged myocytes, and myosin heavy chains, and four myosin light
fibroblasts to produce the extracellular matrix and chains. About 150 myosins are collected together
connective tissue that holds the muscle together.
In a heart, for example, there are more nonmuscle
cells than muscle cells, though the larger myocytes
make the greatest contribution to mass.
238
by the tail to create an assembly that resembles a mediate the interaction between actin and myosin,
bouquet of flowers; the thick filament is composed thereby regulating contraction.
of two bouquets arranged end-to-end. The two ends Another feature that is shared among all mus-
of the thick filament appear bushy from the myosin cles is the basis of interaction between the thick
heads extending outward, while the tails of the two and thin filaments; the sliding filament model, dis-
bouquets are located in the center of the thick fila- cussed earlier in this chapter, applies equally well
ment, in a region devoid of myosin heads. A thick to all actin-myosin interactions. However, the ap-
filament is composed of about 300 myosin hexam- plication of the sliding filament model to muscle is
ers, providing 300 myosin heads on each end. more complicated because of the unique proper-
Thin filaments are similar in structure to cy- ties of muscle myosin, its arrangement into a thick
toskeletal microfilaments, but they are constructed filament, and the integration of thick and thin fila-
with different actin isoforms. Microfilaments are ments into a three-dimensional lattice.
polymers of ␤-actin; thin filaments are made from As you will see later in this chapter, animals
␣-actin. As we learned earlier in this chapter, mi- use these basic elements to produce many types of
crofilaments constantly assemble and disassem- muscles with unique structural and functional fea-
ble. In contrast, thin filaments are stabilized in a tures. One important dichotomy in muscle biology
way that prevents spontaneous growth or shrink- is the distinction between smooth and striated
age. Each thin filament is capped by tropomodulin muscle (Figure 16). Muscles such as cardiac and
at the minus end and CapZ at the plus end, pre- skeletal muscle have a striped appearance, giving
venting changes in length. In some muscles, thin
filaments are decorated at regular intervals with
the proteins troponin and tropomyosin, which
Head Myosin light

chains
Neck
(a)
(a) Thick filament
Actin
(b) Thin filament
(b)
Figure 15 Thick and thin filaments Muscle is
composed of thick filaments and thin filaments. (a) Thick Figure 16 Smooth and striated muscle
filaments consist mainly of myosin molecules connected by (a) Cardiac and skeletal muscles are called striated muscle
the tail with heads extending radially. (b) Thin filaments are because of their striped microscopic appearance. (b) Blood
mainly actin, though numerous actin-binding proteins (not vessels, respiratory tracts, and visceral linings possess
shown) influence thin filament function. muscle termed smooth muscle because it lacks striations.
239
rise to the name striated muscle. In contrast, the of terms that is useful for distinguishing between
muscles that line blood vessels and viscera do not muscle types of one species may be useless in dis-
appear striped, and are called smooth muscle. tinguishing between muscle types in other species.
The difference in microscopic appearance in these Some of the other ways that animal physiologists
muscle types can be traced to the way thick and categorize muscle into subtypes are summarized
thin filaments are organized inside the cell. In the in Table 3.
next section, we begin by discussing how striated
muscle is constructed and regulated, returning to
Striated muscle thick and thin filaments
structure and function of smooth muscle later in
are arranged into sarcomeres
this section. Although we focus on vertebrate mus-
cles, most of the basic features apply equally well Striated muscles arrange their thick and thin fila-
to invertebrates. ments in highly organized arrays. The end of each
thick filament is surrounded by an array of thin fil-
aments, typically six. This unit, called a sarcomere,
is repeated in parallel and in series throughout the
Structure of the Vertebrate Striated muscle cell. While the structure of the sarcomere
Muscle Contractile Apparatus is relevant to striated muscles, the principles of
In the following discussion, we focus on the cellu- contraction apply broadly to all muscles.
lar basis of contraction in vertebrate striated mus- The microscopic appearance of striated mus-
cle, which includes cardiac and skeletal muscles. cle is rooted in sarcomere structure (Figure 17). A
Striated muscle can be used to describe the general protein plate called the Z-disk forms the end of
features of muscle structure and regulation, but it each sarcomere. Thin filaments then extend from
also provides examples of functional diversity. the Z-disk, with the minus end of the actin chain
Striated muscle has been studied for nearly directed toward the center of the sarcomere. The
one hundred years by many researchers working double-headed thick filaments are arranged be-
on diverse models. This rich history has led to con- tween Z-disks, spanning two opposing thin fila-
fusion in the way muscle types are described. A set ment arrays. The region of a sarcomere where
Table 3 Terminology used to classify striated muscle cell types.
Basis of category
(muscle types) Distinction between muscle types
Innervation Phasic (twitch) muscles have single innervation, whereas tonic muscles have
(phasic and tonic) multiple innervations. “Tonic” is sometimes (erroneously) used to describe the
slowest twitch muscles that are continuously stimulated.
Rate of shortening Vertebrate skeletal muscles contract at different velocities, usually due to
(fast and slow) myosin isoform pattern.
Myosin isoforms Most vertebrate myosin heavy chains are formed from these four genes. Some
(I, IIa, IIb, vs IIx/d) lower vertebrates have more isoforms. Invertebrates have fewer myosin
isoforms.
Metabolism Fast-twitch skeletal muscles usually have few mitochondria and derive energy
(oxidative and glycolytic) from glycolysis.
Myoglobin Slow-twitch oxidative fibers usually possess high levels of myoglobin, giving
(red, white, and pink) them a red appearance.
Morphology Myofibrils usually run perpendicular to the plane of contraction, but in
(fusiform and pinnate) pennate muscles the myofibrils run at an oblique angle.
EC coupling Most striated muscles respond to a neural stimulus with a single contraction.
(synchronous and asynchronous) Asynchronous muscles found in some invertebrates contract and relax
repeatedly after a single stimulus.
Excitation Myogenic muscles contract spontaneously, whereas neurogenic muscles
(myogenic and neurogenic) contract in response to a nerve stimulus.
240
thick filaments occur forms a dark

region called the A-band (or
Anisotropic band). The narrower
I-band (or Isotropic band) region
spans a Z-disk, and includes the por-
tion of the thin filaments without
overlap with thick filaments. The
M-line is the central region of the
sarcomere between the two minus
ends of the thin filament. In this re-
gion, the thick filaments do not over- I-band A-band I-band
lap with thin filaments.
Specific proteins maintain these
structural relationships within the
sarcomere. For example, nebulin
runs along the length of the thin fila-
ment; the length of nebulin deter-
mines the length of the thin filament.
CapZ
The thick filament is held into posi- Z disk Titin Tropomodulin Nebulin Z-disk
tion by the protein titin, which con- Thin filament Thick filament
nects the end of the thick filaments to Sarcomere
the Z-disks. Since the distance be-
tween the end of the thick filament Figure 17 The sarcomere Thick and thin filaments, in association with
and Z-disk changes with contraction, structural proteins, comprise the sarcomere. Each thin filament is anchored into the
titin must be compressible. Although Z-disk by the protein CapZ, and capped at the minus end by tropomodulin. Nebulin
parallels the thin filament to establish the appropriate length of each filament. The thick
we discuss sarcomere features based filaments are held in position by titin, which anchors the thick filament to the Z-disk.
on its two-dimensional microscopic
appearance, you should remember the three-
dimensional arrangement of thick filament and thin
filaments (Figure 18). The thin filaments are ar-
rayed in a cylinder around the thick filament, while Sarcomere
the thick filament is held at a constant location near
the center of the thin filament array. In vertebrate
striated muscle, six thin filaments surround each
thick filament, each thin filament interacts with
three separate thick filaments, and the resulting ra-
tio of thick filaments to thin filaments is 1:2. Z-disk
M-line
Z-disk
Thin filament
Myosin II has a unique duty cycle and Thick filament
unitary displacement
The sarcomeric structure, maintained by suites of
proteins, ensures that bouquets of myosin heads are Thin
filament
kept in a location where they are able to bind actin.
The interaction between actin and myosin in mus- Z-disk Myosin
head
cle is very similar to the sliding filament model we
Thick
discussed early in this chapter. However, the struc- filament
tural organization, coupled with unique properties
of muscle myosin, complicates the simple model de-
Figure 18 Arrangement of thick and thin
scribed earlier involving a single myosin head.
filaments Within the sarcomere, thick filaments are
The distinct features of muscle actino-myosin surrounded by thin filaments. This arrangement ensures that
activity are linked to the sarcomeric organization. myosin heads are able to find a microfilament at all times.
241
First, unlike the situation in vesicle traffic, when Most vertebrate striated muscles show a rest-
myosin detaches from actin it cannot drift away. ing sarcomere length of about 2.0 µm. The amount
Myosin heads on the thick filament are held in po- of force generated by a sarcomere is maximal over
sition opposite actin. Second, hundreds of myosin this range because there is an optimal overlap be-
molecules are attached together in the thick fila- tween thick and thin filaments (Figure 19). Muscle
ment. Consider these structural relationships in cells can be stretched, however, changing sarcom-
the context of duty cycle. If muscle myosin had the ere length enough to influence the degree of over-
same duty cycle as vesicle myosins, roughly 0.5, lap. If a muscle cell is stretched beyond a
then at any given time half of the myosins would sarcomere length of about 2.5 µm, some of the
be attached to actin. How could a myosin head pull myosin heads near the midpoint of the thick fila-
the thin filament if dozens of other myosins were ment cannot connect with the thin filament. If it is
firmly attached to actin at the same time? In con- stretched to beyond about 3.5 µm, there is little
trast to other myosins, muscle myosin II has a very overlap between thick and thin filaments; no cross-
short duty cycle, approximately 0.05. That means bridges can form and no shortening can occur. The
that during each cross-bridge cycle, a specific contraction is also weakened if the sarcomere
myosin head is physically attached to the actin fil- length is much shorter than about 2 µm. At this
ament for only 5% of the time. For the remainder point, the thin filaments from adjacent Z-disks start
of the cycle this myosin is unattached and there- to overlap, impeding efficient cross-bridge forma-
fore does not impede other myosins from pulling tion. Below a sarcomere length of about 1.65 m,
the thin filament. thick filaments collide with the Z-disk and no fur-
Muscle myosin II activity is also unusual in its ther contraction is possible. Sarcomeric proteins
unitary displacement. Earlier in this chapter we such as titin and nebulin help maintain sarcomere
discussed how a unitary displacement of 36 nm lengths within a useful range.
was critical for a vesicular myosin to walk along When muscle cells are integrated into complex
the one plane of an actin filament, much like an tissues, sarcomere length can be modulated to al-
acrobat crosses a tightrope. In reality, muscle ter contractile properties. For example, cardiac
myosins behave much less like a tightrope walker myocytes are stretched when the heart fills with
than like an octopus pulling itself through a tube. blood, but typically sarcomere lengths are shorter
Wherever the octopus reaches, it finds a wall to than the optimum length. When the volume of
grasp. Since the thin filaments surround each blood returning to the heart increases, as it may
thick filament, there is little risk of a myosin head during exercise, the additional stretching increases
failing to find a binding site on actin. As a result of sarcomere length, and allows the cardiomyocyte to
the structural relationships between thick and thin
filaments, myosin II is able to function with a
much shorter unitary displacement, typically 5 to
15 nm. You can think of the molecular interactions
1.0
in muscle actino-myosin activity as a series of
myosin heads taking turns pulling along the thin 0.8
Relative force
filaments with small, quick tugs.

0.6
Sarcomeric organization determines 0.4

contractile properties of the muscle cell
0.2
Thick filament movement is the sum of many indi-
vidual cross-bridge events. Cross-bridges can only 0
0 1 2 3 4
form where myosin heads are in a position that
Sarcomere length (μm)
can contact the thin filament. Consequently, the
degree of overlap between thick and thin filaments Figure 19 Sarcomere length-force relationship
can influence contractile properties. For any mus- The ability of a sarcomere to contract depends upon the
degree of overlap of thick and thin filaments. Maximal force
cle, the degree of overlap is reflected in the can be generated within a narrow range of sarcomere lengths,
sarcomere length, measured as the distance be- characteristic of the muscle type.
tween the Z-disks. (Modified from Bers, 1991)
242
generate a stronger contraction.

This phenomenon is known as Star-
ling’s Law.
Many of the processes we have
discussed to this point can be under- Skeletal
stood in terms of the events happen- muscle Heart
Myofibrils
ing in a single sarcomere. However,
Myofiber
muscle cells incorporate hundreds or
Cardiomyocyte
thousands of repeating sarcomeres
into larger structures. A single contin-
20 μm
uous stretch of interconnected sar-
comeres, called a myofibril, is usually
1 to 2 µm in diameter and stretches Nuclei Nucleus
the length of the muscle cell. Although
Myofibril
the myofibril is the contractile element 1–2 μm
within muscle cells, each type of mus-
cle cell organizes its myofibrils in a
particular three-dimensional pattern
(Figure 20). Sarcomere (2 μm)
A cardiac muscle cell, or car- Figure 20 Myofibrils Myofibers and cardiomyocytes are used to construct the
diomyocyte, possesses myofibrils multicellular tissues we know as skeletal muscle and cardiac muscle. Myofibers,
that are typically about 100 sarco- which are formed from the fusion of many different muscle cells, can use very long
meres in length. Thus, a typical myofibrils and arrange many myofibrils in parallel. Cardiomyocytes, which are single
cells, possess short myofibrils composed of about 100 sarcomeres. The myofibril is
mammalian ventricular cardiomy-
composed of sarcomeres connected end-to-end.
ocyte is about 0.2 mm in length.
Most vertebrate cardiomyocytes are individual generation and contraction velocity. Each sarco-
cells, though some have undergone an additional mere is able to generate about 5 pN of force and
round of the cell cycle (without cell division) and can shorten about 0.5 µm; these properties are
possess two nuclei. fairly constant among species and muscle types.
A skeletal muscle cell, or myofiber, pos- Different types of muscle rely on specific arrange-
sesses much longer myofibrils, although they are ments of sarcomeres to carry out specific func-
much more variable in size and arrangement. Be- tions. A myofibril composed of 1000 sarcomeres
cause myofibrils usually run the length of the in series would be about 2.5 mm long. It could
muscle, they are short in small muscles and long shorten by about 0.5 mm, but only generate about
in larger muscles. The smallest muscle in hu- 5 pN of force. What would happen if we arranged
mans, the 1.3-mm-long stapedius, controls the 1000 sarcomeres in parallel? The fiber would be
movement of small bones in the inner ear. The only about 2.5 µm long and could shorten only 0.5
longest muscle in humans is the sartorius, which µm. However, it could generate 1000 times more
stretches about 60 cm from the outside of the hip force than the same number of sarcomeres
to the inside of the knee, winding around the arranged in series. These simple examples illus-
thigh. The greater size of the skeletal myofiber is trate how anatomic variations can allow muscles
possible because it is produced by the fusion of to be optimized for different types of contraction:
many individual cells. maximal shortening versus maximal force.
The differences in cellular organization of The contractile properties of muscle cells are
muscle cells can be traced back to the earliest determined by the molecular properties of the
stages of embryonic development, where muscle thick and thin filaments comprising the contractile
precursor cells are induced to differentiate into element, the organization of the sarcomere, and
myocytes (see Box 2, Genetics and Genomics: the arrangement of the myofibrils. Variations in
Muscle Differentiation and Development). contraction properties help define distinct muscle
The three-dimensional organization of sar- types. We next turn our attention to the processes
comeres and myofibrils influences the contractile that control interaction between the sarcomeric
properties of the striated muscle, such as force proteins in muscle cells.
243
BOX 2 GENETICS AND GENOMICS

Muscle Differentiation and Development
It is difficult to discuss the origins of

muscle diversity without also considering how
muscle is made. Muscle synthesis is really two related
processes: muscle differentiation, or myogenesis, and
muscle development. Our understanding of muscle dif-
ferentiation and development has benefited from re-
search in animal model systems, including Drosophila,
C. elegans, Xenopus, zebrafish, and mice, as well as cul-
tured myoblasts. Each type of muscle follows its own
path to the final phenotype. The control of muscle for-
mation is best understood in skeletal muscle.
One reason why we understand muscle differentia-
tion so well is that many of the processes can be stud-
ied in cell culture. Myoblasts from chickens and rodents
are most useful because they can be grown for hun-
dreds and thousands of “generations” without marked
deterioration of their properties. Neonatal muscle, and
to a lesser extent adult muscle, has a population of
muscle precursor cells called satellite cells. These
cells can be harvested and grown in culture. They rap-
idly proliferate but do not differentiate when grown un-
der the right conditions. Most commonly, they are given
a nutrient medium that is rich in fetal growth factors,
such as TGF-␤ (transforming growth factor beta) and
bFGF (basic fibroblast growth factor). If deprived of the
growth factors, the cells begin to express their own sig-
naling factors, such as IGF-II. These hormones induce
the myoblasts to enter the myogenic program. Within
the first day, the myoblasts begin to express a suite of
proteins that act as transcriptional activators. These myosin II, a-actin, and troponins. Simultaneously, the
transcription factors, including proteins of the myoD and hormone-induced pathways trigger individual myo-
MEF families, in turn induce the expression of genes blasts to line up in parallel and fuse together to form a
that encode the muscle-specific proteins, such as multinucleated myotube. The myotubes have many of
[Ca2⫹] activates the actino-myosin machinery to in-

Contraction and Relaxation duce contraction. Relaxation ensues when the
in Vertebrate Striated Muscle [Ca2⫹] falls to resting levels, which is only possible
Muscle activity is a symphony of cellular processes, when the sarcolemma repolarizes.
integrating membrane events with intracellular In the previous section we discussed the struc-
changes in ions and protein-protein interactions. ture of the contractile elements within muscle.
Muscle activity is initiated by excitation: a depolar- Thus, we begin our discussion of the control of
ization of muscle plasma membrane, or sarco- muscle activity by examining the processes that
lemma. The translation of an excitatory signal at control how thick and thin filaments interact dur-
the sarcolemma into a stimulation of contraction is ing contraction and relaxation. We will return to
called excitation-contraction coupling, or EC excitation and EC coupling later in this section.
coupling: a combination of physical and chemical But before we begin, recognize that any general
changes within the myocyte that elevate calcium discussion of how muscle contraction occurs is
concentration ([Ca2⫹]). This increase in intracellular challenged by diversity in muscle structure and
244
the structural and functional features of myofibers, in- as reserve cells, helping to repair and remodel muscle.
cluding the ability to contract. While in vitro myogenic When muscle is damaged, satellite cells sense chemical
models are useful for many purposes, the process of signals released from damaged muscle, migrate to the
myogenesis is much more complicated in real animals. lesion, and enter myogenesis. Within hours, they activate
For a brief time after fertilization, each cell within the the myogenic transcription factors to trigger expression
embryo has the potential to become any type of cell. A of muscle-specific genes. The differentiating myoblasts
subset of these embryonic stem cells takes the first step can fuse with other myoblasts to form new myofibers, or
toward muscle formation to become myoblasts, which become incorporated into adult muscle. Muscles can
proliferate but do not yet express the genes required to also activate myoblasts to remodel muscle. Muscles can
make them into muscle. During this stage of embryoge- grow bigger either by inducing each muscle cell to in-
nesis, myoblasts use lamellipodia to crawl over other crease in size (hypertrophy) or by incorporating more
cells, following hormonal trails through the embryo. At myoblasts into the mature muscle (hyperplasia). The rel-
their final destination, the community of cells produces a ative importance of these two mechanisms of muscle
number of regulatory factors, including the protein called growth depends on the situation. Cardiac muscle grows
sonic hedgehog. The regulatory factors induce the migrat- under many conditions where cardiac output is elevated
ing myoblasts to stop traveling and enter myogenesis. for long periods. For example, cardiac mass can grow by
(The same regulatory proteins coordinate the differentia- as much as 30% in response to exercise or hypertension.
tion and development of other cell types as well.) As oc- In most situations, cardiac mass increases by hypertro-
curs in cell culture models, the myoblasts initiate the phy, with cardiomyocytes growing in size. Much of the
same cascade of transcription factor activation and mus- early growth of fish is hyperplasic, as additional muscle
cle gene expression. Once the cells commit to myogene- fibers form within the trunk.
sis, they continue to sense the surrounding hormones Although much of our understanding of muscle for-
and neurotransmitters in the diverse multicellular neigh- mation comes from work on model organisms, by
borhood. The complex combination of stimulatory and in- studying these pathways we better understand the rela-
hibitory signals enables each muscle to develop the tionships between evolution and development, provid-
appropriate contractile phenotype. These pathways of ing explanations for diversity in muscle phenotype.
differentiation and development control how much mus-
References
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These pathways of muscle differentiation and devel- the embryo: Defining transcriptional networks in adult myogen-
opment begin early in embryogenesis but continue to esis. Nature Reviews in Genetics 4: 497–507.
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function. The variability among muscle types and species. The athleticism of some animals is due, in
species is due in large part to the diversity in the part, to the molecular specializations of contractile
genes that encode muscle proteins. Each animal proteins.
can draw on a suite of protein isoforms to change
the contractile properties of muscle. This genetic
repertoire provides an animal with the ability to
Thin filament proteins confer Ca2⫹
make different muscle types, such as fast-twitch
sensitivity in striated muscle
and slow-twitch skeletal muscles. Isoform switch- Striated muscles contract when Ca2⫹ levels in-
ing allows individual animals to remodel muscles crease within the myofiber. The Ca2⫹ signal is
in response to physiological changes, such as ex- transmitted to the contractile apparatus by the
ercise, and environmental conditions, such as thin filament proteins troponin and tropomyosin
temperature. Evidence of evolutionary divergence (Figure 21). When [Ca2⫹] is low, the troponin-
in muscle genes is also apparent when you com- tropomyosin complex sits on the thin filament in a
pare the muscle contractile properties of different position that blocks actin’s binding site for myosin.
245
Troponin tributes to Ca2⫹-dependent regulation of contrac-

TnI TnC TnT Ca2+ Tropomyosin tion. The first subunit, TnC, is the Ca2⫹ sensor (the
C in TnC stands for calcium). It is a member of a
large family of Ca2⫹-binding proteins. TnC is a
dumbbell-shaped protein with four Ca2⫹-binding
sites, two in the N-terminal domain and two in the
C-terminal domain. The two C-terminal sites have
a very high Ca2⫹ affinity and are probably always
occupied. They are often termed structural sites
because they help physically anchor TnC into the
Actin Myosin-binding site
troponin complex. The N-terminal Ca2⫹ binding
sites trigger contraction, and are therefore re-
Figure 21 Troponin and tropomyosin Troponin, a
trimer of TnC, TnI, and TnT, binds to every seventh actin on ferred to as the regulatory sites. TnI is the subunit
the thin filament. Tropomyosin extends from troponin over that links troponin to actin, thereby inhibiting
seven actins. Its position on the thin filament in relation to actino-myosin ATPase (I is for inhibitory). The
the myosin binding site either permits or inhibits actino-
third troponin subunit is TnT, an elongated pro-
myosin activity.
tein that binds tropomyosin (T is for tropomyosin).
Tropomyosin is a double-stranded protein that ex-
When [Ca2⫹] rises, they roll out of the way, allow- tends over approximately seven actin monomers
ing myosin to bind to actin to initiate the cross- and blocks the myosin-binding sites on actin. The
bridge cycle. To understand how these processes entire troponin-tropomyosin complex acts as a
are regulated, we must consider in more detail the unit, shifting its position on the thin filament in re-
structures of troponin and tropomyosin, focusing sponse to Ca2⫹ (Figure 22).
2⫹
on how they respond to [Ca ]. In a typical resting muscle, Ca2⫹ is maintained
The troponin component is composed of three at a very low concentration, typically below 200 nM.
subunits: TnC, TnI, and TnT. Each subunit con- At this concentration, the TnC regulatory sites are
unable to bind Ca2⫹. With the regula-
tory sites vacant, TnC assumes a par-
ticular structure that restricts its
interactions with TnI. As a result, TnI
Myosin head binds actin, and the entire troponin-
tropomyosin complex remains in an
Ca2+ TnT
inhibitory position. When the muscle
TnC
Myosin site is activated, cytoplasmic Ca2⫹ levels
TnI
Actin monomer can rise 100-fold. This allows the
Ca2+ Tropomyosin
regulatory sites to bind Ca2⫹, causing
a structural change within TnC that
exposes a hydrophobic region in the
(a) Cross-section
protein. Once uncovered, the hy-
drophobic patch on TnC can bind a
corresponding hydrophobic region
in TnI. Strengthening the TnC-TnI
interaction causes a weakening in
Ca2+ the TnI-actin interaction, allowing
troponin to slide into the groove in
actin. The strong TnT-tropomyosin
Ca2+ interaction ensures that troponin
(b) Longitudinal view and tropomyosin move as a com-
plex. In this position, myosin is now
Figure 22 Regulation of actino-myosin contraction by thin filament
proteins Calcium binding to the low affinity sites of TnC triggers a structural free to bind actin and induce actino-
reorganization of troponin-tropomyosin, sliding it off the myosin-binding site of actin, myosin ATPase activity. Cross-
into the major groove of the thin filament. bridge cycling can continue as long
246
as the troponin-tropomyosin complex remains This general model of Ca2⫹-induced contraction

locked in this permissive position, and there is suf- applies to all striated muscles. However, there is a
ficient ATP to supply the actino-myosin ATPase. great deal of diversity in contraction kinetics. We at-
The actino-myosin activity stops when [Ca2⫹] tribute much of this diversity to the control of cyto-
falls to resting levels and the structural changes plasmic [Ca2⫹]. The strength of contraction depends
are reversed. The regulatory sites on troponin lose on [Ca2⫹] because it influences how many troponin-
their Ca2⫹. The TnC bends to hide its hydrophobic tropomyosin complexes are affected; the duration
TnI binding site. TnI reestablishes its connection of contraction is influenced by how long [Ca2⫹] re-
with actin, and the troponin-tropomyosin complex mains elevated. Before discussing muscle excita-
returns to its inhibitory position. The molecular tion and the control of the Ca2⫹ transient, we will
processes involved in contraction are summarized consider how muscle contraction kinetics are influ-
in Figure 23. enced by the properties of the contractile apparatus
itself. Animals can build muscles with diverse func-
tional properties by altering the composition of
Increase in [Ca2+]
thick and thin filaments, and by using regulatory
proteins to modify their kinetic properties.
Ca2+ binds to TnC
Strengthened TnC: TnI

The troponin-tropomyosin complex
interaction influences contraction kinetics
The troponin-tropomyosin complex plays a cen-
Contraction Weakened TnI: actin tral role in the control of contraction. Animals
interaction
possess multiple isoforms of these proteins, each
with subtly different properties that influence
Tn: tropomyosin move contraction kinetics. By regulating the expression
into actin groove of these isoforms, an animal can fine-tune the
regulatory properties of the muscle. Recent stud-
Actin: myosin cross- ies have shown how variation in the proteins of
bridge cycling the troponin-tropomyosin complex impart unique
kinetic properties that are well suited for specific
Ca2+ binds muscle types or physiological circumstances. Ani-
parvalbumin mals draw upon these suites of thin filament pro-
teins to create distinct muscle fiber types, or subtly
Ca2+ pumped across alter the sensitivities to Ca2⫹, pH, or temperature.
sarcolemma and into SR Muscle myofibrils differ widely in their sensitiv-
ity to Ca2⫹. For example, mammalian cardiac mus-
Ca2+ released by TnC cle myofibrils are less sensitive to Ca2⫹ than are
Relaxation mammalian fast-twitch muscles. This difference in
Ca2⫹ sensitivity is due in large part to the properties
Weakened TnC: TnI
interaction of TnC. Vertebrates possess two separate genes for
TnC; one isoform is expressed in both slow-twitch
skeletal muscle and cardiac muscle (s/cTnC) and
Strengthened TnI: actin
interaction the other in fast-twitch skeletal muscle (fTnC). The
main difference between the isoforms is in the
N-terminal domain. In the s/cTnC, an amino acid
Tn: tropomyosin return
to inhibitory position insertion inactivates the first of the two regulatory
Ca2⫹ binding sites. The two isoforms demonstrate
Figure 23 Summary of ionic events in important differences in Ca2⫹ binding that influ-
contraction Contraction begins when the Ca2⫹ levels
within the muscle cell cytoplasm rise in response to
ence muscle properties. The fTnC has a higher Ca2⫹
excitation. Relaxation begins when the cytosolic Ca2⫹ levels affinity than s/cTnC, and consequently fast-twitch
decline, through the actions of ion pumps. muscle is more responsive to Ca2⫹.
247
These differences in TnC also influence how muscle activity, the muscle cell slowly replaces
vertebrate heart and muscle are affected by tem- fast-muscle TnI with slow-muscle TnI. It is difficult
perature. At low temperature, heart myofibrils be- to show the benefits of this type of TnI isoform
come less sensitive to Ca2⫹, whereas the Ca2⫹ switch because many other features of EC cou-
sensitivity of skeletal muscle is unaffected. Much pling also change during exercise training.
of the difference in the response to temperature Much less is known about the functional prop-
can be traced back to molecular properties of TnC erties of the different isoforms of TnT and
isoforms. Cold temperatures impair the ability of tropomyosin. There are many isoforms of TnT
s/cTnC to bind Ca2⫹, whereas Ca2⫹ affinity of fTnC arising from three genes (cardiac, fast skeletal,
is less affected. Transgenic mice that express fTnC slow skeletal) with multiple forms produced by al-
in the heart exhibit the thermal properties of fast- ternate mRNA splicing. Four tropomyosin genes
twitch skeletal muscle. The Ca2⫹ sensitivity of myo- generate a multitude of isoforms through alternate
fibrils from these hearts was much less affected by splicing. Transgenic studies show that
cold temperature. tropomyosin isoforms can influence the rates of
Troponin isoforms are also responsible for the relaxation and contraction.
pH sensitivity of hearts. Cardiac muscle of adult
mammals is very sensitive to low pH, whereas fe-
tal cardiac muscle is much less affected. Low pH
Thick filaments also influence contractile
reduces the Ca2⫹ affinity of the contractile appara-
properties
tus, such that it needs more Ca2⫹ to reach maximal The composition and properties of thick filaments
contraction. The benefits to the fetus are clear. also influence muscle contraction. Animals have
Since its contractile apparatus is less sensitive to the potential to build different types of thick fila-
pH, it is better able to tolerate the frequent bouts ments by drawing upon the large myosin II gene
of hypoxia experienced in utero. We can trace the family. Vertebrates have eight different myosin II
differences in pH sensitivity back to the TnI iso- genes, each producing a myosin heavy chain with
forms. Mammals express three different isoforms distinct structural or functional properties. Since
of TnI: cardiac muscle, fast-twitch skeletal muscle, muscle myosins combine as homodimers or het-
and slow-twitch skeletal muscle. Fetal hearts ex- erodimers, vertebrates can potentially make 36
press the less pH-sensitive skeletal isoforms of different myosin II dimers from the eight genes.
TnI, switching to the cardiac isoform shortly after Although 36 combinations are possible, each mus-
birth. When researchers created transgenic mice cle cell normally expresses only a subset of the
that expressed the fast-muscle TnI in the adult myosin II genes (Table 4).
heart, they found that the hearts were less affected Vertebrate heart muscle uses two myosin II
by pH. Changes in TnI isoform expression also oc- genes (␣ and ␤) to make three different dimers (␣␣,
cur during exercise. With sustained increases in ␣␤, ␤␤). Each of these combinations has a distinc-
Table 4 Myosin isoform properties in mammals.
Isoform Properties
␣ This fast cardiac isoform is expressed in cardiac muscle, in species with faster heart rates, or in
response to activity.
␤ (ⴝ I) This slow cardiac/slow oxidative isoform is expressed in cardiac muscle, in species with slower
heart rates.
IIa Found in fast oxidative-glycolytic fibers. ATPase rates intermediate between I and IIx/d.
IIx/d Found in fast glycolytic fibers. ATPase rates intermediate between IIa and IIb.
IIb Found in fast glycolytic fibers, this creates the fastest ATPase rates.
Embryonic Expressed in skeletal muscles in early embryonic development, as well as some adult muscle.
Perinatal Expressed in skeletal muscles in late embryonic development, as well as some adult muscle.
Extraoccular Expressed in eye muscles.
248
tive actino-myosin ATPase rate: the ␣␣ combina- it implies that a contracting muscle gets smaller.
tion has the fastest ATPase, whereas ␤␤ has the When a muscle is activated, it may shorten, or re-
slowest, and ␣␤ has an intermediate rate. Animals main the same length, or even lengthen. The
alter the myosin heavy chain profile in response to changes in length depend a lot on how the muscle
changes in activity level. Exercise training may is connected to the rest of the body. In the most fa-
cause cardiac muscle to shift from ␤␤ to ␣␣ myosin miliar situation, a contracting muscle shortens in
isoforms. The relationship with activity level is also length. A simple example of a shortening contrac-
reflected in interspecies comparisons. Some tion is when your bicep contracts and your elbow
species, such as rabbits, typically express their ␤- bends. Alternatively, an activated muscle may re-
myosin II genes, whereas species with higher heart main at a fixed length in what is known as an
rates, such as rats, express their ␣-myosin II genes. isometric contraction. For example, many mus-
Myosin isoform shifts also occur in skeletal cles in your back contract without much of a
muscle, which can express seven different change in length, helping you to maintain posture.
myosins (I, IIa, IIb, IIx/d, perinatal, embryonic, A third possibility is when an activated muscle ac-
and extraoccular). Many of these skeletal isoforms tually lengthens. When you walk down stairs some
vary in their ATPase rates, whereas others differ leg muscles undergo lengthening contractions,
in noncatalytic aspects of myosin function, such as slowing the rate of descent by acting like a brake.
the ability to interact with regulatory or structural In many fields of muscle biology, the terms
proteins. As the names suggest, some isoforms are eccentric and concentric are used to describe the
expressed at discrete points in development. As nature of changes in length in relation to contrac-
embryos develop, their skeletal muscle progresses tion. Concentric literally means “having the same
from embryonic, through perinatal, and then fi- center,” whereas eccentric means “not having the
nally to muscle-specific adult isoforms. It is not yet same center.” The problem with these terms is that,
known how each myosin II isoform influences in some fields, they have been used in ways that can
muscle function during development. In fact, some be misleading, given the strict definition of the
muscles in the jaw and neck continue to use em- term. Cardiovascular physiologists use concentric
bryonic or perinatal myosin II isoforms into adult- and eccentric in an appropriate way when describ-
hood. Adult skeletal muscles are categorized on ing the orientation of contraction with respect to the
the basis of the myosin II isoform as type I (or ␤), center of the chamber. For example, a normal heart
IIa, IIb, or IIx/d. The catalytic properties of produces a concentric contraction because it con-
myosins are matched to the contractile demands tracts symmetrically around the center of the cham-
of the muscle. Slow-twitch skeletal muscle uses ber. If one wall of the heart hypertrophies and gets
predominately ␤-myosin II, the “cardiac” isoform stronger, the contraction may be eccentric, or “off
with low velocity and high efficiency. Fast-twitch center.” However, exercise physiologists use con-
skeletal muscle, in contrast, uses IIb-myosin II, centric to describe a shortening contraction, with
which has faster velocity but lower efficiency. the term chosen because the ends of the muscle
While each myofiber expresses a single myosin move toward the center. Likewise, eccentric con-
isoform, a muscle can be made up of myofibers ex- tractions are used synonymously with lengthening
pressing different myosin II isoforms. contractions, as if the term meant “away from cen-
ter.” While the use of these terms is more common
in the exercise literature, they are more accurately
Muscle contraction can generate force used in describing cardiac physiology. To avoid con-
Activation of actino-myosin ATPase in muscle can be fusion, we use the more descriptive terms: shorten-
considered in terms of molecular interactions, but in ing, isometric, and lengthening contractions.
terms of animal physiology the important factor is In the accompanying feature, we discuss how
how these molecular events translate into changes variation in shortening and force generation
at the whole tissue level. The response of muscle arises at the level of the sarcomeres and cross-
upon activation is described in terms of degree of bridge kinetics (Box 3, Mathematical Underpin-
change in length, the rate of change in length, and nings: Sarcomeric Changes in Force Generation
the amount of force generated during contraction. and Shortening).
In reality, “contraction” is not the best choice
of a term to describe an activated muscle because
249

Sarcomeric Changes in Force Generation and Shortening
Let’s consider the following scenarios to Muscle contractile elements show a sigmoidal relation-
illustrate how differences in contractile proper- ship between [Ca2⫹] and muscle force.
ties arise. Since we have already learned that sarco-
mere length influences contraction, in the following
1.0
scenarios we will assume an optimal sarcomere length,
with all 600 myosin heads able to interact with the thin
filaments in each sarcomere. The contractile properties
of a muscle cell depend on the number of myosin heads
Relative force
involved in the contraction. Each individual myosin head
generates about 5 pN of force during a cross-bridge cy- 0.5
cle. We might assume then that a thick filament with 600
myosin heads, each producing 5pN of force, would pro-
duce 3000 pN of force. However, when we measure the
force of a single thick filament, we find that it generates
only about 150 pN of force. A single thick filament could
generate 3000 pN of force if every single myosin head 0
8.0 7.0 6.0 5.0 4.0
pulled at the same time. In a cross-bridge cycle, each pCa
myosin head is attached only about 5% of the time (its
duty cycle) and can only generate force during that part
of the cycle when it is attached to the thin filament. That the prefix p, as in pCa or pH, signifies that the
600 × 5% ⫽ 30 myosin heads generating concentration is expressed as the negative logarithm
force at any time (pCa 6 ⫽ 10⫺6 M Ca2⫹, or 1 μM Ca2⫹). This strategy of al-
tering Ca2⫹ levels to regulate force is important in car-
30 × 5 pN ⫽ 150 pN force
diac muscle, but most skeletal muscles release enough
How can a sarcomere generate different amounts of Ca2⫹ during each contraction to induce near-maximal
force? Each activated myosin head generates the same force.
amount of force (⫺5 pN), so it stands to reason that What is the relationship between force and the veloc-
force must be dependent on the number of cross- ity of shortening? Or put another way, why can you lift a
bridges that can form. Many types of muscle cells can feather faster than a brick? About 70 years ago, A. V. Hill
use changes in the magnitude of the Ca2⫹ signal to alter tried to explain how force influences the rate of muscle
the number of cross-bridges. If the SR released few shortening. He determined experimentally how con-
Ca2⫹ ions, few troponin-tropomyosin complexes would traction velocity was affected by force, which he altered
be induced to move, and few cross-bridges would form. by changing the amount of weight a muscle lifted.
2 CO N CEP T C HE C K Excitation and EC Coupling

in Vertebrate Striated Muscle
5. Describe duty cycle and unitary displacement in
relation to nonmuscle and muscle myosin So far, we have discussed the machinery involved in
activity. muscle contraction, but we have not yet discussed
6. How does the organization of the sarcomere how muscle contraction is triggered. Excitation in
influence contractile force? most striated muscles occurs when depolarization
7. Compare the constraints on myosin function in of the sarcolemma induces an increase in cytosolic
vesicle traffic versus the contractile apparatus. [Ca2⫹] to trigger contraction. Beyond that simple
8. Is muscle activity more accurately described as summary, it is difficult to make any generalizations
cellular movement or a change in cell shape? about excitation and EC coupling in striated mus-
What types of cells need to move within the
vertebrate body?
cle. As you will see in the following sections, mus-
cles differ in the cause of depolarization, the
250
1.0 think of the cross-bridge cycle in terms of a single

myosin molecule, we see how it reaches forward and
pulls the thin filament. When you factor into this model
the hundreds of other myosin heads, things get a bit
Relative force
more complicated. Each individual myosin can only bind

the thin filament when it reaches forward looking for a
0.5
binding site on actin. Once it binds, several chemical
steps must occur before the head can generate force in
its power stroke. If shortening is fast, other myosin
heads can pull the thin filament back before the myosin
head has a chance to undergo its power stroke. The slid-
0 ing filament bends myosin into the position that it would
Contraction velocity have assumed had it been given the time to undertake
its power stroke. Although the chemical events in the
power stroke (ADP and Pi release) still happen, the
He developed the following equation relating con- structural changes in the myosin head have already oc-
tractile force (P) to velocity of shortening (V): curred. Consequently, this cross-bridge cycle gener-
ates no force. Put simply, high contraction velocity
b 1Po ⫺ P 2 prevents many cross-bridges from generating force.
V⫽
P⫹c Now consider what happens when a muscle generates
where Po is the maximal isometric tension of the muscle, its maximal force, such as when it lifts the heaviest ob-
b is a velocity constant, and c is a force constant. When ject possible. During a cross-bridge cycle, the tension
you lift the feather (P approaching zero), the numerator is on the muscle prevents the thin filament from moving
at its maximum (b Po), the denominator approaches zero, appreciably and each myosin head in a cross-bridge re-
and velocity is at its maximum. But what is the mechanis- mains in a form that allows it to generate force.
tic basis of this relationship in terms of molecular events These sarcomeric changes in force, length, and con-
in the sarcomere? The same number of cross-bridges tractile velocity have important ramifications for muscle
will be involved whether the situation generates maximal function. As we revisit muscles in later chapters, recall
force or maximal velocity of shortening. how these sarcomeric events contribute to muscle
In 1957, Andrew Huxley explained the force-velocity function.
relationship in terms of cross-bridge kinetics. The dif- References
ference between force generation and shortening lies in q Huxley, A. F. 2000. Cross-bridge action: Present views, prospects,
the structural changes in the myosin head. When we and unknowns. Journal of Biomechanics 33: 1189–1195.
pattern of change in membrane potential over time, depolarization, followed by repolarization and hy-
the propagation of depolarization along the sar- perpolarization. The properties of the action po-
colemma, and the cellular origins of Ca2⫹. Let’s tential, such as rates of depolarization and
consider each of these factors in turn, focusing on repolarization and action potential duration, are
the implications for muscle function and the basis deterimined by the density and activities of vari-
of differences among muscle types and species. ous channels in the sarcolemma.
As with other cell types, depolarization is in-
duced when Na⫹ channels are opened. The inward
Muscles are excited by an action potential rush of Na⫹ causes a rapid reduction in membrane
The action potential is also the signal for contrac- potential. At this point, voltage-sensitive Ca2⫹
tion of most muscle cells. The resting membrane channels open, allowing the influx of Ca2⫹ into the
potential of the sarcolemma is about ⫺70 mV. cell from the extracellular space. After a period,
Upon activation, muscles experience a rapid Na⫹ channels and Ca2⫹ channels begin to close and
251
voltage-sensitive K⫹ channels open, causing the Action potential

cell to repolarize. The density and kinetic proper-
ties of these various ion channels determine the

features of the action potential: the rate of depolar- Contraction
ization, the rate of repolarization, and conse-
Force (N)
quently, the duration of the action potential. Since
the depolarization and repolarization leads to
movement of ions, active transporters are respon-
sible for reestablishing the ion gradients. As in
most cells, the Na⫹/K⫹ ATPase is important in
reestblishing Na⫹ and K⫹ gradients. In muscle,
where the action potential also induces Ca2⫹ move-
ment into the cell, a suite of Ca2⫹ transporters is Time (msec)
also essential. This general pattern of an action po- (a) Skeletal muscle
tential, depolarization, and repolarization is simi-
lar among vertebrate striated muscles. However,
muscles show very important differences in the
Action potential
time course of the change in membrane potential.
Cardiac and skeletal muscles have dramatic Membrane potential (mV)
differences in the shape and duration of the action
potential (Figure 24). Striated muscle cells cannot Contraction
Force (N)
be depolarized again until the repolarization phase
is near complete. This window of insensitivity is
called the effective refractory period because the
muscle cell cannot be induced to contract again by
normal physiological regulators. Skeletal myofibers
depolarize and repolarize very quickly, typically
within about 5% of the time required to complete a
contraction-relaxation cycle. Once a skeletal mus-
Time (msec)
cle membrane repolarizes, a second action poten-
tial can induce another contraction even if the (b) Cardiac muscle
muscle has not yet relaxed from the previous con- Figure 24 Action potentials in striated muscle
traction. Cardiomyocytes also depolarize rapidly The time course of change in action potential and force are
but take much longer to repolarize. The main rea- shown for a skeletal muscle (a) and cardiac muscle (b). While
the contraction profiles are similar, the action potential in
son for this is that the voltage-sensitive Ca2⫹ chan-
cardiac muscle is prolonged. This is attributed to Ca2⫹
nels in cardiac muscle stay open for a much longer channels remaining open.
period. As a result, the duration of the action poten-
tial in cardiomyocytes is approximately half the du-
ration of a contraction cycle. The prolonged with characteristic amplitude, duration, and shape.
effective refractory period of cardiomyocytes is crit- That the different types of cardiomyocytes, as well
ical to the function of the heart. Cardiomyocytes are as their organization into heart muscle, are central
connected into an electrical network that transmits to cardiac function.
an action potential between cells to create a wave The maximal contraction rate of striated mus-
of contraction. The long effective refractory period cle depends upon the rate at which the muscle cell
prevents the action potential from stimulating con- can complete the action potential. Rapidly con-
traction in cardiomyocytes that are in the midst of tracting striated muscles, such as fast-twitch skele-
a contractile cycle. Without the effective refractory tal muscle, complete an action potential within a
period, contraction of individual cardiomyocytes or few milliseconds. This prepares the muscle for an-
regions of cardiomyocytes could occur chaotically, other excitation and contraction soon after. Many
a condition known as arrhythmia. In a typical ver- types of skeletal muscle are distinguished by the
tebrate heart, there are many types of cardiomyo- maximal frequency of contraction, due in large
cytes, each of which undergoes an action potential part to differences in the rate of repolarization.
252
Much of the difference in repolarization rate The action potential of the pacemaker cells in-
can be attributed to the properties of the K⫹ chan- duces an action potential in the myocytes to which
nels. Not surprisingly, K⫹ channels are the targets they are connected through gap junctions. In con-
of hormones and drugs that regulate contraction trast to pacemaker cells, depolarization of non-
rate. Regulatory factors, such as acetylcholine and pacemaker cardiomyocytes is due to the opening
adenosine, act by modulating the properties of K⫹ of voltage-dependent Na⫹ channels, much like the
channels. Each muscle cell type has a characteris- situation seen in other excitable cells. Interest-
tic profile of K⫹ channels that confers different pat- ingly, a normal cardiomyocyte has the ability to
terns of repolarization. As with skeletal muscle, contract spontaneously, much like a pacemaker
many of the hormonal pathways that influence cell. In an intact heart, these cardiomyocytes
cardiac contractility exert their effects via the K⫹ would receive an excitatory signal from a pace-
channels that determine the rate of repolarization, maker before they would experience their own
but the properties of the Ca2⫹ channels also influ- spontaneous contraction. However, if the pace-
ence the rate of repolarization. maker cells become damaged, other cardiomyo-
Depolarization is the first step in vertebrate cytes can become the pacemaker to determine the
striated muscle excitation, but it can be induced in rate of cardiac contraction.
different ways. In the next section, we will distin-
guish two general classes of muscle based on the Neurogenic muscle is excited
trigger for sarcolemmal depolarization. Myogenic by neurotransmitters
muscle cells contract spontaneously, whereas
Most vertebrate skeletal muscles are neurogenic
neurogenic muscle cells are stimulated by the
muscles, and receive signals from a motor neuron.
action of neurons.
The motor neuron axon termini are located in a re-
gion of the sarcolemma called the motor end plate
Myogenic muscle cells spontaneously (Figure 25). The sarcolemma at the motor end
depolarize
The most common examples of myogenic myo- Motor neuron
cytes are from the vertebrate heart. Because the
entire heart contracts without neuronal input, Neuromuscular
junction
each of the myocytes of the heart is considered a
myogenic muscle. In the intact heart, some spe- Myofibers
cialized myocytes depolarize spontaneously. Sarcolemma

These pacemaker cells transmit their electrical
signal throughout the heart and cause other car-
diomyocytes to depolarize and contract.
Pacemaker cells are unusual in that they show
an unstable resting membrane potential. These
cells possess an unusual ion channel, the funny
channel or f-channel, that is permeable to both
Na⫹ and K⫹. When the channel is open, an imbal-
Axon terminal
ance in Na⫹ influx and K⫹ efflux leads to a slow de- of motor neuron
polarization. Once the pacemaker cell membrane
depolarizes to a critical voltage, the threshold volt- Synaptic
age, voltage-sensitive Ca⫹ channels open to initi- vesicle
ate the action potential. Though the f-channels

close during the action potential, hyperpolariza- Motor end
plate of
tion of the pacemaker cells at the end of the action skeletal
potential reactivates the f-channels, causing the muscle cell
cells to slowly depolarize again. Many of the fac-
Figure 25 Twitch muscles Motor neurons innervate
tors that regulate heart rate, such as adenosine, individual myofibers, making contacts at regions on the
acetylcholine, and catecholamines, alter the ki- myofiber called motor end plates. Twitch muscles possess
netic properties of the f-channels. myofibers that are innervated by single motor neurons.
253
plate is rich in receptors for the neurotransmitter described as slow twitch muscle. Mammals do
released by the motor neuron: acetylcholine. Upon have a few true tonic muscles, located around the
stimulation of a motor neuron, acetylcholine is re- eye (extraoccular), in the ear, and in the esophagus.
leased from synaptic vesicles into the neuromuscu-
lar synapse. It crosses the synapse and binds
T-tubules enhance action potential
nicotinic acetylcholine receptors within the sar-
penetration into the myocyte
colemma. These ligand-gated ion channels are Na⫹
channels. If enough nicotinic acetylcholine recep- Many twitch fibers depend on simple action poten-
tors are activated, the depolarization at the motor tial conductance along the sarcolemmal surface.
end plate initiates a wave of depolarization along Myofibers can facilitate action potential conduc-
the sarcolemma: the action potential. The passage tance throughout the muscle with the help of exten-
of the action potential along the sarcolemma in- sive sarcolemmal invaginations called transverse
duces an all-or-none contraction. tubules, or T-tubules (Figure 26). When the sar-
Twitch muscles are neurogenic skeletal mus- colemma depolarizes, the action potential follows
cles that are innervated by one or, occasionally, a the T-tubules into the muscle fiber. The relative
few motor neurons. In these muscles the action importance of the T-tubule system depends upon
potential spreads rapidly along the sarcolemma, the nature of the muscle and the work it performs.
causing a uniform contraction along the length of Many muscles do not need to contract quickly. For
the myofiber. Because of their electrical nature, instance, postural muscles, found in the body
action potentials move rapidly, but in many mus- trunk of vertebrates, remain contracted for long
cles passive conductance from the motor end plate periods without relaxing or fatiguing. However,
is inadequate to ensure that the signal reaches the the T-tubule system is extensive in large or quick-
entire muscle essentially simultaneously. There contracting muscles, such as vertebrate fast-
are two main ways that muscles are able to ensure twitch skeletal muscles. T-tubules also exist in the
the entire sarcolemma is depolarized uniformly in cardiac muscle of mammals and some birds, al-
space and time: through multiple innervations though it is generally less developed than in skele-
(tonic muscle) and through invaginations of the tal muscle of the same species.
sarcolemma (T-tubules).
Ca2⫹ for contraction comes from

Tonic muscles have multiple innervations intracellular or extracellular stores
One way in which the challenge of uniform contrac- The regulation of the Ca2⫹ transient during muscle
tion is met in some neurogeneic muscles is through contraction involves many transporters and cellular
multiple innervations. Vertebrate striated muscles compartments. In fact, many aspects of muscle con-
with multiple innervations are called tonic muscle.
When motor neurons are stimulated, neurotrans-
mitter release occurs at many sites along the tonic
muscle fiber. The fiber is then induced to contract
in response to depolarization at multiple points
along the fiber, reducing the dependency on action
potential conductance. Tonic muscles contract
slowly, but maintain tension for long periods. In
contrast to twitch muscles, tonic muscles are not
Sarcolemma
all-or-none. The level of depolarization of the sar-
T-tubules
colemma depends on the number and frequency of
stimulatory signals from the motor neuron.
Sarcoplasmic
Many researchers studying mammals use the reticulum
term tonic muscle to describe muscles that exhibit Myofibril
a long duration of contraction. For example, hu-
man physiologists refer to the postural muscles of
Figure 26 T-tubules Many types of muscle have
the back as tonic muscle. These muscles have only T-tubules, invaginations of the sarcolemma that penetrate deep
single innervation, and thus are more accurately into the myofiber to speed the spread of the action potential.
254
tractile properties can be traced to

Na+ Ca2
+ +
the way these proteins are made and Ca2
2⫹ NaCaX DHPR
utilized to mediate Ca transients. Δψ +
Ca2 ATPase
Most muscles respond to sarcolem-
+
mal depolarization by opening Ca2
RyR
2⫹ Ca 2+
voltage-dependent Ca channels. ATP ADP + Pi
Sarcolemma
Because of the electrochemical gradi-
ATP
ent for Ca2⫹, these channels open to
allow Ca2⫹ to rush into the cell from SR Ca2
+
SERCA
the extracellular space. There are
ADP + Pi
several types of Ca2⫹ channels in stri-
ated muscle sarcolemma, named for
how long they remain open after ac-
tivation. L-type Ca2⫹ channels are Figure 27 Transporters and channels involved in EC coupling
open for a Long period with Large Ion movements during a contraction cycle are mediated by ion channels and pumps
2⫹
conductance, whereas T-type Ca2⫹ within the sarcolemma and the sarcoplasmic reticulum (SR). Ca channels in the2⫹
sarcolemma (the dihydropyridine receptor or DHPR) and the SR open to allow Ca
channels are open Transiently with
to flow into the cytoplasm. Ca2⫹ pumps in the SR, known as SERCA, as well as the
Tiny conductance. Animals also pos- sarcolemma use the energy of ATP to reverse the Ca2⫹ movements allowed by the
sess N-type Ca2⫹ channels that are channels. The Na⫹/Ca2⫹ exchanger (NaCaX) facilitates the reversible exchange of
⫹ 2⫹
Neither L-type nor T-type. The pre- Na and Ca . The membrane potential (⌬ψ) influences many of these transport
dominant channel in the heart of processes. The image in this figure shows the events in a cardiac muscle cell,
where DHPR and RyR are physically separated.
most animals is the L-type Ca2⫹ chan-
nel, a protein that has been shown to
bind a class of drugs called dihydropyridines. Con- In some situations, Ca2⫹ delivery through
2⫹
sequently, the L-type Ca channels are also known DHPR is sufficient to induce contraction. For ex-
as dihydropyridine receptors (DHPR), to distin- ample, the hearts of most fish are able to deliver
guish them from other types of Ca2⫹ channels. enough Ca2⫹ through the DHPR to initiate con-
Though important, the DHPR is only one of traction. However, in most striated muscles, the
many types of Ca2⫹ transporter in muscle. The sar- Ca2⫹ delivery through DHPR is either too slow or
2⫹ ⫹ 2⫹
colemma possesses Ca ATPases and a Na /Ca too minor to achieve the contraction threshold. As
exchanger (NaCaX). The muscle endoplasmic retic- a result, most striated muscles require more ef-
ulum, known as the sarcoplasmic reticulum, or fective means of delivering more Ca2⫹ at much
2⫹ 2⫹
SR, has its own Ca channel (RyR) and Ca ATPase faster rates.
(SERCA). The location of these Ca2⫹ transporters is
summarized in Figure 27.
The rate of Ca2⫹ movement into the muscle cell
DHPR activation induces Ca2⫹ release
upon depolarization depends upon many factors
from the SR
related to the structure and activity of DHPR. Since Most skeletal muscles, as well as the cardiac mus-
individual channels can respond to different volt- cles of birds and mammals, use the sarcolemmal
ages, the degree of depolarization can influence Ca2⫹ channels to signal the release of even greater
2⫹
the number of Ca channels that open. As with amounts of Ca2⫹ from vast intracellular stores in
other membrane proteins, the number of channels the SR. Cardiac and skeletal muscles accumulate
in the sarcolemma can be changed using path- Ca2⫹ within their SR, ensuring the cell maintains a
ways of endocytosis and exocytosis. When animals low intracellular [Ca2⫹]. In striated muscle, the SR
experience prolonged periods of elevated activity, frequently has enlargements, called terminal cis-
signaling pathways can induce synthesis of more ternae (Figure 28) that increase the capacity for
DHPR. Intracellular signaling pathways can also Ca2⫹ storage and localize it to discrete regions
influence how long each channel remains open. within the muscle cell. Because terminal cisternae
The structure of the DHPR influences electrical ensure rapid Ca2⫹ delivery, they are well developed
properties, such as voltage sensitivity and open in muscles that contract quickly, such as fast-twitch
time, or alter the sensitivity of the channel to reg- skeletal muscle. Muscles are able to accumulate
ulatory proteins and ligands. Ca2⫹ to very high levels within the SR. While some
255
vation. Once DHPR open, extracellular Ca2⫹ enters

the cell. Because DHPR are localized near terminal
cisternae, local [Ca2⫹] can increase in the small
space between the sarcolemma and the terminal
cisternae (Figure 29). The high local [Ca2⫹] triggers
the opening of cardiac muscle RyR, and the SR Ca2⫹
stores are released into the muscle cytoplasm. Re-
searchers can demonstrate Ca2⫹-induced Ca2⫹ re-
lease by manipulating the composition of the
T-tubule Sarcoplasmic Terminal Sarcolemma
reticulum cisternae extracellular fluid. If cardiac muscle is bathed in
(a) Skeletal myofiber Ca2⫹-free media, depolarization and activation of
the DHPR does not induce a contraction.
Skeletal muscle differs from cardiac muscle in
how DHPR activation is coupled to RyR activation
(Figure 30). As with cardiac muscle, sarcolemmal
depolarization opens the DHPR and allows Ca2⫹
into the cell from the extracellular space. However,
in skeletal muscle it is the voltage-dependent
changes in the DHPR structure that trigger the
opening of RyR. These two channels physically in-
T-tubule Sarcoplasmic Terminal Sarcolemma teract with each other to couple sarcolemmal de-
reticulum cisternae
polarization with SR Ca2⫹ release. In this case,
(b) Cardiomyocyte activation of RyR is not influenced by local accu-
Figure 28 Terminal cisternae Many striated mulation of [Ca2⫹]. Upon activation of DHPR, the
muscles possess enlargements of the sarcoplasmic RyR opens even if no Ca2⫹ ions move through the
reticulum (SR) near the region of the T-tubules. In mammals, DHPR. This pattern of EC coupling is called
the terminal cisternae are extensive in fast-twitch skeletal
depolarization-induced Ca2⫹ release.
muscle (a) and less well developed in cardiac muscle (b).
of the Ca2⫹ is free in solution, most is bound to Relaxation follows removal of Ca2⫹
calsequestrin, another member of the large Ca2⫹- from the cytoplasm
binding protein family that includes TnC. To this point, we have discussed the mechanisms
During excitation, the SR releases its Ca2⫹ that lead to depolarization and the subsequent in-
stores through a Ca2⫹ channel, frequently called crease in cytoplasmic [Ca2⫹] that induce contrac-
the ryanodine receptor (or RyR) because it can tion. These ion movements across membranes
bind the drug ryanodine, a plant alkaloid. Once the must be reversed to allow relaxation to occur. As
RyR is activated, free Ca2⫹ escapes the SR and mentioned previously, the duration of the action
flows into the cytoplasm. The loss of free Ca2⫹ fa- potential determines how quickly a muscle can re-
vors the release of Ca2⫹ bound to calsequestrin. lax. Once the membrane repolarizes, the muscle
The general features of this pathway apply can start to reestablish Ca2⫹ gradients. In verte-
equally to the many muscles that rely upon SR brate striated muscle, relaxation requires a suite
Ca2⫹ to trigger contraction. Activation of the sar- of transporters to pump Ca2⫹ out of the cytoplasm,
colemmal DHPR induces Ca2⫹ release through the back across the sarcolemma, or into the SR. Both
RyR. This linkage is enhanced by the physical the sarcolemma and the SR possess active Ca2⫹
arrangement of the different Ca2⫹ channels. ATPases that pump Ca2⫹ out of the cell using the
Within the sarcolemma, DHPRs are clustered in energy of ATP hydrolysis. The sarcolemma also
regions directly adjacent to the terminal cisternae. possesses a transporter that exchanges Na⫹ for
However, what differs between muscle types is the Ca2⫹, called the Na/Ca exchanger or NaCaX. Dur-
way DHPR activation is coupled to RyR activation. ing excitation, this reversible exchanger can allow
Cardiac muscle uses a process called Ca2⫹- extracellular Ca2⫹ to enter the cell in exchange for
induced Ca2⫹ release to link DHPR and RyR acti- intracellular Na⫹. However, it is most important
256
during relaxation, where Ca2⫹ efflux +

Ca2
is coupled to Na⫹ influx. As in other NaCaX
Na⫹-driven transport processes, Δψ
DHPR
⫹ ⫹
Ca-ATPase
muscles ultimately use the Na /K
ATPase to reestablish Na⫹ gradients. RyR
The role of each specific Ca2⫹
Sarcolemma
transporter depends upon the way
2⫹ SR SERCA
Ca is used to induce contraction.
Those muscles that primarily rely on
sarcolemmal Ca2⫹ influx to initiate
contraction, such as hearts of lower
vertebrates, use the sarcolemmal Myofibrils
NaCaX and Ca2⫹ ATPase to pump
Ca2⫹ out of the cell. However, muscles
that elevate cytoplasmic [Ca2⫹] using 1 Depolarization of the
plasma membrane
intracellular stores, such as most (sarcolemma) opens
types of mammalian striated muscle, DHPR, allowing Ca2+
use the sarcoplasmic (endoplasmic) to enter the cell.
2⫹
reticulum Ca ATPase, or SERCA, to
resequester Ca2⫹ in the SR.
In addition to the proteins in-
volved in transporting Ca2⫹ across
membranes, relaxation in many mus-
cles also relies upon a cytosolic Ca2⫹ 2 Elevated [Ca2+]
triggers the opening of
buffer called parvalbumin. By bind- RyR, allowing Ca2+ to
2⫹
ing cytoplasmic Ca , parvalbumin escape the SR. The
elevated cytoplasmic
accelerates muscle relaxation. Not [Ca2+] triggers
surprisingly, parvalbumin is found in actino-myosin ATPase.
muscle types that contract and relax
very quickly. Its role in relaxation has
been elegantly demonstrated using
transgenic mice. One group of mice
was engineered to prevent the ex- 3 After repolarization, ion
pumps begin returning
pression of parvalbumin; the muscles Ca2+ to resting
of these parvalbumin-null mutants locations, outside the
cell and in the SR.
relaxed much more slowly than wild-
type mice. Researchers have also en-
gineered transgenic mice that
express parvalbumin in muscles that
normally lack parvalbumin. These
mice had muscles that relaxed faster
than wild-type mice. Figure 29 Ca2⫹-induced Ca2⫹ release At rest, the high membrane
potential (⌬ψ) keeps closed the cardiac sarcolemmal Ca2⫹ channel (DHPR) and
In the natural world, parvalbu- intracellular Ca2⫹ levels are low. The graphs to the left reflect the patterns of action
min levels differ between muscle potential (purple line) and contraction (blue line), as shown in Figure 24.
types and species. The fastest mus-
cles possess very high levels of parvalbumin to least some parvalbumin in their skeletal muscles,
accommodate the high frequencies of contrac- humans do not appear to express parvalbumin.
tion. The highest levels of parvalbumin are found The genetic reasons for their loss of parvalbumin,
in fish white muscle. Fish use white muscle to and the physiological consequences, are not yet
burst away from danger or to attack prey, strate- known.
gies that require very rapid rates of muscle con- Table 5 summarizes the general features of
traction. Although most vertebrates possess at cardiac and skeletal muscle.
257
11. What arrangement of thick and thin filaments

2 CO NCEP T C HE C K allows each myosin to interact with six actins,
and each actin to interact with three myosins?
9. How does the action potential differ between
cardiac and skeletal muscles? Why is this 12. What factors determine the rate of shortening of
important to the function of the muscle? a muscle? What factors affect the rate of
relaxation?
10. Other than myocytes, what other cell types
contribute to the makeup of a muscle?
NaCaX
Ca2
+
Smooth Muscle
DHPR
Δψ Ca-ATPase Much of the discussion of muscle cell
properties has, to this point, focused
RyR
on striated muscle. Vertebrates, as
Sarcolemma
well as many invertebrates, possess
SR SERCA
another form of muscle: smooth
muscle. Many tissues use layers of
smooth muscle to induce slow regu-
lar contractions, or maintain a de-
gree of contraction for long periods.
Myofibrils For example, smooth muscle lines
the walls of blood vessels, controlling
blood flow by regulating the diame-
1 Excitation. ter of the blood vessels. Smooth mus-
Depolarization of the
plasma membrane cle works in a similar fashion in the
opens DHPR. While respiratory system of terrestrial ver-
Ca2+ enters the cell, it
is the changes in DHPR tebrates to control the diameter of
structure that trigger the airways. Circular and longitudinal
opening of RyR.
layers of smooth muscle in the diges-
tive tract propel food down the gut
and control the length of the gas-
trointestinal tract. Reproductive
2 Calcium release. RyR function also depends on smooth
opening allows Ca2+ to
escape the SR. The muscle to propel gametes or off-
elevated cytoplasmic spring along the reproductive tract.
[Ca2+] triggers
actino-myosin ATPase. Although it shares many features
with striated muscles, such as the
basic interaction between actin and
myosin, it has important differences
that provide the smooth muscle cell
with remarkable flexibility in con-
3 Relaxation. After traction dynamics and distinct path-
repolarization, ion
pumps begin returning ways of regulation of EC coupling.
Ca2+ to resting
locations, outside the
cell and in the SR.
Smooth muscle lacks

organized sarcomeres
Although smooth muscle cells are
composed of the same contractile el-
Figure 30 Depolarization-induced Ca2⫹ release At rest, the high ements as striated muscle, animals
membrane potential (⌬ψ) keeps closed the skeletal sarcolemmal Ca2⫹ channel
can organize and regulate smooth
(DHPR). The graphs to the left reflect the patterns of action potential and contraction,
as shown in Figure 24. Note that the DHPR and RyR interact physically in skeletal muscle in various ways. Striated
muscle, unlike the situation in cardiac muscle, as depicted in Figure 29. muscles arrange their thick and thin
258
Table 5 Comparing vertebrate cardiac and skeletal striated muscles.
Cardiac Skeletal
Cell morphology Single cells (cardiomyocytes) about 10 Multiple cells fused into large myofibers
to 20 µm in diameter and 100 µm in that are 10 to 100 µm in diameter and
length. 1 to 100 mm in length.
Excitation Myogenic and involuntary. Neurogenic and usually voluntary.
Action potential Slow repolarization, with long refractory Fast repolarization, with short
period. refractory period.
EC coupling Ca2⫹-induced Ca2⫹ release. Depolarization-induced Ca2⫹ release.
Sarcoplasmic reticulum Well-developed terminal cisternae in Amount of terminal cisternae depends
birds and mammals. Poorly developed on fiber type.
SR in lower vertebrates.
filaments into sarcomeres, producing their char- Nucleus

acteristic striped appearance. Smooth muscle also
has thin filaments and thick filaments, but they
are not organized into sarcomeres. At the cellular Vascular smooth
muscle cell
level, smooth muscle is a collection of individual
cells that are organized into a functional network.
Gap junctions between smooth muscle cells allow
them to communicate and exert a common re-
sponse to local regulators, creating a functional
group that acts as a unit. This cellular organiza-
tion is reminiscent of the organization of cardiac
muscle. One or more functional groups may be
physically linked together by connective tissue,
but regulated independently within that tissue. In Adhesion plaque Thin Microfilament
filaments Dense body
the circulatory system, for example, a layer of
smooth muscle surrounds the blood vessels. The
smooth muscle cells may be induced to contract in
Plasma Thick filament
unison in one region, while a neighboring region membrane
remains relaxed. Many organs have layers of
smooth muscle arranged in a way that allows con- Figure 31 Smooth muscle thick and thin
traction in different planes. For example, the gas- filaments Smooth muscle cells lack organized
trointestinal tract has an inner layer of circular sarcomeres. Thick and thin filaments are arranged in
complex networks throughout the cell: Thin filaments are
muscle that regulates circumference, and a layer fixed to the plasma membrane by adhesion plaques, while
of longitudinal muscle that regulates length. thick filaments overlap separate thin filaments. The thin
The main difference between smooth and stri- filaments are integrated into the cytoskeletal network via
ated muscle is in the organization of the thick and dense bodies, which are points of attachment with
microfilaments.
thin filaments. Instead of parallel arrays of sar-
comeres, smooth muscle scatters clusters of thick
and thin filaments throughout the cytoplasm (Fig- twice as many thin filaments as thick filaments,
ure 31). The aggregated filaments interconnect smooth muscle has about 15 thin filaments for
with each other to form a network within the cyto- each thick filament.
plasm, and attach to the plasma membrane at spe- Smooth muscle also differs in structure from
cific regions called adhesion plaques. This striated muscle in membrane organization. It lacks
three-dimensional arrangement of thick and thin the elaborate sarcolemmal invaginations called
filaments allows smooth muscle cells to contract in T-tubules, and does not have an extensive sar-
all dimensions. In contrast to striated muscle, with coplasmic reticulum. Since these structures aid in
259
excitation and Ca2⫹ delivery, it should not be sur- myosin heavy chains with four myosin light
prising that smooth muscle also differs from stri- chains. In smooth muscle, the myosin light chains
ated muscle in EC coupling. regulate the ability of the myosin heavy chain
heads to form a cross-bridge. Many agents that al-
ter smooth muscle contractility act by changing
Smooth muscle contraction is regulated by the phosphorylation state of myosin light chain.
both thick and thin filament proteins When phosphorylated by myosin light chain ki-
Regulation of contraction is much more complex nase (MLCK), the myosin light chain enhances the
in smooth muscle than in striated muscle. Smooth ability of myosin to bind to actin. When dephos-
muscle contractility is regulated by nerves, hor- phorylated by myosin light chain phosphatase
mones, and physical conditions, such as stretch. (MLCP), myosin light chain prevents the myosin
As in striated muscle activation, many regulators heavy chain from forming the cross-bridge,
of smooth muscle contractility exert their effects thereby allowing the smooth muscle to relax.
by changing [Ca2⫹]. In smooth muscle, however, Many of the effectors that regulate smooth
[Ca2⫹] exerts its effect on both thick filaments and muscle contractility induce their effects via regula-
thin filaments. Furthermore, many types of tion of the activity of MLCK or MLCP. For example,
smooth muscle alter contractility by changing the Ca2⫹ can stimulate MLCK and thereby favor con-
sensitivity to Ca2⫹, rather than [Ca2⫹]. In many of traction. The effects of Ca2⫹ on MLCK are medi-
the subsequent chapters, we consider the specific ated indirectly by calmodulin. Thus, Ca2⫹ exerts
mechanisms by which regulators influence effects on both the thin filament (Ca2⫹-calmodulin-
smooth muscle contractility. In the next section, caldesmon) and the thick filament (MLCK-myosin
we consider in general terms some of the more light chain). The two main pathways of Ca2⫹-
common regulatory cascades that affect smooth dependent regulation of smooth muscle are sum-
muscle contraction through Ca2⫹-dependent and marized in Figure 32. Many of these factors alter
Ca2⫹-independent mechanisms. Ca2⫹ levels in a very complex manner. One hor-
In contrast to striated muscle, smooth muscle mone may cause a small but rapid increase in
lacks troponin; the effects of Ca2⫹ are mediated via Ca2⫹ throughout the cell, whereas another hor-
other regulatory proteins. Caldesmon is an actin- mone might cause a greater Ca2⫹ increase that is
binding protein that binds to the thin filament and localized near the plasma membrane. These com-
prevents myosin from binding to actin. In this sense, plex spatial and temporal patterns of Ca2⫹, known
caldesmon in smooth muscle functionally replaces as Ca2⫹ signatures, affect different signaling cas-
TnC. Caldesmon moves out of this inhibitory posi- cades. Once a hormone binds to its receptor on the
tion in response to Ca2⫹, but it does not directly bind smooth muscle membrane, it may exert effects di-
Ca2⫹. When the [Ca2⫹] increases, the soluble protein rectly on one or more components of the smooth
calmodulin binds to Ca2⫹, then binds to caldesmon. muscle signaling pathway.
The calmodulin-caldesmon complex dissociates Many of the hormones act in ways that do not
from actin and allows the formation of a cross- cause changes in [Ca2⫹] by activating or inhibiting
bridge between myosin and actin. When Ca2⫹ levels MLCK and MLCP. For example, nitric oxide stimu-
fall, the Ca2⫹-calmodulin-caldesmon complex disso- lates smooth muscle relaxation by stimulating
ciates and caldesmon returns to its inhibitory site on guanylate cyclase. The increase in cGMP levels ac-
actin. Many hormones that act on smooth mus- tivates cGMP-dependent protein kinase (PKG),
cle mediate their effects by regulating the Ca2⫹- which phosphorylates and activates MLCP.
dependent effects of caldesmon. These hormones
alter signaling cascades that stimulate protein ki-
nases and protein phosphatases. For instance, when
caldesmon is phosphorylated by a MAP kinase, it is Latch cross-bridges maintain smooth
unable to bind to actin, even though Ca2⫹ levels may muscle contraction for long periods
fall. Thus, caldesmon phosphorylation sustains con- The contractile properties of smooth muscle differ
tractions in a manner that is independent of Ca2⫹. widely in terms of force generation, as well as con-
Much of the regulation of vertebrate smooth
muscle is mediated via the thick filament proteins.
Recall that muscle myosin is a hexamer of two
260
Hormones Hormones Many smooth muscles can exhibit both tonic

and phasic behavior, depending on the regulatory
conditions. However, some smooth muscles have
Sarcolemmal Sarcolemmal cellular specializations that favor one type of con-
Ca2+ channel receptor
traction. Tonic muscles are able to maintain con-
traction for long periods by forming a different type
of cross-bridge. These latch cross-bridges alter the
SR Ca2+ channel
maximal velocity of shortening and expend less en-
ergy during isometric contraction. However, the
Increased [Ca2+]
mechanism for this difference in the latch state is
not yet clear. As previously discussed, most smooth
Free muscle contracts in response to myosin light chain
calmodulin
phosphorylation. MLCK activates myosin light
chain, triggering an increase in actino-myosin
Ca2+-calmodulin Hormones
ATPase and force. However, in the latch state, force
is maintained although myosin light chains are de-
phosphorylated and actino-myosin ATPase activity
Caldesmon-actin MLCK is low. This suggests that tonic muscles in the latch
state are using the existing contractile machinery in
a different way. At this point, we do not know for
Ca2+-calmodulin- Ca2+-calmodulin- certain what factors are responsible for this differ-
caldesmon MLCK
ent type of cross-bridge activity. Some researchers
believe that the entire process of cross-bridge cy-
cling slows. Others believe that the cytoskeleton it-
Actin Myosin light chain
self interacts with actin and myosin to strengthen
the physical interactions in this tonic state.
Phospho-myosin
Hormones MLCP
light chain
Smooth muscle 13. Does smooth muscle have actin and myosin?
contraction Does it have thick and thin filaments? Does it
have sarcomeres?
Figure 32 Control of smooth muscle 14. Discuss the regulation of smooth muscle
contraction Smooth muscle contraction is regulated by contractile properties through Ca2⫹ and Ca2⫹-
pathways that target both thick and thin filament proteins.
independent mechanisms.
traction and relaxation rates. Smooth muscles are

often broadly divided into tonic and phasic smooth Muscle Diversity in
muscles. Tonic muscles are those that remain con- Vertebrates and Invertebrates
tracted for a long period, whereas phasic muscles
contract and relax frequently. Within the digestive In this section, we discuss the origins of variation in
system, for example, phasic muscles contract muscle design. First, we will consider how individ-
rhythmically to push the bolus of food down the uals orchestrate changes in striated muscle fiber by
gut, whereas tonic muscles in sphincters are usu- changing the elements of contraction and EC cou-
ally contracted to prevent movement between pling. Next, we will survey some of the diverse types
compartments. Since these same terms are often of muscle seen in animals. Together, these sections
used to distinguish types of skeletal muscle, it is address how animals achieve diversity in muscle
important to keep in mind that these are simply structure and function within a single muscle over
descriptive terms. Tonic skeletal muscle has very time (through remodeling), within an individual
different properties from tonic smooth muscle, al- (through development), and between homologous
though both exhibit long-term contraction. muscles of different species (through evolution).
261
Physiological and Developmental very high levels of myoglobin and mitochondrial

Diversity in Vertebrate Striated enzymes to ensure that the ATP demands can be
Muscle met by oxidative phosphorylation. In addition, the
slow muscle cell must be integrated into a com-
Muscle performs many different functions in ani- plex, multicellular muscle. The appropriate motor
mals. This flexibility arises from the ability to neurons make connections with the motor end
make distinct muscle types, as well as the capacity plates. The blood vessels grow throughout the tis-
to remodel muscle properties as required. Much of sue to ensure an adequate blood supply. Finally,
the diversity in muscle structure and contractile the slow muscle must also be connected into the
properties begins in embryogenesis. As we know necessary biomechanical framework of the skele-
from examining the regulation of contraction, the ton. The contractile machinery is an important
individual elements of EC coupling exist in many component of the muscle phenotype, but as you
isoforms, including ion channels, pumps, Ca2⫹- can see, many other cellular processes, both in the
binding proteins, and contractile machinery. In muscle cell itself and in surrounding cells, are nec-
principle, these genes could be expressed in essary to construct a functional muscle.
countless combinations resulting in muscles with
a myriad of contractile phenotypes. In actuality,
most animals make only a few different types of Individuals alter fiber type in response
muscle. Diversity in muscle types requires both ge- to changing conditions
netic variation and an ability to express individual The contractile properties of muscle can be altered
genes in specific combinations. in response to changing physiological conditions.
The first remodeling process occurs during early
development, as embryonic skeletal muscles pos-
Animals make muscles of different fiber sess slow muscle isoforms of many proteins. As
types the fetus develops, fast muscle proteins gradually
The genetic controls that determine isoform ex- replace slow muscle isoforms in some muscles.
pression are used to produce muscles with distinct Adult muscles can also be remodeled in response
contractile properties, known as muscle fiber to changes in activity levels and environmental
types. Some vertebrate skeletal muscles are spe- temperature. For example, exercise training can
cialized for burst activity (short duration and high cause profound changes in both cardiac and skele-
intensity), whereas others are suited to endurance tal muscle.
activity (long duration, low intensity). Various de- Both hormonal and nonhormonal mecha-
scriptive terms are used to distinguish between nisms control muscle remodeling. Thyroid hor-
these fiber types. They may be called white and mones have long been known to influence the
red muscle (based upon myoglobin content), fast pattern of myosin isoform expression. Thyroid
twitch and slow twitch (based on the speed of con- hormone exerts its effects on gene expression us-
traction), glycolytic and oxidative (based on meta- ing a specific nuclear receptor protein. The thy-
bolic specialization), or type II and type I (based on roid hormone receptor binds to the promoter
myosin heavy chain isoforms). regions that possess a thyroid hormone respon-
Consider what is necessary to produce a spe- sive element, or TRE. Once it binds to a hormone,
cialized muscle that is used for low-frequency con- the activated receptor recruits other proteins to
tractions. It contracts slowly, but it can continue form a multiprotein complex that can increase or
contraction-relaxation cycles for long periods. decrease the rate of transcription. Thyroid hor-
Slow muscle cells express specific types of pro- mone treatment has reciprocal effects on myosin
teins: “slow” isoforms of thick filament proteins gene expression in cardiac myocytes; it represses
(myosin, myosin light chains), thin filaments (tro- the expression of the ␤-myosin II gene, while in-
ponin, tropomyosin), and ion transport machinery. ducing the ␣-myosin II gene. If the average levels
Slow muscle cells must also regulate the amounts of thyroid hormones remain high over a few
of proteins involved in EC coupling, such as parval- weeks, the contractile machinery is gradually re-
bumin, ion channels, and ion pumps. Fiber-type modeled with ␣-myosin II replacing ␤-myosin II.
specialization also demands the appropriate levels As mentioned previously, ␣␣-myosin dimers ex-
of metabolic proteins. Slow muscle fibers produce hibit the fastest actino-myosin ATPase rates. Thy-
262
roid hormones regulate many of the genes in- Sonic muscles produce rapid contractions
volved in muscle synthesis, as well as many other but generate less force
genes in other tissues. By using a circulating en-
Many animals use sound-producing organs in
docrine hormone like thyroid hormone to respond
combination with muscles that are more special-
to physiological challenges, animals are able to co-
ized for high-frequency contraction. The muscles
ordinate the remodeling of many tissues and phys-
of the shaker organ in a rattlesnake tail contract
iological functions.
100 times per second (100 Hz). The cicada is an
In contrast to endocrine control, many aspects
insect that buzzes by bending a region of its exo-
of muscle remodeling occur in response to local
skeleton, called a tymbal, about 200 times a sec-
signals induced by the muscle itself (Figure 33).
ond. The toadfish produces a shrill, whistlelike
Mechanoreceptors in muscle cells can detect phys-
sound using a sonic muscle that vibrates its swim
ical changes in muscle shape and trigger changes
bladder at more than 200 Hz. What is striking
in signaling pathways. When a muscle cell is
about each of these muscles is the way in which
stretched, it synthesizes regulatory proteins that
the animal modifies the muscle machinery to op-
influence muscle remodeling. One such protein is
erate at such frequencies, often 10 times faster
the protein insulin-like growth factor II, which is
than the fastest locomotive muscles in the same
synthesized then secreted into the extracellular
animal. Surprisingly, the contractile machinery of
space. The IGF II binds to receptors on muscle
sonic muscles is not very different from that of lo-
plasma membranes to trigger signaling pathways
comotive muscle. Typically, sonic muscles are built
that alter the expression of genes encoding muscle
using fast skeletal isoforms of thick and thin fila-
proteins. This type of autocrine stimulation, in
ment proteins, resulting in cross-bridge cycling
combination with endocrine pathways, allows
rates and ATPase rates that are similar to fast-
muscle to be remodeled in response to physiolog-
twitch fibers. So what makes a sonic muscle able
ical challenges.
to contract and relax so quickly?
1 Stretching a cell changes the shape of

IGF-II Growth the cytoskeleton, stimulating a
5 factor membrane-bound mechanoreceptor,
receptor which activates a protein kinase.
Mechanoreceptor
2 Cytoplasmic target proteins, including
transcription factors, are
Cytoskeleton phosphorylated. This enhances the rate
1 of expression of genes encoding
4 regulatory proteins, such as IGF-II.
Kinase Kinase
Vesicle
3 After export from the nucleus, the
mRNA for the protein is translated in the
Golgi
rough ER, and packaged into transport
vesicles.
2
Rough ER
4 Vesicles fuse to the plasma membrane,
6 causing exocytosis of IGF-II.
3
5 Once IGF-II binds its receptor, it

activates another protein kinase.
Regulatory protein
Transcription
factor
Nucleus 6 Phosphorylation of other transcription
Muscle protein
factors leads to a change in expression
Genes of genes for muscle-specific proteins.
Figure 33 Control of gene expression by stretch receptors Some muscle cells

sense the degree of stretch and respond by a cascade initiated by stretch receptors and
culminating in changes in muscle gene expression.
263
First, the muscles have a very fast Ca2⫹ tran- seen in toadfish, rattlesnakes, and cicadas were
sient. Sonic muscles have very abundant SR. Upon made possible because they evolved in combina-
excitation, the flood of Ca2⫹ from the SR rapidly tion with dedicated sound-producing organs.
saturates the regulatory sites of TnC to activate
contraction. Flooding the cytoplasm with Ca2⫹ is a
great way to speed contraction, but it presents a
Heater organs and electric organs are
bit of a problem for relaxation. Sonic muscles
modified muscles
speed relaxation by removing Ca2⫹ from the myo- Genetic diversity in contractile proteins affords an-
fibril and the sarcoplasm very quickly. Though the imals the opportunity to produce muscles with
structural basis remains unclear, sonic muscle tro- unique contractile properties. These capacities
ponin releases Ca2⫹ faster than skeletal muscle arise through relatively modest changes in the pro-
troponin. The SR has very active Ca2⫹ uptake ma- file or arrangement of muscle proteins. Although
chinery. These muscles also have very high levels the diverse muscle fiber types may have differences
of the Ca2⫹ buffer parvalbumin. Collectively, these in contractile properties, each muscle remains rec-
processes allow for a very fast Ca2⫹ transient. ognizable as a muscle. In some cases, a muscle may
The second property necessary for rapid con- undergo trans-differentiation, in which it is di-
traction rates is fast cross-bridge cycling. The verted from a typical developmental program to
myosin head must form a cross-bridge, undergo create a tissue endowed with novel properties. Let’s
the power stroke, then detach. The slowest step in examine two situations that occur in fish, where
this cycle is the detachment of myosin from actin. embryonic muscle undergoes trans-differentiation
Sonic muscle myosin detachment rates are about to create a tissue with a non-contractile function.
six times faster than toadfish fast-twitch fibers. This first example of a trans-differentiated
The molecular basis of this difference in cross- muscle is found in billfish, a group that includes
bridge kinetics is not yet established. marlin and swordfish. These fish possess a trans-
Third, some muscles are able to shorten sar- differentiated eye muscle that functions as a heater
comeres beyond the limit seen in most muscles. As organ. By warming the optical sensory system, bill-
shown in Figure 19, the minimum sarcomere fish are thought to maintain visual function even
length for most muscles is achieved when the ends when pursuing prey into the deep, cold waters. We
of the thick filament butt up against the Z-disk. In can gain some insight into the mechanism of heat
some sonic muscles, the Z-disk has perforations generation by examining how the cellular structure
that allow the thick filaments to penetrate into the of this heater organ differs from that of a conven-
adjacent sarcomeres. It is thought that this ability tional muscle. Heater organs have few myofibrils,
to change length to such a dramatic degree is im- but abundant SR and mitochondria. To understand
portant in achieving the high frequency–low force how heater organs function, let’s consider how
contraction in sonic muscles. normal muscles produce heat. All muscles produce
We know that the mechanical properties of the some heat as a by-product of muscle metabolism,
sound-producing structures also impinge on the and all tissues produce heat in the reactions that
muscle contractile performance. The muscle de- lead to ATP production, as well as the reactions
signs that enable these high-frequency contrac- that lead to ATP hydrolysis. As in most tissues,
tions also limit their ability to generate force. considerable heat is produced by mitochondria
Sound-producing organs use elements that are during oxidative phosphorylation. In muscles,
made in such a way that they can be vibrated or ATP is hydrolyzed by the ATPase reactions at the
bent with relatively little force. They are dedicated myofibrils during cross-bridge cycling, and at the
structures that can change radically without af- ion-pumping ATPases required in EC coupling.
fecting other physiological systems. In contrast, Heater organs are thought to generate heat by cy-
animals that use the respiratory system for vocal- cling Ca2⫹ in and out of the SR (Figure 34). Activa-
ization face constraints on just how radically the tion allows Ca2⫹ to escape the SR through RyR into
sound-producing machinery can be modified in the cytoplasm. Ca2⫹ is then pumped back into the
evolution. Any adaptations in these animals must SR using the Ca2⫹ ATPase, fueled by mitochondrial
adequately serve the dual purposes of the struc- ATP. The entire process of Ca2⫹ cycling and mito-
tures, namely respiration and sound production. It chondria energy metabolism generates enough
is possible that the specialized muscle properties heat to warm the eye and optical nerves.
264
distant groups of fish. Researchers have been able

to follow the developmental processes that led to
the production of electric organs. Muscle precur-
sor cells called myoblasts cluster together to form
a blastema. This ball of cells then begins to differ-
entiate into muscle, expressing muscle-specific
proteins and organizing sarcomeres. While the
(a) Marlin cells at the periphery of the blastema continue to
differentiate into mature muscle, the central cells
grow in size and then lose their sarcomeres. This
Heater
tissue
Superior transition probably occurs when the muscle be-
rectus comes innervated by specialized electromotor
muscle
neurons. These cells eventually become the elec-
trocytes.
Invertebrate Muscles
Eye
All muscles share the features of myosin-based
thick filaments and actin-based thin filaments, but
the variation in the arrangement of filaments and
(b) Heater organ
regulation of contraction is much more pro-
nounced in the invertebrates than the vertebrates.
Researchers have studied the structural diversity
in muscle of invertebrates for many years, identi-
Ca2+
Heater tissue fying many variations in myofibrillar organization
RyR muscle cell and muscle design. More recently, studies of com-
mon invertebrate model species (Drosophila, C.
SR ATP
elegans) have furthered the understanding of the
molecular basis of muscle development and regu-
lation through functional genomics.
ADP + Pi Invertebrates possess smooth, cross-

striated, or obliquely striate muscle
(c) Ca2+ cycling As in vertebrates, some invertebrate muscles are
Figure 34 Billfish heater organ Billfish, such as smooth (lacking sarcomeres) or striated, with nu-
marlin and the swordfish (a), possess heater organs. They merous sarcomeres attached end-to-end to form
are modified muscles found near the eye (b), where they are long myofibrils. Unlike vertebrates, invertebrates
thought to warm the optical system to maintain optical show many muscle forms that are intermediate
function in cold water. (c) Heat is generated by futile cycling
of Ca2⫹ in and out of the SR, fueled by mitochondrial oxidative
between smooth and striated. There is also a great
phosphorylation. deal of variation in the arrangement of thick and
thin filaments, with ratios ranging from 1:3 to
A second type of trans-differentiated muscle is 1:10 in different muscles and species.
the electric organ, a tissue with modified muscle Recall that cross-striated muscle is composed
cells called electrocytes. These cells produce an of sarcomeres attached end to end to form a myo-
electrical discharge in response to neuronal stim- fibril that is attached to the sarcolemma at each
ulation. Large fish like the electric eel can produce end. The cross-striated pattern arises because the
enough electricity to shock a predator or stun its sarcomeres are attached side by side, perpendicu-
prey. Smaller species that live in dark, murky wa- lar to the sarcolemma. Obliquely striated mus-
ters may use weak electrical signals to communi- cle, found in many invertebrates, differs from
cate. Electric organs have a polyphyletic origin,
meaning they have arisen independently in many
265
cross-striated muscle in two respects. First, the achieve a graded contraction because EPSPs can
sarcomeres are not connected side by side, dis- summate. When the nerve sends two rapid im-
rupting the pattern of cross striation. Second, in- pulses, the neurotransmitters affect a broader area
stead of long myofibrils of sarcomeres, each
individual sarcomere is attached to a pinnacle ex-
tending from the sarcolemma perpendicularly
through the thin muscle cell. The protrusions are

called dense bodies, and are similar in many re-
spects to the dense bodies of smooth muscle. The
Force (N)
dense bodies are attached to the inside of the sar- Small Weak
colemma, which is in turn connected via extracel- EPSP contraction
lular matrix proteins to the basal lamina, which in
turn is connected to the cuticle. When obliquely
striated muscle contracts, it pulls on the dense
bodies, causing a local shortening of the body. In
the case of C. elegans, the obliquely striated mus-
cle runs under the cuticle, such that contraction Stimulus
causes the body to bend at that point.
Invertebrate muscles contract in response

to graded excitatory postsynaptic potentials Intermediate

EPSP Intermediate
The vertebrate striated muscles we have discussed
Force (N)
contraction
to this point all contract when the sarcolemmal
membrane potential briefly depolarizes. In the
case of a neurogenic skeletal muscle, activation of
the motor neurons controlling that myofiber in-
duces depolarization of that cell and a subsequent
contraction. Contraction of each fiber is “all-or-
none” in response to the neuronal signal; a
Stimulus
suprathreshold stimulus triggers massive depolar-
ization and contraction. Vertebrate twitch mus-
cles, which are composed of multiple myofibers, Summed Strong
EPSP contraction
can produce graded contractions by recruiting dif-
ferent numbers of motor units. Strong contractions

result when many motor neurons are stimulated to Force (N)
activate many myofibers within the muscle.
Some invertebrate muscles have a different
way of translating excitatory information from the
nervous system into a graded muscle contraction.
Unlike vertebrate twitch muscle, these invertebrate
myofibers do not contract in an all-or-none manner.
In the simplest system, a single muscle fiber is in-
nervated by a single motor neuron that controls the Stimulus
myofiber at multiple motor end plates, much like a Time
vertebrate tonic muscle. When the neuron fires a
Figure 35 Graded excitatory postsynaptic
single impulse, the muscle experiences a minor de- potentials in invertebrate muscles Invertebrate
polarization. The muscle responds with a small el- muscles receive impulses from motor neurons. The degree
evation of Ca2⫹ and a weak contraction. Because of depolarization depends on the number of stimuli from the
neurons. A single stimulus causes a small depolarization,
this depolarization induces an excitation of the
or excitatory postsynaptic potential (EPSP), which is capable
muscle, it is called an excitatory postsynaptic po- of triggering a small contraction. Multiple stimuli trigger a
tential, or EPSP (Figure 35). This system is able to greater depolarization and stronger contraction.
266
of the sarcolemma and induce a greater depolariza-

tion, which in turn causes a greater release of Ca2⫹.
Membrane potential (mV))

The strongest contractions result when multiple
impulses trigger a very large depolarization and
maximal Ca2⫹ release.
In many cases, these muscles are innervated
by multiple neurons, each with a different effect on
the muscle membrane potential. One excitatory
neuron may induce a strong depolarization with a
single impulse, acting in many ways like a motor
neuron in a twitch fiber. Other excitatory neurons
may innervate the same muscle cell but exert
smaller effects on membrane potential, acting pri-
marily through the summation of EPSPs. The mus-
cle may also be innervated by inhibitory neurons.
When these neurons fire, they hyperpolarize the
[Ca2+]
membrane to make it more difficult to induce a
contraction. In general, the invertebrates use com-
plex innervation to control simple muscles,
whereas vertebrates use a multiplicity of fibers
with more straightforward innervation.
Asynchronous insect flight muscles do not

use Ca2⫹ transients
As we have seen, many muscles rely on the Ca2⫹
transient to trigger cycles of contraction and relax-
Force (N)
ation. In the fastest of vertebrate skeletal muscles,

the toadfish sonic muscle, Ca2⫹ transients occur as
fast as one hundred times a second (100 Hz). How-
ever, vertebrate muscles cannot be induced to con-
tract faster than this due to the limits of the
vertebrate EC coupling machinery. The sonic mus-
cles of the cicada are unusual in that their mode of
EC coupling is fundamentally similar to that of ver- Time
tebrate skeletal muscles, yet they are able to con- Figure 36 Stretch-activated asynchronous
tract and relax much faster. The flight muscles of muscles Asynchronous muscles generate multiple cycles
many insects are even faster. The high-frequency of contraction and relaxation in response to a single neuronal
stimulation. During the period following excitation, Ca2⫹
buzz of flying insects arises when the wings beat levels likely remain high. Relaxation occurs in response to
in the range of 250 to 1000 Hz. They are able to contraction-induced inaction. Contraction is in response to
contract at these remarkable frequencies by using stretch activation.
a different mode of EC coupling.
Recall that vertebrate muscles contract in re- tential is followed by a long series of contraction
sponse to a single spike of Ca2⫹ arising from a sin- and relaxation cycles. During flight, multiple action
gle action potential. To relax, these muscles must potentials occur but the frequency is much lower
reduce Ca2⫹ to low levels to inactivate the actino- than the wing beat frequency. This type of muscle
myosin ATPase. Insect flight muscles differ from is called asynchronous flight muscle because
this model in the linkage between neuronal stimu- nervous stimulation is not synchronized with con-
lation and contraction (Figure 36). As with other traction. Most flying insects use asynchronous
neurogenic muscles, the insect first activates the flight muscle to fly, although many also incorporate
flight muscle by a single neuronal stimulation. synchronous flight muscles, particularly to control
However, unlike other muscles, a single action po- the fine movements required for navigation.
267
The asynchronous flight muscle is able to con- the thick filament, around which a monolayer of
tract and relax at high frequency because the tran- myosin molecules is attached. Myosin itself is dis-
sition between contraction and relaxation does not tinct from vertebrate myosins, and can be regu-
require a Ca2⫹ transient. Although it has not been lated directly by Ca2⫹. (Recall that the thick
measured, it is likely that the Ca2⫹ levels probably filament of vertebrate smooth muscle is also regu-
remain high in asynchronous muscles for the entire lated by Ca2⫹, though indirectly.)
contraction-relaxation cycle and for the duration of When the catch muscle is stimulated by cholin-
flight. Once the muscle contracts, it becomes insen- ergic nerves, the acetylcholine triggers an increase
sitive to Ca2⫹, which is then released from TnC, al- in sarcoplasmic [Ca2⫹] (Figure 37). When Ca2⫹ binds
lowing the muscle to relax. Once relaxed, the myosin, cross-bridge cycling occurs and the muscle
muscle is stretched by elastic elements in the flight contracts. Sustained cholinergic activity for a time
apparatus. Once stretched, the myofibril regains its ensures that [Ca2⫹] remains elevated and force is
affinity for Ca2⫹. Although the phenomenon of generated. However, after a time, Ca2⫹ levels de-
stretch activation–contraction inactivation has cline, yet the catch muscle remains contracted. It is
been recognized for decades, the molecular basis not until serotonergic nerves release serotonin that
remains a bit obscure. Recent studies suggest that the muscle relaxes, without changes in [Ca2⫹]. Re-
stretch activation is linked to peculiar structural markably, during this period of sustained contrac-
variations in thin filament regulatory proteins. In- tion, the muscle consumes very little energy,
sects with asynchronous flight muscle express a suggesting that cross-bridge cycling has ceased.
type of TnC with only a single Ca2⫹ binding site. The The mechanisms by which the catch muscle
flight muscles in these insects possess myofibrils sustains contraction remain unclear, but it is
with combinations of both the normal two-site TnC thought that the changes are related to phosphory-
and the unusual one-site TnC. The two-site TnC lation of another unusual protein, twitchin. This
may be responsible for initiating contraction in re- protein is related to titin, the enormous protein that
sponse to the Ca2⫹ trigger induced by the action po- controls the length of a sarcomere. When twitchin
tential. The second form of TnC
may be responsible for the pat-
Relaxed Active Catch Relaxed
tern of stretch activation.
Mollusc catch muscles

maintain contraction for
long periods Serotonin
Bivalve molluscs (clams, oysters,

Contraction
Contraction
and mussels) possess a most re-

markable muscle that is capable [Ca2+]
of generating long duration con-
tractions while expending re-
markably little energy. The [Ca2+]
ACh
muscles, often adductor muscles,
are responsible for rapidly closing
the shells and maintaining this
state for very long periods, pro- Twitchin Phosphorylated Dephosphorylated Phosphorylated
tecting the animal from predators
or harsh external conditions. Phosphorylation
These muscles possess a of twitchin
thick and thin filament structure Figure 37 Molluscan catch muscle contraction and relaxation
similar in many respects to that Upon stimulation by cholinergic nerves, the increase in acetylcholine induces
of vertebrate smooth muscle, contraction of the mollusk adductor muscle. Even though Ca2⫹ levels decline, the
muscle remains contracted in the catch state, where little energy is consumed.
but with important differences. Relaxation ensues after serotonergic nerves fire. The changes in catch state coincide
A large dimeric protein, with changes in phosphorylation of the protein twitchin.
paramyosin, forms the core of (Adapted from Funabara et al., 2005)
268
is phsophorylated, the muscle is capable of twitch or alternately creates other types of interactions be-
activity: contracting and relaxing. However, when tween thick and thin filaments.
the catch muscle is engaged, twitchin becomes pro-
gressively dephosphorylated, likely via the action of
a calmodulin-sensitive protein phosphatase cal- 2 C O NC E P T C H E CK
cineurin. The dephosphorylation of twitchin coin-
cides with the entry into the catch state. Upon exit 15. What are muscle fiber types and how are they
produced?
from the catch state, serotonin activates protein ki-
nase A (PKA), which phosphorylates twitchin. It re- 16. Why are heater organs and electric organs
considered modified muscles?
mains unclear how dephosphorylated twitchin
17. Compare and contrast EC coupling in synchronous
works to attain the catch state. It is possible that the
and asynchronous insect flight muscles.
protein strengthens the actin-myosin cross-bridges
Summary
Cytoskeleton and Motor Proteins Muscle Structure and Regulation
k The cytoskeleton (microtubules, microfila- of Contraction
ments) in combination with motor proteins k Myocytes are contractile cells unique to animals
(dynein, kinesin, myosin) conducts many types that generate force in muscles, which have vital
of intracellular and cellular movement. Suites of roles in many physiological systems.
accessory proteins control cytoskeletal assem-
k Myocytes have thick filaments, mostly myosin,
bly and disassembly.
and thin filaments, mostly actin. Striated mus-
k Motor proteins, enzymes that use the energy of cle filaments are arranged into sarcomeres.
ATP to move in specific directions along cyto- The sarcomere length reflects the degree of
skeletal tracks, are encoded by large gene fami- overlap, and consequently the ability to form
lies, providing the cell with functional flexibility. cross-bridges.
k Microtubules, polymers of tubulin, assemble k Sarcomeres can be arranged in series or in par-

and disassemble spontaneously, subject to allel to achieve a favorable balance between the
tubulin concentration, temperature, and micro- degree of shortening and force generation.
tubule-associated proteins or MAPs.
k Contraction in striated muscle occurs in re-
k Two types of motor proteins use microtubules. sponse to Ca2⫹-dependent activation of thin fil-
Kinesin moves along microtubules in the posi- ament regulatory proteins. At rest, the
tive direction, whereas dynein moves in the troponin-tropomyosin complex is located on the
negative direction. Cilia and flagella are com- actin filament in a position that prevents myosin
posed of microtubules and dynein. from binding. The increase in [Ca2⫹] upon exci-
tation causes a structural change in TnC that
k Microfilaments are polymers of actin that work
initiates a chain reaction of structural changes
with myosin as a motor protein. Each myosin
in other troponin subunits and tropomyosin.
shares a general structure of a head, a neck,
and a tail. k These thin filament regulatory proteins exist in
many isoforms, each with subtle differences in
k The sliding filament model describes how
sensitivity to physiological regulators such as
myosin forms cross-bridges with actin, then un-
Ca2⫹, pH, and temperature.
dergoes conformational changes that cause
myosin to walk along the microfilament. k Muscle myosin has an unusual unitary displace-
ment and duty cycle. Animals have different
k The distance myosin reaches with each cross-
myosin II isoforms that allow them to fine-tune
bridge cycle is called the unitary displacement.
actino-myosin ATPase activity.
The duty cycle is the proportion of time in the
cross-bridge cycle that each myosin is attached k EC coupling describes how extracellular
to actin. processes trigger elevation of muscle [Ca2⫹].
269
Striated muscles contract in response to mem- k Sonic muscles contract and relax rapidly, due in
brane depolarization, which can occur sponta- part to faster cross-bridge kinetics, faster Ca2⫹
neously (myogenic) or in response to nerve transients, and Z-disks that allow shorter sar-
stimuli (neurogenic). comere length.
k Tonic muscles are innervated at many locations k Smooth muscle lacks organized sarcomeres,
along the muscle fiber, while twitch muscles are scattering thick and thin filament arrays
usually innervated at a single motor end plate. throughout the cell with a complex geometry.
k Depolarization of muscle membranes, particu- k Contraction of smooth muscle can be controlled
larly in larger fibers, is facilitated by T-tubules, by Ca2⫹-dependent and Ca2⫹-independent
inward extensions of the sarcolemma deep into ways, acting at both the thick and thin filament.
the fiber.
k Ca2⫹ levels influence both caldesmon regulation
2⫹
k Depolarization opens voltage-dependent Ca and myosin light chain phosphorylation, acting
channels (DHPR) that trigger Ca2⫹ release from through the soluble Ca2⫹-binding protein
the SR. Muscles differ in how they link DHPR ac- calmodulin.
tivation to SR Ca2⫹ release; heart muscle uses
k A number of hormones affect myosin light chain
Ca2⫹-induced Ca2⫹ release to trigger contrac-
phosphorylation by acting on MLCK or MLCP.
tion, while skeletal muscle uses depolarization-
induced Ca2⫹ release. k Tonic smooth muscle can alter the fundamental
properties of cross-bridge reactions. They can
k Relaxation requires removal of Ca2⫹ from the
reduce the velocity of shortening and the actino-
cytoplasm using pumps and exchangers in the
myosin ATPase rate without sacrificing force.
sarcolemma and the SR.
The mechanisms by which these long-lasting
Muscle Diversity in Vertebrates “latch” cross-bridges form is not yet clear.
and Invertebrates
k Some insect muscles can exhibit graded contrac-
k Animals possess large gene families for many
tions, with the strength of contraction depen-
thick and thin filament proteins, allowing them
dent on summation of postsynaptic potentials,
to make countless distinct muscle fiber types.
either excitatory (EPSP) or inhibitory (IPSP).
k Individuals can alter muscle properties during
k Some insect muscles contract so quickly that
development, as well as in response to physio-
Ca2⫹ transients are not possible. These asyn-
logical and environmental changes.
chronous flight muscles rely on stretch activa-
k Heater organs and electric organs are examples tion of opposing muscles to elevate and depress
of extreme modifications in striated muscle opposing wings.
fiber design. They trans-differentiate, during
k Catch muscles strengthen cross-bridges to main-
development, losing muscle properties and
tain tension while consuming minimal energy.
gaining unique features.
Review Questions
1. What is the role of energy in construction and 5. What is the difference between the latch state
use of the cytoskeleton? of vertebrate smooth muscle and the catch
2. How do animals use muscle in physiological state of mollusc adductor muscle?
systems? 6. What are muscle fiber types? How do animals
3. Compare the contractile properties of sonic alter muscle fiber types in response to physio-
and locomotor muscles of fish. logical challenges?
4. Contrast the properties exhibited by 7. Discuss the role of Ca2⫹-binding proteins in
myosins that walk on microfilaments versus muscle contraction.
thin filaments.
270
Synthesis Questions
1. What genomic and genetic events might have 5. Recall what you know about the main path-
contributed to the expansion of the myosin II ways of energy production: glycolysis and mi-
family in vertebrates? tochondria. Discuss how these metabolic
2. What would happen if cells could only add or pathways integrate into the EC coupling pat-
remove tubulin (or actin) from one end of the terns of different muscles.
microtubule (or microfilament)? 6. Striated muscle cells are postmitotic and can
3. Describe the molecular processes of neuro- live for the lifetime of the organism. Discuss
muscular excitation, from the sites of neuro- how this property affects muscle biology, both
transmitter synthesis to Ca2⫹ release within normally and in disease.
the muscle.
4. Hummingbird hearts beat at about 30 Hz. Pre-
dict what you would find if you examined the
structure of a hummingbird cardiomyocyte.
1. Many cellular structures require metabolic en- axon? How many moles of GTP and GDP are
ergy to build and maintain. Calculate the cost tied up in the structure of this microtubule?
of building the microtubule support for the 2. Most skeletal muscles generate about 20 N of
axon of a motor neuron. Assume that the axon force per cm2 of cross-sectional area. If a
is 1 m long, 1 µm in diameter with 50 micro- myosin head generates 5 pN of force, and a
tubules aligned in parallel. If a tubulin thick filament has about 600 myosin heads,
monomer is 8 nm long, how many tubulins are how many thick filaments appear per cm2 of
needed to produce the microtubules of the cross-sectional area?
For Further Reading

See the Additional References section at the end Sellers, J. R. 2000. Myosin: A diverse superfamily.
of the chapter for more readings related to the Biochimica et Biophysica Acta 1496: 3–22.
topics in this chapter.
These two articles examine the relationships
Cytoskeleton and Motor Proteins between the structure and function of the three
These two textbooks are good general references motor proteins that work in conjunction with the
for cellular and molecular aspects of the cytoskeleton.
cytoskeleton and motor proteins. Burgess, S. A., M. L. Walker, H. Sakakilbara, P. J.
Alberts, B., A. Johnson, J. Lewis, M. Raff, K. Knight, and K. Oiwa. 2003. Dynein structure
Roberts, and P. Walter. 2002. Molecular biology and power stroke. Nature 421: 715–718.
of the cell, 4th ed. New York: Garland Science. Kull, F. J., R. D. Vale, and R. J. Fletterick. 1998.
Becker, W. M., L. J. Kleinsmith, and J. Hardin. The case for a common ancestor: Kinesin and
2002. The world of the cell, 5th ed. San myosin motor proteins and G proteins. Journal
Francisco: Benjamin Cummings. of Muscle Research and Cell Motility 19:
877–886.
Muscle myosin evolution is responsible for
much of the diversity in muscle function seen Muscle Structure and Regulation
in animals. These reviews examine myosin of Contraction
evolution in the context of the broader roles of These excellent reviews address the molecular
myosins in animals, including muscle and genetic mechanisms that control changes in
function. muscle contractile properties.
Berg, J. S., B. C. Powell, and R. E. Cheney. 2001. Baldwin, K. M., and F. Haddad. 2001. Plasticity
A millennial myosin consensus. Molecular in skeletal, cardiac and smooth muscle.
biology of the cell 12: 780–794. Journal of Applied Physiology 90: 345–357.
271
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Muntener. 2000. Calcium ion in skeletal Chock, and K. Wang. 2006. What the buzz was
muscle: Its crucial role for muscle function, all about: Superfast song muscles rattle the
plasticity and disease. Physiological Reviews tymbals of male periodical cicadas. FASEB
80: 1216–1265. Journal 20: 2017–2026.
Bers, D. M. 1991. Excitation-contraction coupling Rome, L. C., R. P. Funke, R. M. Alexander, G.
and cardiac contractile force. Dordrecht, the Lutz, H. Aldridge, F. Scott, and M. Freadman.
Netherlands: Kluwers Academic. 1988. Why animals have different muscle fibre
types. Nature 355: 824–827.
This review discusses the impact of structural
variation in muscle myosin. It focuses on how This interesting review discusses how animals
structural variations in vertebrates affect control their modified muscles in relation to
function, particularly in relation to muscle neuroethology.
diseases. Bass, A. H., and H. H. Zakon. 2005. Sonic and
Reggiano, C., R. Bottinelli, and G. J. M. Stienen. electric fish: At the crossroads of neuroethology
2000. Sarcomeric myosin isoforms: Fine- and behavioral neuroendocrinology. Hormones
tuning of a molecular motor. News in and Behavior 48: 360–372.
Physiological Sciences 15: 26–33.
Muscle Diversity in Vertebrates and

Invertebrates
These reviews discuss the ways specialized
muscles are produced, and the importance of
structural variation on muscle function.
Huxley, H. E. 1969. The mechanism of muscular contraction. Qiu, F., A. Lakey, B. Agianian, A. Hutchings, G. W. Butcher, S.
Science 164: 1356–1365. Labeit, K. Leonard, and B. Bullard. 2003. Troponin C in
Lutz, G., and L. C. Rome. 2004. Built for jumping: The design different insect muscle types: Identification of two
of the frog muscular system. Science 263: 370–372. isoforms in Lethocerus, Drosophila and Anopheles that
Maughm, D. W., and J. O. Vigoreaux. 1999. An integrated are specific to asynchronous flight muscle in the adult
view of insect flight muscle: Genes, motor molecules, and insect. Biochemical Journal 371: 811–821.
motion. News in Physiological Sciences 14: 87–92. Rome, L. C., R. P. Funke, R. M. Alexander, G. Lutz, H.
McDonald, K. S., L. J. Field, M. S. Parmacek, M. Soonpaa, J. Aldridge, F. Scott, and M. Freadman. 1988. Why animals
M. Leiden, and R. L. Moss. 1995. Length dependence of have different muscle fibre types. Nature 355: 824–827.
Ca2⫹ sensitivity of tension in mouse cardiac myocytes Squire, J. M., and E. P. Morris. 1998. A new look at thin
expressing skeletal troponin C. Journal of Physiology, filament regulation in vertebrate skeletal muscle. FASEB
London 483: 131–139. Journal 12: 761–771.
Metzger, J. M., M. S. Parmacek, E. Barr, K. Pasyk, W. I. Lin, K. Vale, R. D., and R. A. Mulligan. 2000. The way things move:
L. Cochrane, L. J. Field, and J. M. Leiden. 1993. Skeletal Looking under the hood of molecular motor proteins.
troponin C reduces contractile sensitivity to acidosis in Science 288: 88–95.
cardiac myocytes from transgenic mice. Proceedings of the Valiron, O., N. Caudron, and D. Job. 2001. Microtubule
National Academy of Sciences, USA 90: 9036–9040. dynamics. Cellular and Molecular Life Sciences 58:
Pieples, K., and D. F. Wieczorek. 2000. Tropomyosin 3 2069–2084.
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Credits
196 Art Resource, NY, HIP/Art
Resource, NY
197 photolibrary, Image Source Limited/photolibrary.
197 Photo Researchers, Inc., Juergen Berger/Photo
Researchers, Inc.
213 Phototake, Eric Grave/Phototake.
213 (a) Nina Zanetti.
218 Studiotouch/shutterstock.
272
273
Sensory Systems
Animals are equipped with a diverse array of sensory opens a mechanosensitive ion channel on the surface of the
systems that they use to monitor their internal and external membrane, allowing ions to move across the membrane and
environments. When we think of these sensory systems, we depolarize the cell. This depolarization opens voltage-gated
often imagine the complex ears of vertebrates, or the multi- Ca2⫹ channels, causing an action potential that sends a sig-
faceted eyes of insects. Complex sensory organs such as nal to the cilia to reverse the direction of their beating.
eyes and ears contain a large number of sensory cells and Paramecia can also detect environmental chemicals. They
accessory tissues, but animal sensory systems may be as move toward some chemicals, but are repelled by others.
simple as an isolated sensory cell that sends information to Exposure to an attractant chemical hyperpolarizes the
the brain for processing. Indeed, at the level of the sensory membrane, whereas exposure to a repellent chemical
cell, the sensory systems of multicellular animals have depolarizes the membrane, changing the beating
much in common with the sensory mechanisms used by of the cilia. A paramecium can also detect environmental
unicellular organisms. temperature. If you acclimate a paramecium to a particular
Consider a unicellular eukaryote, the paramecium. A temperature, it will swim away from water that is either
paramecium swims by coordinated beating of its cilia. warmer or colder than the acclimation temperature. The cell
Neuron Structure and Function, if you gently touch a parame- membrane of the paramecium contains heat-sensitive and
cium, it will back away from the touch stimulus by reversing cold-sensitive Ca2⫹ channels. When these channels are
the direction of beating of its cilia, turn slightly, and then activated, the resulting Ca2⫹ current changes the beating of
proceed forward. Touching the surface of the paramecium the cilia, changing swimming behavior.
274
Sensory Systems
Deerfly eye.
Paramecia can also sense a variety of other environ-

mental parameters using sensory mechanisms that we do
not yet understand. For example, paramecia tend to swim Paramecium.
up toward the surface of a container, but they lose their

ability to orient toward the surface in low-gravity environ- suggests that the organism can sense vibrations, even
ments, which suggests that they can detect gravitational though they do not ordinarily respond to them.
cues. Paramecia are also sensitive to electrical currents. The sensory mechanisms used by single-celled
When placed in an electrical current, a paramecium will organisms like the paramecium have a lot to teach us
swim toward the cathode and away from the anode. Elec- about the sensory mechanisms used by animals. In fact, as
trical shocks are a noxious stimulus for a paramecium; we will see in this chapter, the role of a sensory system
when given an electric shock, it rapidly swims away. (whether it is in a paramecium or a complex multicellular
Together, these observations suggest that paramecia are animal) is to detect an environmental stimulus and
sensitive to electric fields and discharges. Interestingly, transduce this signal into a change in the membrane
paramecia do not ordinarily change their behavior in potential of the sensory cell. This change in membrane
response to vibrations, but if an individual is conditioned by potential then acts as a signal to the nervous system that
repeatedly exposing it to an electrical shock and a vibration, can be interpreted and used by the organism to regulate
it will soon begin to respond to the vibration alone, which physiological systems or behavior.2
275
Sensory Systems
Overview The change in membrane potential caused by

the detection of the incoming stimulus ultimately
The sensory receptors of animals can be as simple sends a signal onward to integrating centers such
as a single sensory neuron, or can involve complex as the brain. The integrating centers must then
sense organs, such as the eye, that contain multiple interpret this incoming sensory information and
sensory receptor cells and accessory structures. elicit appropriate responses. Thus, sensory re-
Sensory receptor cells are typically specialized to ception is a process with many steps, including
detect a single type of stimulus, but no matter what (1) reception of the signal, (2) transduction of the
kind of stimulus they detect, all sensory receptor signal, (3) transmission of the signal to the inte-
cells work via mechanisms that are broadly similar grating center, and (4) perception of the stimulus
to those used by cells to detect incoming chemical at the integrating center. In this chapter we begin
signals. by discussing some of the general features of sen-
Sensory receptor cells take incoming stimuli of sory reception, and then we examine how spe-
various types and transduce (convert) them into cific sensory systems perform the steps of
changes in membrane potential (Figure 1). In most sensory reception.
sensory receptor cells, specialized receptor pro-
teins in the membrane absorb the energy of the in-
coming stimulus and undergo a conformational General Properties
change. The conformational change in the recep- of Sensory Reception
tor protein then activates a signal transduction
pathway that, directly or indirectly, opens or The terminology used in the field of sensory phys-
closes ion channels in the cell membrane, chang- iology can be confusing, because similar terms can
ing the membrane potential. be used for very different structures. In this chap-
ter, we use the term sense organ to describe a
Chemical stimulus Pressure Light

stimulus stimulus
Ion Ion Ion
Receptor channel channel channel
protein
Signal Signal
Signal transduction
transduction transduction
pathway pathway
pathway
Change in Change in Change in

membrane membrane membrane
potential potential potential
Signal to Signal to Signal to

integrating integrating integrating
center center center
(a) Chemoreceptors (b) Mechanoreceptors (c) Photoreceptors
Figure 1 An overview of sensory receptors pressure stimulus distorts the cell membrane, it changes the
Sensory receptors detect incoming stimuli of many kinds. conformation of the mechanoreceptor protein, opening ion
(a) Chemoreceptors detect chemical stimuli. For most channels and changing the membrane potential of the
chemoreceptors, chemicals bind to the receptor, causing a sensory cell. (c) Photoreceptors detect light by absorbing the
conformational change and activating a signal transduction energy carried by the incoming light stimulus, and changing
pathway that opens or closes ion channels, which alters the shape, activating a transduction pathway that opens or closes
membrane potential of the sensory cell. (b) Mechanoreceptors ion channels, resulting in a change in the membrane
detect stretch or tension on the cell membrane. When a potential of the sensory cell.
276
Sensory Systems
complex structure consisting of multiple tissues tential exceeds the threshold potential for the neu-
that work together to allow an organism to detect ron. The spike-initiating zone of a sensory neuron
an incoming stimulus. The eyes of vertebrates are need not be located in the axon hillock of the neu-
an example of a sense organ. We use the term ron. Sensory neurons are often bipolar or unipolar
sensory receptor to refer to a cell that is special- neurons, with their spike-initiating zones located at
ized to detect incoming sensory stimuli. Sensory the distal end of the neuron between the dendrites
receptor cells can be found within complex sen- and the axon. The action potentials are then con-
sory organs, as is the case for the light-sensitive ducted along the axon to the axon terminals of the
cells in the retina of vertebrate eyes. Other sensory neuron where they cause the release of a neuro-
receptors are isolated cells embedded within a transmitter. This neurotransmitter conveys the sig-
nonsensory tissue, as is the case for many of the nal to other neurons and onward to integrating
touch-sensitive cells in the skin of vertebrates. The centers such as the brain, where they are inter-
membranes of sensory receptor cells contain spe- preted.
cific receptor proteins that are specialized to de- When the sensory receptor cell is separate
tect incoming sensory signals. A change in the from the afferent sensory neuron, the initial
conformation of these proteins activates signal graded potential in the sensory receptor cell is
transduction pathways within the sensory recep- called a receptor potential. The receptor poten-
tor, causing a change in membrane potential that tial spreads across the sensory receptor cell to the
can act as a signal in the nervous system. site of the synapse with the afferent neuron, where
Afferent neurons send signals in the form of it triggers the release of neurotransmitter. The
action potentials from the periphery to integrating neurotransmitter then binds to receptors on the
centers such as the brain. Some sen-
sory receptors are themselves affer- Stimulus Stimulus
ent neurons. These afferent neurons Receptor
detect incoming signals and trans- protein
Receptor
duce them into action potentials that protein Dendrite
of afferent
can be sent to the integrating center. neuron Epithelial
This type of sensory receptor is sensory
Depolarization cell
termed a sensory neuron (Figure 2a). (receptor potential)
Depolarization
Other sensory receptors are epithe- (generator Ca2+ Vesicle with
lial cells that send a signal to a sepa- potential) neurotransmitter
rate afferent neuron that then sends
Trigger
signals zone Neurotransmitter
in the form of action potentials to the Action
receptor
integrating center (Figure 2b). In the potential
Dendrite
Graded
case of a sensory neuron, a receptor potential of afferent
protein in the dendrite of the neuron neuron
detects the incoming sensory signal,

Trigger
and changes conformation. The zone
change in the conformation of the re-
Action
ceptor protein alters the activity of a potential
signal transduction pathway that ul-
timately results in a change
To integrating center To integrating center
in the membrane potential of the re-
ceptor. This change in membrane po- (a) Sensory neuron (b) Epithelial sensory receptor cell
tential is a type of graded potential Figure 2 The types of sensory receptor cells (a) An incoming stimulus
that is termed a generator poten- activates a receptor protein in the sensory neuron, causing a depolarization called a
tial. The generator potential spreads generator potential. The generator potential triggers action potentials in the axon of
along the membrane to the spike-ini- the neuron. (b) An incoming stimulus activates a receptor protein on the surface of the
receptor cell, causing a receptor potential. The receptor potential opens voltage-gated
tiating (trigger) zone of the neuron, Ca2⫹ channels, causing the release of neurotransmitter onto the primary afferent
where it will generate action poten- neuron. The stimulated afferent neuron generates action potentials that are conducted
tials in the axon, if the generator po- to integrating centers.
277
Sensory Systems
primary afferent neuron and causes a postsynaptic The most physiologically meaningful classifica-
graded potential. This potential then travels to the tion of sensory receptors is based on the type of stim-
trigger zone of the afferent neuron, where it initi- ulus that the receptor can detect, which is sometimes
ates action potentials if it exceeds threshold. The called the stimulus modality. Chemoreceptors de-
action potentials are conducted along the axon to tect chemical signals. They form the basis of the
the axon terminals of the afferent neuron, causing senses of smell and taste and are important in sens-
the release of neurotransmitter and communicating components of the internal environment such as
ing the signal to the nervous system. blood oxygen and pH. Pressure and movement
Whether a sensory receptor is a neuron or an stimulate mechanoreceptors, which are involved
epithelial cell, however, its function is to detect an in the senses of touch, hearing, and balance, as
incoming stimulus and transduce it into changes well as in proprioception, or the sense of body po-
in membrane potential that convey information sition. Mechanoreceptors are also involved in de-
about the signal to integrating centers. tecting many important internal body parameters,
such as blood pressure. Photoreceptors detect
light, and are the basis for the sense of vision.
Thermoreceptors sense temperature. Electro-
Classification of Sensory Receptors receptors and magnetoreceptors sense electric
Sensory receptors and sense organs can be classi- and magnetic fields, respectively.
fied in a number of different ways. In elementary
school, you probably learned about the five senses
(touch, taste, smell, hearing, and vision). This clas-
sification, first developed by Aristotle over 2000
Receptors may detect more than one
years ago, is an explicitly human-centered system
stimulus modality
that focuses only on the senses that we consciously Although most receptors have a preferred (or
employ, ignores some obvious senses such as our most sensitive) stimulus modality, called the
ability to detect temperature changes, and entirely adequate stimulus, some receptors can also be
neglects sensory information that we are not con- excited by other stimuli, if the incoming signal is
sciously aware of, such as internal environmental sufficiently large. For example, if you press on
parameters like blood pressure and blood oxy- your eyelid when your eye is closed, you may per-
genation. This classification scheme also neglects ceive a bright spot of light. Although light is the
the wide range of sensory systems in other ani- adequate stimulus for the photoreceptors of your
mals. Many animals have senses that humans do eyes, sufficient pressure can also stimulate these
not appear to possess, such as the ability to detect photoreceptors, causing them to send a signal to
electric or magnetic fields. Similarly, some ani- your brain. Your brain interprets this signal as a
mals lack one or more of the five senses defined light, because it has been programmed to inter-
for humans. pret any signal coming from the photoreceptors of
your eyes as a light stimulus.
A few types of receptors are naturally sensitive
Receptors can be classified based on to more than one stimulus modality. For example,
stimulus location or modality in the noses of sharks, sense organs called the
An alternative way of classifying sensory receptors ampullae of Lorenzini are sensitive to electric-
is by the location of the stimulus. In this classifica- ity, touch, and temperature. Receptors that can
tion, telereceptors (or teleceptors) detect stimuli detect more than one class of stimulus are some-
coming from locations at some distance from the times called polymodal receptors. The most
body. Vision and hearing are good examples of tele- common polymodal receptors in humans are the
receptive senses. Exteroceptors detect stimuli oc- nociceptors, which detect extremely strong stim-
curring on the outside of the body, such as pressure uli of various kinds, including temperature, pres-
and temperature, and interoceptors detect stimuli sure, and chemicals. Nociceptors are responsible
occurring inside the body, such as blood pressure for the sensation of pain in humans and many
and blood oxygen. This classification is of limited other animals. Although not all nociceptors are
utility to physiologists, however, because it tells us polymodal, many appear to be sensitive to a vari-
little or nothing about how the receptors work. ety of tissue-damaging stimuli.
278
Sensory Systems
Stimulus Encoding in Sensory recall the ampullae of Lorenzini, receptors in

Systems sharks that are sensitive to electricity, pressure, and
temperature. How could such a receptor encode in-
Whatever the type of stimulus, sensory receptors formation regarding stimulus modality? A receptor
ultimately convert the signal to a series of action sensitive to more than one sensory modality likely
potentials in an afferent neuron. Since all action encodes information in the temporal pattern of its
potentials are essentially the same, how can an or- action potentials. For example, bursts of action po-
ganism differentiate among stimuli, or detect the tentials could convey a different message than a
strength of a signal? In order for an organism to continuous series. In addition, the relative firing
interpret an incoming signal in a coherent way, a patterns of several adjacent sensory cells may carry
sensory receptor must be able to encode four im- information regarding stimulus modality. For ex-
portant pieces of information about the stimulus ample, imagine a situation in which each sensory
into action potentials: stimulus modality, stimulus cell is sensitive to more than one type of stimulus,
location, stimulus intensity, and stimulus duration. but their relative sensitivities vary (for example, the
first receptor might be very sensitive to stimulus A,
but less sensitive to stimulus B, while a second re-
Sensory pathways encode stimulus
ceptor has the opposite pattern). By comparing the
modality
relative intensity of the signal coming from the two
One way in which sensory systems can encode receptors, an afferent neuron could code informa-
stimulus modality is described by the theory of lation regarding the stimulus modality. The mecha-
beled lines, derived from the “law of specific nerve nisms underlying this “cross-fiber” coding of
energies” proposed more than 150 years ago by information are not yet entirely understood, but
Johannes Müller. Müller hypothesized that differ- may be important for the coding of information
ent kinds of nerves lead from sensory organs such from senses such as taste in the vertebrates.
as the ear or eye to the brain, and that each of
these nerves has its own “specific nerve energy”
that transmits information about a particular kind
Receptive fields provide information about
of stimulus. Thus, the optic nerve transmits the
stimulus location
signal “light” whenever the eye is stimulated, even Sensory systems must also encode the location of
if the stimulus is actually pressure on the eyeball. the stimulus. The task of encoding stimulus loca-
While Müller was not quite correct in his theory tion varies among receptors. We discuss how sen-
(because all neurons use the same signal—the ac- sory systems such as vision and hearing encode
tion potential), his hypothesis did outline some of the location of a stimulus later in the chapter. But
the essential features of the labeled-line theory. for many sensory systems, the main factor coding
Since most sensory receptors are maximally sen- stimulus location is the location of the stimulated
sitive to only one type of stimulus, and a sensory receptor on the body. Thus, the labeled-line the-
receptor is part of or synapses with a particular af- ory, which in part accounts for coding of stimulus
ferent neuron, signals in that afferent neuron must modality, can also explain how these sensory sys-
represent a specific stimulus modality. Sensory tems code for stimulus location.
systems are often organized into sensory units In this section, we use the sense of touch in the
consisting of multiple sensory receptors that form vertebrates as an example of how a sensory system
synapses with a single afferent neuron. In general, can encode the location of a stimulus. Afferent neu-
all of the sensory receptors associated with a sin- rons involved in the sense of touch have a receptive
gle afferent neuron are of the same type, and thus field, which corresponds to the region of the skin
the theory of labeled-line perception can, in most that causes a response in that particular afferent
cases, account for our ability to distinguish among neuron. The size of the receptive field varies among
different stimulus modalities. neurons. Neurons with large receptive fields de-
The fundamental assumption of the labeled- tect stimuli across a larger area than neurons with
line theory is that there is a discrete pathway from small receptive fields, and thus neurons with small
a sensory cell to the integrating center. However, it receptive fields provide more precise localization of
is clear that not all information about stimulus the stimulus, or greater acuity, than neurons with
modality can be encoded in this way. For example, large receptive fields. However, the information
279
Sensory Systems
from a single afferent neuron can only signal (A2, B2, and C2). In contrast, a strong stimulus such
whether a stimulus has occurred within the recep- as a pin pushing into the skin in the center of the
tive field, and cannot provide more precise localiza- receptive field of neuron B causes it to release a
tion. Animals improve their ability to localize large amount of neurotransmitter onto its second-
stimuli by having afferent neurons with overlap- order neuron (B2). This pin prick also causes the
ping receptive fields. A stimulus that causes both skin to bend slightly in the area of the receptive
neuron A and neuron B to respond must be located fields for the adjacent neurons A and C, weakly stim-
within the area of overlap between the receptive ulating them. A weak stimulus to neurons A and C
fields of the two afferent neurons. This is an exam- would ordinarily cause them to release a small
ple of a phenomenon termed population coding, in amount of neurotransmitter onto their second-
which information about the stimulus is encoded in order neurons (A2 and C2). But in the example
the pattern of firing of multiple neurons. shown here, there are lateral interneurons that
Many sensory systems take advantage of a form synapses between the axon terminals of neu-
phenomenon termed lateral inhibition to further ron B and neurons A and C. The strong response
improve acuity. In the simplified example shown in of neuron B causes it to release neurotransmitter
Figure 3, a weak stimulus such as a gentle touch onto these lateral interneurons. These interneu-
across the receptive fields of neurons A, B, and C rons release an inhibitory neurotransmitter that
would cause each neuron to release a small amount prevents the release of neurotransmitter from
of neurotransmitter onto its second-order neuron, neurons A and C onto their second-order neurons.
stimulating all three of the second-order neurons Thus, rather than exhibiting a weak response,
Weak stimulus Strong stimulus Weak stimulus

Response proportional A B C
to stimulus strength
Lateral inhibitory
neurons inhibit
pathways A and C
A B C
Lateral inhibition A B C
1 1 1
enhances contrast
A B C
1 1 1
Figure 3 Determining the location of a stimulus neurotransmitter onto neurons A and C, reducing the amount
with multiple receptors A stimulus at the center of of neurotransmitter that they release. As a result, neuron B2
the receptive field of neuron B strongly stimulates this receives a strong stimulus that triggers action potentials,
neuron, and weakly stimulates the adjacent neurons A and C. while neurons A2 and C2 receive a weak stimulus that does
Neuron B forms synapses with lateral interneurons that not trigger action potentials. Lateral inhibition increases the
make connections with the axon terminals of neurons A and contrast between the signals in neurons A2, B2, C2, improving
C. These lateral interneurons release an inhibitory the ability to discriminate between stimuli.
280
Sensory Systems
neurons A2 and C2 do not fire. Lateral inhibition in- Dynamic range

creases the contrast between the signals from neu-
Magnitude of response
rons at the center of the stimulus and neurons on
the edge, allowing finer discrimination.
Receptor
saturation
Sensory receptors have a dynamic range
Threshold
Action potentials are all-or-none electrical events intensity
that do not usually code intensity through changes
in magnitude. Instead, action potentials code stim-
ulus intensity through changes in frequency. 0 250 500 750 1000 1250 1500
Strong stimuli typically trigger high-frequency se- Stimulus intensity
ries (or trains) of action potentials, whereas (a) Dynamic range of a receptor
weaker stimuli trigger lower-frequency trains of
action potentials. B
Most sensory receptor cells are able to encode
stimuli over a relatively limited range of intensi-
ties, called the dynamic range of the receptor A
(Figure 4a). The weakest stimulus that produces a
response in a receptor 50% of the time is termed
the threshold of detection. Many sensory receptors
are extremely sensitive and can detect signals that
are close to the theoretical detection limits for the
stimulus. For example, some of the photoreceptors
in the human eye can detect a single photon of 0 250 500 750 1000 1250 1500
light, and some mechanoreceptors on human fin- Stimulus intensity
gertips can detect depression of the skin of less (b) Varying sensitivity
than 0.1 micron. Below the threshold stimulus in-
tensity, the receptor cell fails to initiate action po-
tentials. At the top of the dynamic range, the
receptor cell is saturated and cannot increase its

response even if the signal strength increases. In
principle, any of the steps in sensory transduction A B C
can set the top of the dynamic range of a receptor.
A receptor reaches the top of its dynamic range if
all of the available receptor proteins become satu-
rated. The receptor could also reach the top of its 0 500 1000 1500 2000 2500 3000 3500 4000
dynamic range if all available ion channels have Stimulus intensity
(c) Range fractionation
Figure 4 Stimulus-response relationships in
sensory receptors (a) Sensory receptors have a
dynamic range over which the response of the receptor
increases with increasing stimulus intensity. (b) Receptors

with varying dynamic range. Receptor A is saturated at high
intensity, but has a relatively small change in response for
each change in stimulus intensity. Receptor B is saturated at
low stimulus intensity, but has a large change in response for
each change in stimulus intensity. (c) Using the strategy of
range fractionation, several receptors can work together to
provide fine discrimination across a wide range of stimulus
intensities. (d) Some receptors encode signals 0 1 10 102 103 104 105 106 107 108
logarithmically, allowing fine discrimination at low stimulus
Stimulus intensity
intensities and coarser discrimination at high stimulus
intensities. (d) Logarithmic encoding
281
Sensory Systems
opened or closed. The receptor will also reach the The lowest action potential frequency that is likely
top of its dynamic range if the membrane potential to be physiologically meaningful is on the order of
reaches the equilibrium potential for the particular one per second, and the maximum frequency of
ion involved in the receptor or generator potential action potentials in most neurons is around 1000
(because no net ion movement will occur beyond per second, yielding a dynamic range of approxi-
this point). The maximum rate of release of neuro- mately 1000-fold. In contrast, the intensity of
transmitter from the receptor cell, or the maxi- many environmental stimuli varies across a much
mum frequency of action potentials in the afferent larger range. For example, a jet engine is about
neuron can also set the top of the dynamic range. 1.4 million times as loud as the faintest sound that
a human being can hear. So how can a sensory re-
There is a trade-off between dynamic ceptor code for such a wide range of stimulus in-
range and discrimination tensities with such a small range of action
potential frequencies? Range fractionation can ex-
Figure 4b illustrates two hypothetical receptors
tend the dynamic range of a receptor, but many re-
with varying dynamic ranges. Receptor A has a
ceptors use another strategy.
large dynamic range and can detect both very weak
and very strong stimuli. In contrast, receptor B can
only detect very weak stimuli, and becomes satu- Many receptors encode signals
rated at moderate stimulus levels. Because the logarithmically
range of stimulus intensities is large and the range It is possible to encode a wide range of stimulus in-
of action potential frequencies is limited, receptor A tensities using a single sensory receptor cell, without
has relatively low power to discriminate among dif- resorting to range fractionation. Figure 4d shows a
ferences in intensity. A relatively large change in hypothetical example of a receptor that encodes
stimulus intensity causes only a small change in the stimuli logarithmically so that the response increases
response of receptor A, whereas a relatively small linearly with the logarithm of the stimulus intensity.
change in stimulus intensity causes a large change In this relationship there is a large increase in the re-
in the response of receptor B. Receptor B is sensi- sponse to changes in stimulus intensity when stimu-
tive to only a small portion of the possible range of lus intensity is low, providing fine discrimination, but
stimulus intensities, but it has the ability to provide when stimulus intensity is high there is only a limited
very fine discrimination within that range. change in the response even when there is a very
large change in the stimulus. Thus, there is only
Range fractionation increases sensory coarse discrimination at high stimulus intensities.
discrimination This type of curve represents a compromise between
One way to improve sensory discrimination is to a broad dynamic range and fine discrimination be-
use populations of receptors. Groups of receptors, tween similar stimulus intensities. Logarithmic cod-
each sensitive to a different range of stimulus ining allows a receptor to have a constant response to
tensities, can work together to provide fine dis- a given percentage change in stimulus intensity.
crimination across a wider range of intensities. Many of our sensory systems employ this kind
With this strategy, called range fractionation, in- of strategy. For example, if you stand in a darkened
dividual receptor cells are sensitive to only a small room and light a candle, it is easy to notice the
portion of the possible range of intensities, but change in light intensity, but if you do the same
multiple receptors cover different parts of the thing in a bright room, you are unlikely to notice the
range (Figure 4c). In a system designed in this difference. You have the ability to make fine dis-
way, stimulus intensity is actually coded through criminations between intensities at low light levels,
the behavior of populations of sensory receptors. but cannot make fine discriminations at high light
levels. Similarly, if you help a friend to move furni-
ture, you’re unlikely to notice the change in weight
Sense organs can have a very large if someone puts a book on top of the sofa, but you
dynamic range could easily detect the weight of the book if that was
The upper limit of the frequency of action poten- the only object you were holding. This logarithmic
tials is set by the refractory periods of the voltage- relationship between actual and perceived stimulus
gated channels involved in the action potential. intensity is known as the Weber-Fechner relation-
282
Sensory Systems
Figure 5 Phasic and tonic
(afferent axon) (mV)

Membrane potential
Membrane potential
receptors (a) Tonic receptors
(axon) (mV)
remain depolarized throughout
the duration of a stimulus. Many
tonic receptors show the
phenomenon of adaptation, in
–70 –70 which the response declines with
time.
(b) Phasic receptors adapt very
rapidly, and thus depolarize only
potential (mV)
potential (mV)
at the beginning of a stimulus.
Receptor
Receptor
Stimulus intensity
Stimulus intensity
(mV)
(mV)
0 0
Time (msec) Time (msec)

On Off On Off
(a) Tonic receptors (b) Phasic receptors
ship. Sensations such as brightness, loudness, and after a while you may not detect the smell at all.
weight all obey the Weber-Fechner relationship. Receptor adaptation is a physiologically critical
mechanism because it allows animals to tune out
unimportant information about factors in their en-
Tonic and phasic receptors encode
vironment that aren’t changing, and to focus pri-
stimulus duration
marily on novel sensations.
Two functional classes of sensory receptors code
stimulus duration (Figure 5). Tonic receptors fire
action potentials as long as the stimulus continues, 2 C O NC E P T C H E CK
and thus can convey information about how long
1. For the following stimuli, determine whether the
the stimulus lasts. However, most tonic receptors receptor involved is a mechanoreceptor, a
do not fire action potentials at the same frequency chemoreceptor, or a photoreceptor: blood oxygen,
throughout the duration of a prolonged stimulus. acceleration, a light, sound waves, blood glucose.
Instead, action potential frequency often declines if 2. Compare and contrast receptor potentials,
the stimulus intensity is maintained at a constant generator potentials, and graded potentials.
level. This process is known as receptor adapta- 3. How does lateral inhibition enhance contrast?
tion. In fact, some receptors adapt so quickly that 4. Explain the advantages of encoding sensory
they produce action potentials only when the stim- signals logarithmically.
ulus begins. These receptors, termed phasic re- 5. Do you think the sensory receptor cells in the eye
ceptors, code changes in the stimulus but do not are tonic or phasic receptors? Justify your answer.
explicitly encode stimulus duration.
We have all experienced the phenomenon of
receptor adaptation. When you first step into a hot Chemoreception
bath, the water may feel uncomfortably warm, but
very soon you will no longer feel that the water is Most cells can sense incoming chemical signals, and
too hot. Similarly, if you walk into a house where animals have many types of chemoreceptors that
someone has been cooking strong-smelling food, they use to sense their external and internal chem-
at first you may find the scent very noticeable, but ical environments. Here we focus on the senses of
283
Sensory Systems
smell and taste, which multicellular organisms use of olfaction. However, current evidence suggests
to sense chemicals in their external environment. that the olfactory systems of the vertebrates and
For terrestrial animals, olfaction, or the sense of insects evolved independently. We first discuss the
smell, is generally defined as the detection of chem- mechanisms underlying olfaction in the verte-
icals carried in air. Thus, olfaction provides the abil- brates. We then briefly compare and contrast the
ity to sense chemicals whose source is located at analogous mechanisms in the insects.
some distance from the body. This is in contrast to
the sense of taste, or gustation, which allows the de-
The vertebrate olfactory system can
tection of dissolved chemicals emitted from ingested
distinguish thousands of odorants
food. Although it is easy to distinguish between gus-
tation and olfaction for terrestrial organisms, it is Vertebrate olfactory systems have an enormous ca-
more difficult to make this distinction in aquatic or- pacity to distinguish among odorants, the chemi-
ganisms. In aquatic vertebrates, gustation always in- cals detected by the olfactory system. Studies on
volves detecting sensations involving food, whereas humans indicate that most people can distinguish
olfaction involves detecting a wide variety of envi- among tens of thousands of different odorants, and
ronmental chemicals including those associated even a very small change in the structure of an
with food, predators, potential mates, and particular odorant can cause a huge difference in the subjec-
locations. In the vertebrates (whether aquatic or ter- tive perception of an odor. For example, humans
restrial), olfaction and gustation are also distinct perceive the compound octanol as smelling like or-
from one another based on structural criteria; they anges or roses, and describe the compound oc-
are performed by different sense organs, use differ- tanoic acid as smelling rancid or sweaty. The only
ent signal transduction mechanisms, and separate difference between octanoic acid and octanol is
integrating centers process the incoming informa- that octanoic acid ends with a carboxylic acid
tion from the senses of taste and smell. group, whereas octanol ends in a hydroxyl group.
The vertebrate olfactory system is located in
the roof of the nasal cavity (Figure 6). Olfaction be-
The Olfactory System gins when an odorant molecule comes in contact
The ancestors of all animals undoubtedly pos- with the mucus layer that lines and moistens the ol-
sessed chemoreceptors, and vertebrates and in- factory epithelium of the nose. The mucus contains
sects share many similarities in the mechanisms odorant binding proteins, which are thought to
Olfactory epithelium
Sinus
cavities
Olfactory bulb
Olfactory
Nasal bulb
cavity
Olfactory
epithelium Inter-
neuron
Odorant Odorant Olfactory Cribriform

binding receptors receptor plate
proteins cell
Figure 6 The olfactory organ of a dog The so that the ciliated end of the neuron is located in the
olfactory epithelium of mammals, located in the nasal cavity, olfactory epithelium. The cilia of the bipolar neurons contain
contains supporting cells and olfactory receptor neurons. the odorant receptor proteins that detect incoming chemical
These bipolar sensory neurons have one end that forms stimuli. These cilia project into a mucus layer containing
synapses within the olfactory bulb of the brain. These odorant binding proteins that coats the olfactory epithelium.
neurons then pass through holes in the bony cribiform plate
284
Sensory Systems
be involved in allowing lipophilic odorant mole- for odorant receptors (for example, the mouse
cules to dissolve in the aqueous mucus layer. Ver- genome contains at least 1000 potential odorant re-
tebrate olfactory receptor cells are bipolar neurons ceptor genes). Each odorant receptor cell expresses
with one end in the olfactory epithelium and an- only a single kind of odorant receptor protein out of
other end that passes through holes in the bony this wide range of possible proteins.
cribiform plate and forms synapses with neurons When an odorant molecule binds to an odor-
in the olfactory bulb of the brain. On the outer sur- ant receptor, the receptor undergoes a conforma-
face of the olfactory epithelium the membrane of tional change that sends a signal to an associated
the olfactory receptor cell is highly modified and G protein, Golf. Activated Golf signals via adenylate
covered in cilia, which project into the mucus layer cyclase, activating a signal transduction pathway
lining the inside of the nose. The cilia on the olfac- (shown in Figure 7) that ultimately causes a depo-
tory receptor neurons are nonmotile, and thus they larizing generator potential. If the depolarization
do not beat, but they contain the odorant recep- is sufficiently large, action potentials will be trig-
tor proteins, which are the receptor proteins in- gered in the dendrite of the olfactory receptor neu-
volved in detecting incoming chemical signals. ron. Note that these action potentials travel
toward the cell body of this bipolar neuron, in con-
trast to the arrangement found in a motor neuron,
Odorant receptors are G protein coupled in which the action potential always travels away
Odorant receptor proteins are G-protein-coupled from the cell body. These action potentials are ul-
receptors, similar in many respects to those intimately transmitted to the other end of the neu-
volved in hormonal communication. Odorant re- ron, where the axon terminals form synapses with
ceptor proteins are members of a large multigene the neurons of the olfactory bulb in the brain.
family, and all of the vertebrate genomes that have Recent evidence suggests that additional sig-
been sequenced so far contain many genes coding nal transduction pathways may also play a role in
Cilium of 1 Binding of odorant to an odorant receptor

olfactory causes a conformational change.
cell
1 Odorant
receptor Voltage-gated 2 The activated G protein, Golf, moves
Odorant +
Na channels through the membrane and activates
protein
adenylate cyclase.
Golf
2 7 Na+
3 Adenylate cyclase converts ATP into cAMP.
Adenylate ATP
cyclase To cell
3 Depolarization body 4 cAMP opens cAMP-gated ion channels.
cAMP 5
5 Ca2+ and Na+ enter the cell, causing a
Cl– generator potential.
Na+, Ca2+
4 6 2+ 2+
2+
Ca -activated 6 The Ca also opens Ca -activated Cl–
Cl– channel channels, causing Cl– to leave the cell,
increasing the depolarization.
7 The generator potential opens voltage-gated

cAMP-gated ion channel Na+ channels, triggering action potentials.
Figure 7 Signal transduction in an olfactory receptor cell
285
Sensory Systems
odorant detection in mammals. For example, Main

some odorant receptors are coupled to G proteins olfactory
bulb
that activate a phospholipase C (PLC)–mediated Olfactory Accessory
signal transduction cascade, in which PLC hy- epithelium olfactory
drolyzes phosphatidylinositol-4,5-bisphosphate Nasal
bulb
(PIP2) in the plasma membrane, producing inositol cavity
trisphosphate (IP3) and diacylglycerol (DAG),
Tongue
which results in an increase in intracellular Ca2⫹,
causing plasma membrane Cl⫺ channels to open.
However, just as with the cAMP-mediated signal
Nasopalatine Vomeronasal
transduction cascade, the ultimate result of the duct organ
PLC-mediated signal transduction cascade is to
(a) Vomeronasal organ of mammals
depolarize the cell, triggering action potentials.
Although vertebrate genomes contain up to a
thousand genes coding for odorant receptor pro- Nasal cavity
teins, the total number of odors that an animal can
distinguish is even larger, possibly numbering in
the tens of thousands. Experiments in mammals
such as rats and humans indicate that each olfac-
tory neuron expresses only one odorant receptor
Vomeronasal
gene, but that each odorant receptor can recognize organ
more than one odorant. Thus, a given odorant ex-
(b) Vomeronasal (Jacobson's) organ of reptiles
cites multiple olfactory neurons, but to different
degrees. As a result, each odorant excites a unique
Figure 8 Vomeronasal organs (a) In mammals, the
combination of olfactory neurons. The number of vomeronasal organ, which detects pheromones, is located at
distinct odorants that can be discriminated using the base of the nasal cavity and is connected to the mouth via
such a combinatorial code is extremely large. Even the nasopalatine duct. (b) In reptiles, the vomeronasal organ
if each odorant were coded by a combination of (called Jacobson’s organ) is located in the palate.
only three different receptors, there would be ap-
proximately 1 billion potential combinations. The tissue that separates the two nostrils). In reptiles,
code for each odor actually involves more than the vomeronasal organ (often called Jacobson’s or-
three receptors, and thus the potential for odor gan, after the scientist who discovered it) is found
discrimination by the vertebrate olfactory system on an analogous location on the palate. A narrow
may be much larger than a billion. tube leads from the vomeronasal organ to either
the oral cavity or the nasal cavity, depending on
the species. For example, in snakes this tube is lo-
An alternative chemosensory system cated in the oral cavity, and a snake can use its
detects pheromones tongue to transfer pheromones to the vomeronasal
Terrestrial vertebrates use an organ called the organ by flicking its tongue into its mouth.
vomeronasal organ to detect a particular class of Like the olfactory epithelium, the epithelium of
environmental chemicals, termed pheromones. the vomeronasal organ expresses chemorecep-
Pheromones are chemical signals that are re- tors. However, the pheromone receptors of the
leased by an animal that affect the behavior of an- vomeronasal organ differ from the odorant recep-
other animal of the same species. Pheromones tors of the olfactory epithelium. Vomeronasal re-
play an important role in maintaining social hier- ceptors activate a phospholipase C-based signal
archies and stimulating reproduction in many an- transduction system, while most olfactory recep-
imals. The vomeronasal organ is an accessory tors activate an adenylate cyclase–cAMP signal
olfactory organ that is structurally and molecu- transduction pathway. The vomeronasal receptors
larly distinct from the primary olfactory epithe- have some similarity to the vertebrate receptors
lium (Figure 8). In mammals, the paired for bitter tastes, which we discuss in later sections
vomeronasal organs are found on each side of the of this chapter covering the gustatory system.
base of the nasal cavity near the nasal septum (the
286
Sensory Systems
Invertebrate olfactory mechanisms differ ally involve cAMP as a second messenger, just as in
from those in the vertebrates the vertebrates. Similarly, odorant binding proteins
and G-protein-coupled odorant receptors have
Invertebrate olfactory organs are evolutionarily
been detected in every species of invertebrate ex-
distinct from those in the vertebrates and can be
amined so far. However, the odorant receptors of
located in many parts of the body, although they
invertebrates share little sequence similarity with
are most often concentrated at the anterior end,
mammalian odorant receptors, and are likely inde-
on or near the head. In arthropods (such as insects
pendently derived from G-protein-coupled recep-
and crustaceans), the invertebrates for which ol-
tors found in the common ancestor of all animals.
faction has been most intensively studied, the pri-
Even within the invertebrates, odorant receptors
mary olfactory organs are generally located on the
share little similarity among groups. For example,
antennae or antennules. The antennae are cov-
the odorant receptors in Drosophila (a fruit fly) are
ered with hundreds of hairlike projections of the
unlike those found in Caenorhabditis elegans (a
cuticle called sensilla (Figure 9). Sensilla are com-
nematode).
plex sensory organs that have a variety of mor-
Although the odorant code has not yet been
phologies and functions, including both
deciphered for any invertebrate, the mechanisms
mechanosensory and chemosensory transduction.
of signal processing likely differ among inverte-
Olfactory sensilla have a small pore at their tip to
brate groups. In Drosophila, as in the vertebrates,
allow odorants to cross the exoskeleton. Olfactory
each olfactory neuron expresses a single odorant
sensilla also contain odorant receptor neurons. As
receptor, and olfactory neurons likely code odor-
in the vertebrates, these neurons express odorant
ant information combinatorially. In contrast, in
receptor proteins.
C. elegans, each olfactory neuron expresses sev-
The signal transduction mechanisms activated
eral different odorant receptors, and thus the
by odorant receptor proteins have been studied in
“odorant code” cannot be a simple combinatorial
only a few species of invertebrates, but they gener-
system like that found in mammals.
Most invertebrate groups also produce and de-
tect pheromones. Aquatic invertebrates are thought
to use essentially the same system for detecting
both odorants and pheromones, but in terrestrial
invertebrates such as insects these two systems are
separated. Insects have specialized pheromone-
sensitive sensilla on their antennae that are similar
in structure to those that detect odors, but their
numbers and distributions differ between males
Pore
and females. The sensory neurons of these sensilla
are exceptionally sensitive and highly selective. In
fact, the pheromone-sensitive sensilla of the silk
Dendrites moth Bombyx mori can detect as little as a single
of sensory
neurons molecule of the pheromone bombykol.
Cuticle
The Gustatory System
Cell bodies of
Unlike the olfactory system, the gustatory system
sensory neurons (or sense of taste) is not able to discriminate
among thousands of different molecules. Instead,
at least in humans, tastes can be grouped into one
Figure 9 The structure of a chemosensitive of five classes: salty, sweet, bitter, sour, and
sensillum Insect sensilla are complex sensory organs umami. Umami is a word coined by a Japanese
that can contain both chemoreceptive and mechanoreceptive
scientist from the words umai (delicious) and mi
sensory neurons. Sensilla are involved in olfaction, detection
of pheromones, gustation, and the senses of touch and (essence), and corresponds to a savory or meaty
hearing in insects. sensation. Sweet, umami, and salty tastes indicate
287
Sensory Systems
nutritionally important carbohydrates, proteins, taste receptor cell. The apical surface of the taste
and ions, whereas bitter and sour tastes generally cell is folded into numerous microvilli, which con-
reflect potentially toxic substances. tain the receptors and ion channels that mediate
the transduction of the taste signal.
Taste buds are vertebrate gustatory
receptors Vertebrate taste receptors use diverse
In terrestrial vertebrates, taste receptor cells are
signal transduction mechanisms
found on the tongue, soft palate, larynx, and Figure 11 summarizes the signal transduction
esophagus and are clustered into groups known mechanisms used by taste receptor proteins for
as taste buds (Figure 10). In aquatic vertebrates, salty, sour, sweet/umami, and bitter tastes, respec-
taste buds can also be located on the external sur- tively. Salty tastes are conveyed by Na⫹ ions in food,
face of the body. For example, many fish have while sour tastes are conveyed by H⫹ ions. Sugars
taste buds on the barbells (whiskerlike projections and related organic molecules convey sweet tastes,
from the lower jaw). The sea robin even has taste while amino acids and related molecules convey
buds on the tips of its fins, which are useful be- the sensation umami. In contrast, a wide range of
cause these fish use their fins to probe in the mud organic molecules can convey a bitter taste, includ-
for food. Although the shapes, sizes, and distribu- ing compounds like caffeine, nicotine, and quinine.
tions of taste buds vary among vertebrate species, The receptor protein for salty substances is
all taste buds share certain common features. not actually a receptor at all, but instead a Na⫹ ion
Taste buds are onion-shaped structures that con- channel (Figure 11a). These Na⫹ channels are also
tain multiple taste receptor cells (in humans each permeable to H⫹ ions, and thus may play a role in
bud contains between 50 and 100 taste receptor the perception of sour tastes. Because Na⫹ and H⫹
cells), with a pore that opens out to the surface of compete for access to the channel, however, these
the body. Dissolved chemicals from food, termed channels are probably important for the percep-
tastants, enter through this pore and contact the tion of “sourness” only in species with relatively
low Na⫹ levels in their saliva. Thus, hamsters,
which have low saliva Na⫹, use these channels to
Microvilli Pore Taste receptor cell detect sourness, while humans and rats, which
have relatively high saliva Na⫹, taste sourness
through other mechanisms.
A number of sour-taste transduction mecha-
nisms have been proposed, depending on the species
being investigated. Figure 11b summarizes one of
these potential mechanisms, which was first de-
scribed in the taste receptor cells of salamanders.
These taste receptor cells sense sourness via an api-
cally localized K⫹ channel that is blocked directly by
protons. Blocking these K⫹ channels leads to depolar-
ization of the taste cells, by decreasing K⫹ permeabil-
ity and altering the resting membrane potential, as
described by the Goldman equation. This depolariza-
tion ultimately causes neurotransmitter release. In
contrast, in frogs, taste cells contain H⫹-gated Ca2⫹
Epithelial Primary Support channels and H⫹ transporters that are believed to be
cell afferent cell involved in detecting sourness, although the specific
neurons
proteins involved have not yet been sequenced.
Figure 10 Structure of a vertebrate taste bud A Recent molecular studies in mammals have
taste bud consists of a pore containing sensory receptor cells suggested that acid-sensing ion channels (ASICs) may
and support cells. The apical surface of the receptor cells is
be important for detection of sourness.
covered with microvilli that project into a pore open to the
surface of the body. Receptor proteins on these microvilli
detect tastants dissolved in saliva or other fluids.
288
Sensory Systems
Taste receptor cell
Primary afferent
neuron
1 1 Na+ from salty food K+ channel H+ ion 1 H+ ions from sour foods
Na+ enters through a Na+ 1 block the K+ channel.
channel channel.
2 2 This blockage prevents
Na+ 2 The resulting K+ K+ from leaving the cell.
depolarization opens
voltage-gated Ca2+
2 channels. 3 3 The resulting
depolarization opens
Ca2+ Ca2+ voltage-gated Ca2+
Voltage-gated 3 The influx of Ca2+ Voltage-gated channels.
Ca2+channel causes neurotransmitter Ca2+channel
release.
4 The influx of Ca2+
causes neurotransmitter
release.
3 Taste 4 Taste
receptor receptor
cell cell
Afferent Afferent
neuron neuron
(a) Salty (b) Sour
Gustducin 1 A sweet substance binds Transducin 1 A bitter substance binds

Sweet Adenylate to its receptor, causing a Bitter to its receptor, causing a
molecule cyclase conformational change. molecule conformational change.
PLC
2 2
2 The activated G protein, 2 The activated G protein,
1 3 1
gustducin, activates transducin, activates
adenylate cyclase. phospholipase C (PLC).
cAMP
ATP PIP2 3 IP3
4 3 Adenylate cyclase 3 PLC catalyzes the
Protein
kinase catalyzes the conversion conversion of PIP2
P of ATP to cAMP. into the second
K+channel Ca2+ messenger IP3.
channel
K+ 4 The cAMP activates a 4 Ca2+
protein kinase that 4 IP3 causes the release of
5 phosphorylates and Ca2+ from intracellular
Voltage-gated
Ca2+channel closes a K+ channel. stores.
Ca2+
5 The resulting 5 The influx of Ca2+
depolarization opens causes neurotransmitter
6 Taste voltage-gated Ca2+ 5 Taste release.
receptor channels. receptor
cell cell
Afferent 6 The influx of Ca2+ Afferent
neuron causes neurotransmitter neuron
release.
(c) Sweet (d) Bitter

Figure 11 Signal transduction in taste receptor cells (a) Signal transduction
for salty substances. (b) Signal transduction for sour substances. (c) Signal transduction for
sweet or umami substances. (d) Signal transduction for bitter substances.
289
Sensory Systems
These channels appear to be Na⫹ channels that through a variety of signal transduction mecha-
open in response to changes in pH. nisms, unlike odor receptor proteins, which are al-
The signal transduction pathway for sweet- ways coupled to G proteins. Each taste receptor
taste receptors is summarized in Figure 11c. Sweet cell expresses more than one kind of taste recep-
substances such as sugars bind to G-protein-cou- tor protein, unlike olfactory neurons, which each
pled receptors at the apical cell surface, and acti- express only a single olfactory receptor protein.
vate the G protein gustducin, which signals Unlike olfactory receptor cells, which are bipolar
through an adenylate cyclase signal transduction sensory neurons, taste receptor cells are epithelial
pathway. The receptors for “sweetness” have re- cells that release neurotransmitter onto a primary
cently been identified in mice. These receptors are afferent neuron, and a single taste neuron may
sensitive to many kinds of sweet substances, in- synapse with more than one taste receptor cell,
cluding monosaccharides, polysaccharides, high- suggesting that coding of taste information may be
potency sweeteners, and some amino acids. This very complex. Thus, coding in the gustatory sys-
suggests that the sweet-taste receptors are broad- tem is unlikely to operate via a mechanism in
spectrum receptors that do not discriminate which a neuron is responsible for a single partic-
among alternative sweet substances. Some sweet ular taste sensation. Instead, it is probable that
substances (in particular, strong artificial sweeten- each taste is coded by the complex pattern of ac-
ers such as saccharine) may also activate an IP3- tivity across many neurons, and the code for per-
mediated signal transduction cascade, which ception of tastants must be quite different from the
leads to the closing of K⫹ channels and depolariza- code for perception of odorants. However, despite
tion of the receptor cell. the fact that olfaction and gustation are very differ-
The taste umami, which is caused by L-glutamate ent from a physiological perspective, they work to-
and other amino acids present in foods, as well as the gether closely, and our perception of the taste of a
food additive MSG, can be detected by two different substance is dependent on our sense of smell.
kinds of receptors, one that is similar to the recep-
tors responsible for detecting sweetness and an-
other that is similar to the glutamate receptors
Taste reception differs between
found in the brain. When glutamate binds to this
vertebrates and invertebrates
modified glutamate receptor, the receptor under- Taste receptors in arthropods are located in sen-
goes a conformational change, activating an associ- silla that are structurally similar to olfactory sen-
ated G protein. The G protein then activates a silla. Gustatory sensilla are found on many parts of
phosphodiesterase that degrades cAMP into AMP. the insect body including the outside of the pro-
The decreases in cAMP are thought to trigger neu- boscis or mouth, in the internal mouth parts
rotransmitter release, although the precise path- (pharynx), along the wing margin, at the ends of
ways involved have not yet been identified. the legs, and in the female vaginal plates. Like ver-
Bitter-taste receptors appear to be much more tebrates, arthropods can distinguish among the
complex and specific than sweet-taste receptors. primary tastants, but the mechanisms underlying
Humans have at least 25 genes coding for bitter- these taste perceptions are quite different from
taste receptors, and each taste cell that is sensitive those in the vertebrates. Arthropod taste receptor
to “bitterness” expresses many of these genes. cells are bipolar sensory neurons, similar to the
The way in which this complex pattern of expres- neurons involved in olfaction in the vertebrates, and
sion is translated into the perception of bitterness unlike the epithelial cells that synapse with a sen-
is still unknown, although the signal transduction sory neuron in vertebrate gustation. In insects, the
mechanisms within the bitter-taste receptor cells gustatory receptors belong to the G-protein-coupled
have been worked out (Figure 11d). receptor superfamily, similar to the olfactory re-
ceptors of vertebrates. There are approximately
60 members of the gustatory receptor gene family
Coding differs between the olfactory in the Drosophila genome, suggesting substantial
and gustatory systems functional complexity. In Drosophila, each gusta-
There is considerable debate among sensory neu- tory neuron appears to express only a single recep-
robiologists as to how the perception of a taste is tor protein, quite unlike the situation in mammals
coded in the brain. Taste receptor proteins act in which each gustatory receptor cell expresses
290
Sensory Systems
several different receptor proteins. These data ance, and it plays a critical role in regulating blood
suggest that, at least in Drosophila, the gustatory pressure in the vertebrates. Most mechanoreceptor
code may be combinatorial, similar to the olfac- cells are small and widely dispersed, making it chal-
tory code of mammals. lenging to use traditional biochemical approaches to
The mechanisms of gustation clearly differ be- isolate the proteins responsible for mechanosensory
tween insects and vertebrates, and they differ transduction. Thus, despite decades of investiga-
among invertebrates as well. For example, in tion, the mechanisms by which a mechanoreceptor
nematodes (the only other invertebrate for which converts a mechanical stimulus to an electrical stim-
the molecular basis of gustation has been worked ulus are only now being elucidated.
out in detail), many receptor proteins are ex- Genetic studies in Drosophila and C. elegans
pressed in each neuron, similar to the situation in have demonstrated that there are two main types
mammals, and different from the mechanisms in of mechanoreceptor proteins in animals: ENaC
insects. The differences between the mechanisms (epithelial sodium channels) and TRP (transient
of gustation in vertebrates and among inverte- receptor potential) channels (Figure 12). Although
brates suggest that gustatory organs must have these channels were first identified in inverte-
evolved independently several times. brates, they have recently been isolated from
Extracellular
2 CO NC E P T C HE C K anchor
6. Compare and contrast olfaction ENaC Extracellular link

and gustation in the vertebrates. channel
7. What would happen to the ability
to smell if a drug that inhibited
adenylate cyclase were applied
to the olfactory epithelium of a Cuticle Membrane of
vertebrate? Would this drug affect Intracellular mechanosensory
the sensing of pheromones if link neuron
applied to the vomeronasal
epithelium? Justify your answer. Mechanosensory Cytoskeleton
8. How would the response of a neuron
taste receptor cell differ between (a) ENaC channels in a C. elegans touch receptor
a food that is slightly salty and a
food that is very salty? How
would this affect action potential Extracellular
generation in the afferent anchor
neuron?
TRP Extracellular link
channel
Sensilla
Mechanoreception Membrane of
Cuticle Intracellular mechanosensory
Mechanoreceptors are specialized Supporting link neuron
cells or organs that can transform cells
mechanical stimuli, such as pressure Mechanosensory Cytoskeleton

neuron
changes, into electrical signals that
can then be interpreted by the rest of (b) TRP channels in a Drosophila touch receptor
the nervous system. All organisms, Figure 12 Mechanosensory protein complexes (a) C. elegans touch
and probably all cells, have the ability receptors contain mechanosensory neurons with ENaC-type channels in their
to sense and respond to mechanical membranes. (b) Drosophila touch receptors contain mechanosensory neurons with
TRP-type channels in their membranes. In both cases, mechanical stimuli cause the
stimuli. Mechanoreception is impor-
extracellular anchors to move relative to the cytoskeleton, pulling on the channel and
tant for cell volume control, and the causing a conformational change that opens or closes the channel, changing the
senses of touch, hearing, and bal- membrane potential of the cell.
291
Sensory Systems
the mechanoreceptors in the ears and skin of ver- Merkel's

tebrates, suggesting that they play an important Free nerve disks
endings
role in all forms of mechanoreception. Both ENaC
and TRP-like mechanoreceptor proteins are at-
tached to the cytoskeleton and to extracellular
matrix proteins. Mechanical stimuli such as touch
and pressure move the extracellular anchoring
proteins, pulling on the ion channel and causing
a conformational change that alters the move-
ment of ions across the membrane, changing the
membrane potential of the cell, and allowing the
cell to transduce mechanical signals into electri-
cal signals.
Touch and Pressure Receptors

The mechanoreceptors that detect touch and pres-
sure can be grouped into three classes. Baro-
receptors detect pressure changes in the walls of Root Pacinian
blood vessels, parts of the heart, and in the diges- hair corpuscle
plexus Ruffini
tive, reproductive, and urinary tracts of verte- corpuscle
brates. Tactile receptors detect touch, pressure,
Figure 13 Touch and pressure receptors in
and vibration on the body surface. Both verte- vertebrate skin Skin mechanoreceptors may be free
brates and invertebrates have tactile receptors, al- nerve endings or sensory neurons associated with complex
though their structure and function vary accessory structures.
substantially between these groups.
Proprioceptors monitor the position of the body, The nerve endings of the root hair plexus,
and are found in both vertebrates and inverte- which are wrapped around the base of hair folli-
brates, although like the tactile receptors, their cles, monitor movements across the body surface.
structures vary greatly between these groups. When a hair is displaced, the movement of the hair
follicle causes the sensory nerve endings to stretch,
stimulating mechanoreceptor proteins on the den-
Vertebrate tactile receptors are widely dritic membrane. These receptors are rapidly
dispersed adapting phasic receptors, so they are most sensi-
Vertebrate tactile receptors are isolated sensory tive to changes in movement. For example, you can
cells embedded in the skin (Figure 13). Some of often sense when an insect crawls across your skin,
these receptors are simply free nerve endings that but you may not detect an insect that is not moving.
are interspersed among the epidermal cells of the Pacinian corpuscles are located deep within
skin, whereas others are associated with accessory the skin and in the muscles, joints, and internal or-
structures. Merkel’s disks are free nerve endings gans. At almost a millimeter in length, they are ac-
that are associated with an enlarged epidermal cell tually visible to the naked eye in sections of skin,
called the Merkel cell. These receptors have a very and a typical human hand contains as many as 400
small receptive field, and are used for fine tactile of these receptors. Pacinian corpuscles contain a
discrimination. Both the free nerve endings and sensory dendrite surrounded by up to 70 layers of
Merkel’s disks are slowly adapting tonic receptors tissue with a viscous gel between them. These lay-
that are most sensitive to indentation of the skin, ers, called lamellae, are actually modified Schwann
and are thus important for sensing light touch and cells and layers of connective tissue. When
pressure on the surface of the skin. We use the something presses on a Pacinian corpuscle, the
Merkel’s disks in our skin when we perform tasks, lamellae change shape, changing the shape of the
such as reading Braille letters, that require very fine sensory dendrite and initiating a change in the
discrimination. membrane potential. The viscous gel quickly re-
turns to its original position, even in the presence of
292
Sensory Systems
continuous pressure, returning the membrane po- Proprioceptors typically do not adapt to stimuli,
tential to its resting level. As a result, the sensation and thus constantly send information to the cen-
of pressure disappears even though the pressure is tral nervous system regarding body position. An-
still present at the surface of the skin. When the other class of more rapidly adapting receptors is
pressure is removed, the connective tissue layers responsible for detecting movement, and provides
return to their normal shape, pulling on the nerve the sense of kinesthesia.
ending, which causes another change in membrane
potential, and another stimulus. Thus, Pacinian
corpuscles are rapidly adapting sensory receptors
Insects have several types of tactile
that are sensitive to both the beginning and end of
and proprioceptors
a stimulus. This property makes Pacinian corpus- Insects and other arthropods are encased in a
cles especially sensitive to vibrations. So when you hard exoskeleton, so their sense of touch cannot
feel your cell phone vibrating, it is your Pacinian function via free nerve endings in the body sur-
corpuscles that detect the incoming call. Pacinian face, as is the case for the touch receptors in the
corpuscles have relatively large receptive fields, vertebrates. Instead, most insect touch receptors
and thus do not allow for fine-scale discrimination are grouped into complex organs called trichoid
of touch sensations. sensilla that consist of a hairlike projection of the
Ruffini corpuscles are located in the connec- cuticle associated with a bipolar sensory neuron
tive tissue of the skin and with the connective tis- (Figure 14a). When the hair bends in the socket of
sue of the limbs and joints. They are sensitive to a trichoid sensillum (as a result of a touch or vibra-
stretching of the skin and movement of the joints tion), accessory structures transfer the movement
as we move around. Ruffini corpuscles work to-
gether with other proprioceptors to help an ani-
mal determine the location of its body in space.
When you hit the snooze button on your alarm
Hairlike projection
clock without even opening your eyes, it is your
Ruffini corpuscles that helped you do so!
Cuticle
Vertebrate proprioceptors monitor body Accessory structure
position Dendrite of sensory neuron

In addition to touch and pressure receptors such
as Ruffini corpuscles, there are three major groups Bipolar sensory neuron
of vertebrate proprioceptors associated with the
joints and limbs:
1. Muscle spindles on the surface of skeletal (a) Trichoid sensilla

muscles monitor the length of the muscle.
Dome-shaped projection Accessory structure
Each muscle spindle consists of modified mus-
Cuticle
cle fibers called intrafusal fibers enclosed in a
connective tissue capsule.
2. Golgi tendon organs are located at the junction Dendrite of sensory neuron
between a skeletal muscle and a tendon.

These receptors are stimulated by changes in Bipolar sensory
neuron
the tension in the tendon.
3. Joint capsule receptors are located in the cap-
sules that enclose the joints. Several types of (b) Campaniform sensilla
receptors are in this category, including recep-
Figure 14 Variation in the structure of insect
tors similar to free nerve endings, Pacinian sensilla (a) A trichoid sensillum is associated with a
corpuscles, and Golgi tendon organs. These hairlike projection of the cuticle. (b) A campaniform
receptors detect pressure, tension, and move- sensillum is associated with a dome-shaped projection
ment in the joint. of the cuticle.
293
Sensory Systems
to the tip of the bipolar sensory neuron located be-

neath the hairlike projection. The movement opens
stretch-sensitive TRP ion channels in the mem-
brane of the mechanoreceptor neuron, changing
the membrane potential, and sending a signal in the
form of action potentials to the insect’s nervous sys-
tem. Trichoid sensilla can be extremely sensitive,
detecting even small changes in air movements. In- Cuticle
sects use their trichoid sensilla to detect the air
movements caused by the motion of a predator, and
can use this information to take evasive actions (ex-
plaining why it is so difficult to swat a fly!). Attachment cell
(cap cell)
Insects use another type of sensillum on the ex-
ternal surface of the cuticle, called a campaniform
sensillum, for proprioception (Figure 14b). Cam-
Dendritic cilium
paniform sensilla resemble trichoid sensilla except
that they lack the hair shaft and instead are cov- Scolopale cell
ered with a dome-shaped section of thin cuticle.
Dendrite of
They are usually found in clusters, particularly on sensory neuron
or near the joints of the limbs, and detect the de-
formation of the cuticle as an insect moves. Thus, Sheath cell
campaniform sensilla are critical in allowing an in-
sect to make coordinated movements. Cell body of
sensory neuron
Insects also have a proprioceptor that can de-
tect bending of the cuticle. These proprioceptors
are organized into functional units called scolopidia Axon of
sensory neuron
(Figure 15), which consist of a specialized bipolar
sensory neuron and a complex accessory cell (the Schwann cell
scolopale) that surrounds the ciliated sensory den-

drite at one end. This structure is attached to the Figure 15 Structure of an insect scolopidium
cuticle via a ligament or attachment cell. These Scolopidia are associated with the internal surface of the
cuticle. The bipolar sensory neuron of the scolopidium is
mechanoreceptors can exist as isolated cells or may
surrounded by sheath cells and scolopale cells. The
be grouped to form complex organs called attachment (or cap) cell links the complex to the cuticle.
chordotonal organs, which (as we discuss later in
the chapter) form the basis for the sense of hearing
in some insects. volved in the senses of equilibrium and hearing.
Insects also have a variety of internal The sense of equilibrium, sometimes called the
mechanoreceptors that function as stretch recep- sense of balance in humans, involves detecting the
tors and proprioceptors. Unlike the mechanore- position of the body relative to the force of gravity.
ceptors associated with the cuticle, these receptors The sense of hearing involves detecting and inter-
are not organized into complex organs, and do not preting sound waves. In the vertebrates the ear is
contain ciliated bipolar neurons. Instead, these the organ responsible for both equilibrium and
mechanoreceptors are usually isolated multipolar hearing. In invertebrates, however, the organs of
neurons associated with muscle and connective equilibrium are entirely separate from the organs
tissue. These mechanoreceptors use ENaC chan- of hearing.
nels for signal transduction.
Statocysts are the organ of equilibrium for

invertebrates
Equilibrium and Hearing Many invertebrates have organs called statocysts
In addition to detecting touch, pressure, and the that they use to detect the orientation of their bod-
location of the limbs, mechanoreceptors are in- ies with respect to gravity (Figure 16). Statocysts
294
Sensory Systems
Vertical crista
Statoliths Anticrista
Ciliated Transverse crista

sensory
neurons
Macula
(a) Lobster statocyst (b) Octopus statocyst
Figure 16 Invertebrate organs of equilibrium simple statocysts. (b) Cephalopod molluscs have complex
Statocysts contain ciliated sensory neurons and calcified statocysts that consist of three cristae, oriented in different
statoliths. When a mechanical stimulus such as a change in planes, with a sac called the macula at the base. The cristae
body orientation disturbs the statoliths, their motion detect angular acceleration, while the macula detects
stimulates receptor proteins on the cilia of the sensory forward acceleration, providing the cephalopod with detailed
neurons, depolarizing the cell. (a) Most invertebrates have information about body position and movement.
are hollow, fluid-filled cavities that are lined with

Insects use a variety of organs for hearing
mechanosensory neurons, and contain dense par- There is a great deal of variation in the ability to
ticles of calcium carbonate called statoliths. When hear among insect species; some species lack spe-
the orientation of the animal changes, the statolith cialized organs for detecting sound, while others
moves across the sheet of mechanoreceptors. This have specialized “ears” in several locations. The
movement stimulates the mechanoreceptive cells, simplest type of insect ear is composed of groups
sending a signal to the nervous system. This signal of modified trichoid sensilla. Sound waves (which
provides a cue about the position of the body rela- represent vibrations carried in air) cause these
tive to gravity. Most marine invertebrates have rel- thin sensilla to bend, and send a signal to a bipo-
atively simple statocysts (as shown in Figure 16a), lar sensory neuron. However, this type of ear is not
but cephalopod molluscs, such as the octopus, particularly sensitive, and most insect ears are de-
have a particularly complicated statocyst system rived from the chordotonal organs that insects use
(Figure 16b). An octopus has two statocysts, one on for proprioception.
each side of the head. Each statocyst is composed of Many insects, including cockroaches, honey-
a globelike structure called the macula, and three bees, and water striders use a modified chordo-
cristae, each oriented in a different plane. The tonal organ called the subgenual organ to detect
cristae and macula contain statoliths that move in vibrations carried through the ground (or the sur-
response to mechanical stimuli. The crista detects face of the water in the case of a water strider), and
angular acceleration, or the turning of the body, in at least some species, these subgenual organs
while the macula detects linear acceleration, or the may also be able to detect sound waves (which rep-
degree of forward motion. This system is analogous resent vibrations carried in air). Subgenual organs
to the organs of equilibrium in the vertebrates. are located inside the insect leg. Vibrations of the
295
Sensory Systems
leg cause the subgenual organ to vibrate, opening a

mechanosensitive ion channel on the sensory neu- Tip link
ron within the chordotonal organ, initiating action
potentials that send a signal to the integrating cen- Stereocilia
ters of the nervous systems. Kinocilium
An alternative type of insect ear is a modified
chordotonal organ called the Johnston’s organ,
which is located at the base of the antennae of
many insects, including moths, fruitflies, honey-
bees, and mosquitoes. Sound waves bend fine
hairs on the antennae, stretching the membrane
of the cells within the underlying chordotonal or-
gan, opening mechanosensitive ion channels, and
Hair cell
initiating action potentials in the mechanosensory
neuron. These insects use Johnston’s organ to de- Nucleus
tect sounds such as mating calls.
The most sensitive insect ears are called
tympanal organs. A tympanal organ consists of a
very thin region of the cuticle, called the tympanum,
located over an air space similar to the air space
in a drum. Sound waves cause the thin tympanum
to vibrate, causing the air within the air space to
Afferent sensory
vibrate. A chordotonal organ in this air space de- neuron
tects these vibrations, and sends signals in the
Figure 17 The structure of a vertebrate hair
form of action potentials to the nervous system. cell Vertebrate hair cells (except those in the ears of adult
Tympanal organs are found on many locations on mammals) have a long kinocilium and several short
the insect body, including the legs, abdomen, tho- stereocilia. The kinocilia and stereocilia are connected to
rax, and wing base. each other via tip links and a variety of other structures that
cause the stereocilia to work together as a bundle.
Vertebrate organs of hearing and reocilia are actually microvilli that contain poly-
equilibrium contain hair cells merized actin molecules. There are hundreds of
The vertebrate organs that are involved in the actin filaments along most of the length of a stere-
senses of hearing and equilibrium contain multiple ocilium, but there are far fewer (only a few dozen)
mechanosensory cells and accessory structures. at the base of the stereocilium. As a result, stere-
Unlike the mechanoreceptor cells that we have dis- ocilia taper at their bases, having the appearance
cussed so far, in these organs the mechanoreceptor of pencils balanced on their points.
cells are not themselves sensory neurons, but in- The hair cells in the ears of adult mammals
stead contain modified epithelial cells that synapse lack the kinocilium, suggesting that the kinocilium
with a sensory neuron. These highly specialized is not necessary for mechanoreception. Instead,
sensory receptor cells have extensive extracellular the stereocilia play a critical role in mechanosen-
structures associated with them and are termed sory transduction. The stereocilia and kinocilium
hair cells because of the prominent cilia that ex- (when present) are arranged in a tight bundle,
tend from the apical end of each cell (Figure 17). with the shortest stereocilia placed farthest away
Most vertebrate hair cells have a single long from the kinocilium in the bundle, and with the
cilium, the kinocilium, and many shorter projec- stereocilia gradually becoming taller the closer
tions, called stereocilia. Invertebrates also have they are to the kinocilium. The stereocilia are con-
mechanoreceptors that are similar to hair cells, nected to each other and the kinocilium by a series
but these cells can contain between 1 and 700 of small fibers that cause the bundle of hair cells to
kinocilia. The kinocilium of a vertebrate hair cell is act as a single unit. One particular type of these
a true cilium with a 9 ⫹ 2 arrangement of micro- fibers, called a tip link, connects the top of each
tubules, although it is nonmotile, but the ste-
296
Sensory Systems
shorter stereocilium to the side of the adjacent tect not just movement, but the direction of that
taller one. These tip links are thought to play a movement. The change in the membrane potential
critical role in sound transduction. of the hair cell is also asymmetric—the change is
Mechanosensitive ion channels localized near larger in one direction than the other.
the tips of the stereocilia are involved in sound trans-
duction (Figure 18). These channels are thought to
be members of the TRP family of channels, although
Tip links are critical for mechanosensory
the precise identity of the mechanosensitive channel
transduction
in the vertebrate hair cell is currently somewhat So far, we have not discussed how the
debated. At rest, about 15% of these mechanosen- mechanosensitive channels on the stereocilia are
sitive ion channels are open, yielding a resting opened and closed by the pivoting movement of
membrane potential of about ⫺60 mV. Under the stereocilia. Experiments using chemicals that
these conditions, a modest number of voltage- destroy the tip links that connect adjacent ste-
gated Ca2⫹ channels are open on the hair cell, reocilia indicate that removing the tip links abol-
causing some release of neurotransmitter onto ishes mechanosensory transduction, and that
the primary afferent neuron, and a modest fre- transduction is restored once the tip links regen-
quency of action potentials in the afferent sensory erate. These results suggest that the tip links play
neuron. a critical role in detecting mechanical stimuli. The
When a hair cell is exposed to a mechanical tip links are proposed to function as part of a
stimulus such as a vibration, the stereocilia pivot “gating spring” mechanism that physically pulls
about their bases, acting as rigid rods that do not the channel open. When the stereocilia pivot in
bend. If the movement is toward the kinocilium (or response to a mechanical stimulus, the vertical
longest stereocilium in the hair cells of the mam- distance between the top of adjacent stereocilia
malian ear), mechanosensitive ion channels on the changes; pivoting in one direction increases the
tips of the stereocilia open. These mechanosensi- distance, while pivoting in the other direction de-
tive channels are relatively nonselective, and al- creases the distance. The tip links are ideally
low the passage of a variety of ions, including K⫹ placed to detect these changes. Increasing the
and Ca2⫹. However, at least in the hair cells of the vertical distance pulls on the tip links, whereas
vertebrate ear, the extracellular fluid around the decreasing the vertical distance pushes on the tip
hair cell is very high in K⫹. As a result, K⫹ enters links. The tip links are connected to the mechan-
the hair cell down its concentration gradient, ically gated ion channels on the stereocilia via a
causing the hair cell to depolarize by about 20 mV. series of elastic connector proteins that act as
This depolarization opens voltage-gated Ca2⫹ springs that either pull open the channel or push
channels on the membrane of the hair cell, allow- it closed, depending on the direction of movement
ing additional Ca2⫹ to enter the cell (compared to of the stereocilia.
the resting state), increasing the exocytosis of neu-
rotransmitter from the hair cell onto the afferent
neuron, and increasing the frequency of action po-
Hair cells are found in the lateral line and
tentials in the afferent neuron.
ears of fish
If the movement of the stereocilia is in the Hair cells are found in a variety of mechanosensi-
other direction, the mechanosensitive channels tive organs. For example, fish, larval amphibians,
close. The closed channels prevent K⫹ from enter- and adult aquatic amphibians have structures
ing the cell and cause the hair cell to hyperpolar- called neuromasts that can detect water move-
ize by about 5 mV (relative to the resting state), ments, such as those caused by potential predators
decreasing the release of neurotransmitter and or prey as they move through the water. Neuro-
the frequency of action potentials in the sensory masts consist of hair cells (from a few to over a
neuron. Note that these sensory neurons associ- hundred, depending on the species) and accessory
ated with a hair cell fire action potentials all the supporting cells encased in a gelatinous cap (Fig-
time; neurotransmitter release from the hair cell ure 19). Neuromasts are found in the skin, either
simply increases or decreases the frequency of scattered over the body surface or grouped in partic-
these action potentials depending on the direction ular areas (often at the anterior end of the animal).
that the stereocilia move. Thus, hair cells can de- Most fish species (and some aquatic amphibians)
297
Sensory Systems
Mechanically-
gated cation K+
channels K+
(TRP) K+ K+
K+
K+
K+
K+
K+ K+
Voltage-gated
Ca2+ channels
Ca2+
Ca2+
Ca2+
Ca2+
Neurotransmitter
Primary
Recording afferent
electrode neuron
+30 +30 +30

–60 –60 –60
Time (msec) Time (msec) Time (msec)

(a) At rest (partially depolarized) (b) Depolarized (c) Hyperpolarized
Figure 18 Signal transduction in a vertebrate Ca to enter the cell. The influx of Ca2⫹ causes increased
2⫹
hair cell (a) At rest the hair cell is slightly depolarized release of neurotransmitter onto the primary afferent
and releases moderate amounts of neurotransmitter onto neuron, increasing the frequency of action potentials.
the primary afferent neuron, causing an intermediate (c) When a pressure signal causes the stereocilia to pivot
frequency of action potentials. (b) When a pressure signal away from the kinocilium, the mechanically gated channels
causes the stereocilia to pivot toward the kinocilium, on the stereocilia close, hyperpolarizing the cell and closing
mechanically gated channels on the stereocilia open, voltage-gated Ca2⫹ channels. The resulting reduction in
allowing additional K⫹ to enter the cell from the extracellular intracellular Ca2⫹ decreases the release of neurotransmitter
fluid, which has a high concentration of K⫹. The resulting onto the primary afferent neuron, reducing the frequency of
depolarization opens voltage-gated Ca2⫹ channels, allowing action potentials.
298
Sensory Systems
Lateral line structure of a representative mammalian ear.

The external structures are called the outer ear
and in mammals consist of the pinna, which
forms the distinctive shapes of mammalian ears,
and the auditory canal. The auditory canal leads
to the middle ear, which contains a series of small
bones that transfer sound waves to the inner ear.
The inner ear is embedded within the skull and
consists of a series of fluid-filled membranous sacs
and canals. Most nonmammalian vertebrates lack
obvious outer ears, and fish lack both outer and
middle ears, but all vertebrates have an inner ear.
It is the inner ear that contains the mechanosensi-
tive hair cells that play a role in hearing and the
Cupula sense of equilibrium.
(filled with
viscous gel)
The vestibular apparatus is the organ
of equilibrium in vertebrates
The vestibular apparatus of the inner ear detects
Hair cell movements or changes in body position with re-
spect to gravity and is thus responsible for the sense
of equilibrium or balance. In all craniates, except
Primary the lampreys and hagfish, the vestibular apparatus
afferent
neurons consists of three semicircular canals with an en-
larged region at one end (called the ampulla), and
Figure 19 Structure of a vertebrate neuromast
Neuromasts are cup-shaped sensory organs. In aquatic
organisms, neuromasts are found either scattered across the
surface of the skin or grouped into structures such as the
lateral line. When a mechanical stimulus contacts the cupula
of a neuromast, the gel within the cupula shifts, stimulating
the hair cells. The hair cells release neurotransmitter onto Pinna
primary afferent neurons, sending a signal to the rest of the
nervous system.
have a conspicuous array of neuromasts arranged

in a line along both sides of the body. This lateral
line system consists of either pits (ampullae) or
tubes running along the side of the animal’s body
and head. The lateral line system allows fish to de- Middle ear
tect changes in water pressure, such as those caused
Stapes Semicircular
by the movements of other fish. In some species, the canals
Incus Inner
lateral line system has been modified to allow elec- Malleus Cochlea ear
troreception (see Box 1, Evolution and Diversity:
Electroreception, for more details on the functions
Auditory canal Auditory tube
of electroreception).
Vertebrate ears function in hearing Outer ear

Tympanic Middle ear
and equilibrium membrane cavity
Hair cells are also found within the ears of verte- Figure 20 The structure of the mammalian ear
brates, where they participate in the senses of Mammalian ears consist of an outer ear, a middle ear, and
hearing and equilibrium. Figure 20 shows the an inner ear.
299
Sensory Systems
two saclike swellings called the utricle and the Semicircular Semicircular
canals canals
saccule (Figure 21). In most vertebrates, the sac-
cule also contains a small extension called the
lagena. In birds and mammals, the lagena is
Utricle
greatly extended and is called the cochlear duct (in
birds), or the cochlea (in mammals). The utricle, Utricle
Ampulla
Ampulla
saccule, and the ampullae of the semicircular Lagena
canals contain mechanoreceptive hair cells that are Saccule Saccule
Lagena
involved in the sense of equilibrium. The cochlea
also contains hair cells, but it is involved in hearing (a) Teleost fish (b) Frog
and is not a part of the vestibular apparatus.
The mechanoreceptors of the ampullae and Semicircular Semicircular
the vestibular sacs differ. The utricle and saccule canals canals
contain a series of mineralized otoliths suspended
in a gelatinous matrix above a membrane called
the macula that is densely covered with more than
100,000 hair cells (Figure 22). The ampullae of the Utricle
Utricle
semicircular canals lack otoliths, and instead con- Saccule
tain cristae that consist of hair cells located within Ampulla
a cup-shaped gelatinous mass called the cupula. Saccule
Cochlear Cochlea
The cristae of semicircular canals detect angular duct
acceleration, and motion in circular patterns, such
as when you shake your head. In contrast, the
(c) Bird (d) Mammal
maculae of the vestibular sacs detect linear accel-
eration, or motion along a line, and are stimulated Figure 21 Vertebrate inner ears The inner ear in
most vertebrates consists of three semicircular canals
when the body is in a tilted position.
arranged in planes at right angles joined at their base by a
When you move your head to one side, the swelling called the ampulla, and a series of sacs including
otoliths and the gelatinous masses of the maculae the utricle and the saccule. In many vertebrates, the floor of
in the utricle and saccule induce a drag on the hair the saccule contains a small pocket called the lagena. In
birds and mammals, the lagena is greatly extended to form
cells, stimulating them. The macula of the utricle
the cochlear duct or cochlea.
is oriented horizontally in the ear, and can detect
motion in the horizontal plane (Figure 23a–d). The
macula of the saccule is oriented vertically, so it sates by altering posture in order to maintain your
can detect motion in the vertical plane. Within the position.
utricle and saccule, the hair cells are oriented in In contrast to the vestibular sacs, which detect
two different directions so that a single sheet of whether the body is tilted, the semicircular canals
hair cells can detect motion forward and back or detect angular acceleration (Figure 24). Most ver-
side-to-side, covering two dimensions of move- tebrates have three semicircular canals that are
ment. The utricle can also detect tilting of the head arranged perpendicular to each other, so that each
(Figure 23e). When you tilt your head, gravity canal detects acceleration in a single plane. When
pulls on the gelatinous mass of the sacs, which you turn your head in the plane of a particular
stimulates particular subsets of the hair cells, de- canal, the fluid in that canal is set in motion. Be-
pending on the direction of the tilt. Since different cause of the inertia of the fluid there is a difference
hair cells are stimulated by a forward and a back- between the movement of the fluid and the move-
ward tilt, the brain can determine the direction of ment of the wall of the canal, causing the fluid to
the tilt. The intensity of the hair cell response is re- slosh against the ampulla, stimulating the hair
lated to the angle of tilt, so the brain can also de- cells. Because each canal is oriented in a different
termine the degree of tilt. The vestibular sacs play plane, acceleration of the fluid in a particular canal
an important role in maintaining the orientation depends on the plane of the movement, allowing
of the body with respect to gravity. If your head the vestibular system to sense the direction of
and body start to tilt, the vestibular sacs send a movement by comparing the degree to which the
signal to the brain, which automatically compen- hair cells in each canal are stimulated.
300
Sensory Systems
Balance and body orientation depend on in-

puts from the visual system, proprioceptors, and
the inner ear. You can observe this effect if you ask
someone to try to stand still with his or her eyes
Macula of
utricle closed. It is almost impossible to do—you will no-
tice that your subject makes small movements and
Macula of rocks back and forth. The semicircular canals also
saccule play an important role in keeping your eyes ori-
ented on a single point even when your head is
moving. For example, if you try to read this text
Otolith while nodding or shaking your head, you should
have little difficulty reading the words. In contrast,
if you quickly move the book in front of your face
Gelatinous
matrix while holding your head still, you will likely find it
difficult to read the words.
Hair cell
The inner ear detects sounds
In addition to detecting body position, the inner
Supporting
cell ear detects sounds. In fish, incoming sound waves
cause the otoliths in the vestibular sacs to move,
(a) Macula of an utricle or saccule causing the stereocilia of the hair cells to pivot,
and stimulating the auditory neurons. Some fish
use their swim bladder to help amplify the sounds
coming to the inner ear. The clupeids (fish in the
herring family) have a gas duct that connects the
swim bladder to the hearing system. Sounds cause
the swim bladder to vibrate, and this vibration is
passed through the gas duct to the ear. Clupeid fish
such as shad use their excellent hearing to detect
Cupula in the echolocation sounds produced by whales and
ampulla
dolphins (their main predators).
In carp, the swim bladder is connected to the
inner ear via a system of bones called the
Weberian ossicles (Figure 25). Carp have excellent
hearing because the Weberian ossicles transmit
Wall of sounds to the inner ear.
ampulla
Cupula In terrestrial vertebrates, hearing involves

the inner, middle, and outer ears
Hair cell Sound does not travel as well in air as in water,
Supporting and much of the sound that travels through air is
cell simply reflected when it contacts an object with
(b) Crista of an ampulla much higher density, such as the body of an ani-
mal. As a result, sound transfers poorly between
Figure 22 The mechanoreceptors of the inner ear
air and the fluid-filled inner ear. To compensate,
(a) The mechanoreceptors of the utricle and saccule are found
in structures called maculae. The hair cells of each macula the ears of terrestrial animals have a number of
are embedded in a gelatinous matrix that is overlain with a specializations to increase sound detection. In
series of otoliths. (b) The mechanoreceptors of the mammals, the pinna of the outer ear acts as a fun-
semicircular canals are located in the ampullae in structures
nel that collects sound waves in the air from a
called cristae. Cristae are similar in structure to the
neuromasts shown in Figure 19, consisting of hair cells large area, concentrating them onto the auditory
embedded in a cup-shaped gelatinous mass called the cupula.
301
Sensory Systems
Otoliths
Gelatinous layer
Hair cell
Supporting cell
(a) Hair cells of the utricle

potential (mV)
potential (mV)
Membrane
Membrane
Time Time
(b) Rest or constant motion (c) Forward acceleration
potential (mV)
potential (mV)
Membrane
Membrane
Time Time
(d) Backward acceleration (e) Head tilted forward
Figure 23 Functions of the utricles in mammals on the stereocilia, which depolarizes the cell, increasing its
(a) The hair cells of the utricles are overlain with a gelatinous release of neurotransmitter and thus increasing the
layer topped with bony otoliths. (b) At rest or during constant frequency of action potentials in the primary afferent
motion, the hair cells are partially depolarized. (c) During neurons. (d) During backward acceleration or
forward acceleration, the hair cells pivot toward the longest (e) forward tilt of the head, the stereocilia pivot away from
stereocilium (recall that mammalian hair cells lack a the longest stereocilium, reducing the frequency of action
kinocilium). This bending activates mechanogated channels potentials.
302
Sensory Systems
Semicircular
canal Cupula
(filled with
endolymph)
Neuromast
Stereocilia
Cupula
Hair cell Hair cell

Ampulla
Afferent sensory
neuron
(a) Semicircular canal (b) Ampulla
Semicircular
canal
Pressure Pressure
from endolymph from endolymph
Recording
electrode Ampulla Head rotation Head rotation
potential (mV)
potential (mV)
potential (mV)
Membrane
Membrane
Membrane
Time Time Time

(c) Rest (d) Acceleration to the left (e) Acceleration to the right
Figure 24 Functions of the semicircular canals fluid in the semicircular canal exerts pressure in the opposite
(a) A semicircular canal consists of a fluid-filled tube with a direction, causing the stereocilia of the hair cells to pivot.
swelling, termed the ampulla, at the bottom. Depending on the orientation of the hair cells, this will either
(b) The ampulla contains a neuromast that senses pressure. (d) hyperpolarize the hair cell, decreasing the frequency of
(c) At rest, the hair cells of the neuromast are partially action potentials, or (e) depolarize the hair cell, increasing
depolarized. When the head is rotated in one direction, the the frequency of action potentials.
Inner ear canal. Ears with a larger pinna capture more of

the sound wave for a given sound intensity and
hence receive more sound energy, so animals with
Weberian
ossicles
large external ears typically have excellent hear-
ing. While passing the pinna, sound also goes
through a filtering process. For example, in hu-
mans sounds are enhanced in the frequency range
where human speech is normally found. The filter-
ing process also adds directional information.
Swim
bladder The middle ear plays the most important role
in improving detection of sounds in air. Although
Figure 25 Structure of a carp ear The inner ear is the details of middle ear structure vary substan-
connected to the swim bladder via a series of bones called tially between groups of organisms, the funda-
the Weberian ossicles. mental design principles are similar. The air-filled
303
Sensory Systems
Oval the oval window. Vibrations of the

window oval window transfer the sound
Incus stimulus to the fluid-filled inner ear.
In mammals, the malleus, incus,
Malleus Stapes
and stapes are connected to each
other with the biological equivalent
of hinges, which tend to amplify the
vibrations such that a vibration of
the tympanic membrane as small as
0.1 angstrom (less than the size of a
hydrogen atom) can cause a re-
sponse large enough to stimulate
Round Cochlea
window the hair cells of the inner ear.
Auditory Tympanic
canal membrane
The inner ear of mammals
(a) Middle and inner ear has specializations for sound
detection
Stapes Oval Vestibular Cochlear Organ of
window duct duct Corti The coiled cochlea of mammals is
specialized for sound detection. Fig-
ure 26b shows the cochlea uncoiled,
and from this diagram you can see
that the two outer compartments
(the vestibular and tympanic ducts)
are actually one continuous tube, al-
though early anatomists gave them
two different names because they
Round Basilar Tectorial Hair cells Tympanic appear to be distinct structures in
window membrane membrane duct the tightly coiled cochlea. The
(b) Cochlea (uncoiled for clarity) vestibular and tympanic ducts are
filled with a fluid called perilymph,
Figure 26 Anatomy of the mammalian middle and inner ear
(a) The middle ear contains three small bones (the malleus, incus, and stapes) that
which is similar in composition to
transmit sound waves from the tympanic membrane to the oval window of the cochlea. other extracellular fluids. The
(b) When the cochlea is illustrated uncoiled, it becomes apparent that it consists of a cochlear duct is filled with a fluid
bent tube leading from the oval window to the round window. The top portion of the called endolymph that is quite
tube is called the vestibular duct and is lined with the vestibular membrane. The
bottom of the tube is called the tympanic duct and is lined with the organ of Corti,
different from other extracellular
which contains hair cells embedded in the basilar membrane. fluids, being high in K⫹ and low in
Na⫹. The organ of Corti contains
middle ear is separated from the outer ear by the the hair cells and sits on the basilar membrane
tympanic membrane and from the fluid-filled in- that lines one side of the cochlear duct. Vertebrate
ner ear by the oval window (Figure 26a). Within inner ears contain several types of hair cells that
the middle ear are one or more small bones that perform slightly different auditory functions. In
together span the space from the tympanic mem- mammals, these types are called the inner hair
brane to the oval window. Mammals have three of cells and the outer hair cells. Inner hair cells de-
these bones, called the malleus (hammer), the tect sounds, and outer hair cells help to amplify
incus (anvil), and the stapes (stirrup). Sound sounds.
waves traveling through the auditory canal cause Incoming sounds cause the oval window of the
the thin tympanic membrane to vibrate. Vibration inner ear to vibrate, causing waves in the peri-
of the tympanic membrane causes the first of the lymph of the vestibular duct. These waves in the
bones (the malleus in mammals) to vibrate. The vi- perilymph push on the basilar membrane, causing
bration is transferred through the bones (from the it to vibrate. The stereocilia on the inner hair cells
malleus to the incus to the stapes in mammals) to of the organ of Corti pivot in response to the vibra-
304
Sensory Systems

Electroreception
Electroreception, the ability to sense sory organs that are located in a series of pores distrib-
electric fields or weak electrical discharges, is uted across the head. These pores, termed the ampul-
common in aquatic organisms. Aquatic environments lae of Lorenzini after the Italian anatomist who first
are full of electric fields. For example, the flow of water described them in 1678, are filled with an electrically
over objects causes a static electrical discharge. Simi- conductive jelly and lined with modified hair cells. A net
larly, seawater moving over the magnetic field lines of negative charge inside the ampulla causes an electrical
the Earth causes a weak electric field. In addition, all change in each hair cell, triggering the release of neu-
animals produce weak electric fields as a result of the rotransmitters to adjacent clusters of afferent sensory
actions of their muscles and nerves. Thus, aquatic or- neurons. Some sharks, such as the scalloped hammer-
ganisms can use electroreception for detecting both the head shark (Sphyrna lewini), can detect electric fields of
abiotic features of their environment and the presence less than 0.1 nV/cm, equivalent to the electric field of a
of other animals. Sharks have a particularly keen elec- flashlight battery connected to electrodes over 16,000
trical sense. For example, the electrosensitive great km apart in the ocean.
hammerhead shark (Sphyrna mokarran) can detect Although many fish have electroreceptors, and some
buried stingrays by sweeping its wide head over the bot- species of amphibians are thought to have similar ones,
tom of the ocean like a metal detector. none have yet been identified in any species of bird, rep-
Some fish (the so-called weakly electric fish) have a tile, or placental mammal. However, the monotremes
specialized electric organ that can produce electrical (the egg-laying mammals, including the echidna and
discharges, and electroreceptors to detect these dis- platypus) do have electroreceptors. In the platypus, the
charges, which they use to communicate with each electroreceptors are located in the bill. They are bipolar
other. They can also “electrolocate” in their murky envi- sensory neurons, rather than modified epithelial cells
ronments. The discharges of the electric organ produce as in fish, which suggests that the ability to sense elec-
an electric field around the fish. Objects or other ani- tric fields has evolved independently several times.
mals in the environment alter the shape of this electric
References
field. Electric fish can detect these perturbations of the
q Gibbs, M. A., and R. G. Northcutt. 2004. Development of the lat-
electric field and use this information to locate the ob- eral line in the shovelnose sturgeon. Brain, Behavior, and Evolu-
ject, in a process analogous to echolocation in bats. tion 64: 70–84.
In fishes, electroreceptors are modified from the lat- q Kajiura, S. M., and K. N. Holland. 2002. Electroreception in juve-
eral line; however, the hair cells of the electroreceptor nile scalloped hammerhead and sandbar sharks. Journal of Ex-
are highly modified and lack cilia. These modified hair perimental Biology 205: 3609–3621.
cells detect changes in electric fields rather than q Pettigrew, J. D. 1999. Electroreception in monotremes. Journal of
changes in pressure. Sharks have elaborate electrosen- Experimental Biology 202: 1447–1454.
tions of the basilar membrane. As with the hair The basilar membrane is stiff and narrow near
cells in the lateral line of a fish, the tip links connect- its attachment point close to the round and oval
ing the stereocilia pull open the mechanosensitive windows (the proximal end), but wider and more
ion channels in the membrane of the inner hair flexible at the other (distal) end. This differential
cells, causing them to depolarize. The inner hair stiffness helps the cochlea to encode information
cells then release a neurotransmitter, glutamate, about the frequency of a sound. Stiff objects vibrate
that excites sensory neurons to send nerve impulses at higher frequencies than flexible objects. The stiff
down the auditory nerve. In this way, the cochlea proximal end of the basilar membrane vibrates
transduces the pressure waves in the perilymph most in response to high-frequency sounds, while
into electrical signals. The round window of the the flexible distal end of the basilar membrane vi-
cochlea serves as a pressure valve, bulging outward brates most in response to low-frequency sounds.
as fluid pressure rises in the inner ear, which pre- Thus, different areas of the basilar membrane vi-
vents the waves from doubling back through the brate in response to sounds of different frequency,
fluid thus improving sound clarity. transforming a frequency signal carried by the
305
Sensory Systems
sound waves into a spatial signal coded by location The ears can detect sound location
on the basilar membrane. Neurons from each part
The brain uses information from both ears to es-
of the basilar membrane form synaptic connections
timate the location of the stimulus, including the
with neurons in particular areas in the auditory
time lag and differences in sound intensity. If a
cortex of the brain; therefore, specific areas of the
sound comes from one side, the sound waves will
auditory cortex respond to particular frequencies.
not reach both ears at the same time because the
This phenomenon is called place coding.
distance from the sound source is slightly differ-
ent between the two ears. The brain registers the
Outer hair cells amplify sounds time lag, helping to localize the sound. Sounds
coming from one side must also pass through the
Inner hair cells code for sound loudness in much
head to reach the other ear, altering the intensity
the same way as do other mechanosensory cells.
of the sound in that ear. The discrepancy between
Loud noises cause greater movement of the basi-
the sound in the two ears helps to pinpoint the
lar membrane, and greater depolarization of the
sound location. If a sound does not come from the
hair cell, which in turn generates a higher fre-
sides, but rather from above, below, or immedi-
quency of action potentials in the afferent sensory
ately in front of the face, there is no time lag or
neurons. The outer hair cells also play an impor-
discrepancy in intensity between the ears, and it
tant role in the loudness of sounds. Current theo-
is more difficult to determine the location of a
ries of sound transduction in the inner ear suggest
sound. In mammals, the outer ears also help in
that the outer hair cells amplify sounds by increas-
localizing sounds. However, this mechanism is
ing the movement of the basilar membrane for a
not particularly efficient, so most animals move
sound of a given loudness, thus causing a larger
their head or rotate their outer ears in order to
stimulus to the inner hair cells.
better localize the source of a sound.
Outer hair cells perform this amplification func-
tion because, unlike inner hair cells, outer hair cells
change shape in response to sound waves, rather
than releasing neurotransmitter. When the stere- 2 C O N C EP T CH E CK
ocilia of an outer hair cell pivot in response to a
9. What are possible advantages of having both
sound wave, the mechanosensory channels on the tonic and phasic touch receptors in the skin of
stereocilia open, allowing K⫹ to enter the cell. The vertebrates?
resulting depolarization acts as a signal to a volt- 10. Why do insects have complex touch organs,
age-sensitive motor protein, which causes the cell rather than isolated sensory neurons associated
to change shape and pull on the basilar membrane, with the body surface as in mammals?
increasing the amount the basilar membrane 11. What is the functional significance of having a
moves in response to a particular sound. The pro- hairlike projection in the trichoid sensilla of
tein responsible for this change in shape of the insects? Why not simply have a touch receptor
similar to the campaniform sensilla?
outer hair cells has been identified, and if the gene
12. What would happen to sound transduction if the
that codes for this protein (called prestin) is
endolymph of the vertebrate inner ear had high
knocked out in mice, the animals are born pro- [Na⫹] and low [K⫹]?
foundly deaf. Certain types of deafness in humans
13. How does the structure of the basilar membrane
are also caused by mutations in the prestin gene. of the mammalian ear allow fine discrimination
Outer hair cells make contact with very few af- of different sound frequencies?
ferent neurons that carry signals to the brain. In-
stead, they form synapses with efferent neurons
that carry signals from the brain to the ear. These
efferent neurons are part of a feedback loop; they Photoreception
release the neurotransmitter acetylcholine onto the
outer hair cells in response to loud noises, reducing Photoreception is the ability to detect a small por-
the response of the outer hair cells. Since outer hair tion of the electromagnetic spectrum from the
cells normally amplify sounds, this feedback loop near ultraviolet to the near infrared, that is, wave-
acts as a protective mechanism for the inner hair lengths of approximately 300 nm to just greater
cells, which can be damaged by loud noises. than 1000 nm, although most species detect only
306
Sensory Systems
a portion of this range (humans can 1012 nm 109 nm 105 nm 104 nm 102 nm 1 nm 10–2 nm
only detect wavelengths from approx-
Radio TV Micro- Infrared UV X-rays Gamma
imately 350 to 750 nm; Figure 27a). waves rays
Animals lack the ability to detect
other wavelengths of electromag-
netic radiation such as radio waves.
This concentration on a very narrow Visible light
(Detectable by humans)
band of the electromagnetic spec-
trum supports the idea that animals
750 nm 350 nm
evolved in water. The wavelengths
(a) The electromagnetic spectrum
that represent visible light travel rel-
atively well through water, whereas
water blocks most other wave-
(Signal lost per meter underwater)

lengths. Figure 27b shows the de- 104
gree of attenuation, or the amount
of signal lost, for an electromagnetic Attenuation
102
signal that passes through a meter
of water. From this figure, you can
see that water is relatively transpar- 100
ent to violet, blue, and green light,
but that it quickly becomes rather
10–2 Electric Radio TV Microwaves Visible
opaque to yellow, orange, and par- fields
ticularly to red light. A meter of wa-
1015 1013 1011 109 107 105 103 101
ter almost completely blocks far red
Wavelength (nm)
and near infrared light. Only at the
other end of the electromagnetic (b) Attenuation of electromagnetic radiation in water
spectrum, at very long wavelengths, Figure 27 Electromagnetic radiation and the electromagnetic
are signals able to pass through wa- spectrum (a) The types of electromagnetic radiation. (b) Most wavelengths of
ter effectively. Thus, animals living electromagnetic radiation do not travel well through water. Only visible light and very
long wavelength electromagnetic radiation penetrate into deeper water. Animals
in water can use only a narrow detect a narrow band of the electromagnetic spectrum in the visible light range, which
range of the electromagnetic spec- suggests the possibility that photoreceptors evolved in aquatic organisms.
trum. The degree of attenuation of
light also varies depending on the presence of gans such as eyes. Finally, we examine how the
light-absorbing compounds in the water. Some interaction of multiple photoreceptive cells in
aquatic animals, particularly those living in complex eyes allows the formation of images and
light-poor habitats have poor vision, and have the detection of complex image properties such
instead developed the ability to sense electric as color.
fields (Box 1, Evolution and Diversity: Electrore-
ception).
The structure of photoreceptor cells
differs among animals
Two major types of photoreceptor cells are found
Photoreceptors in animals (Figure 28). Ciliary photoreceptors
Photoreceptive organs range in complexity from have a single cilium protruding from the cell, often
single light-sensitive cells to complex eyes that with a highly folded ciliary membrane that forms
can form sharp, focused images. In this section, lamellae or disks that contain photopigments,
we first consider the structure of individual pho- the molecules specialized for absorbing the energy
toreceptive cells, and look at the signal transduc- coming from incoming photons. In contrast, in
tion mechanisms they use to convert an incoming rhabdomeric photoreceptors (also called mi-
photon of light to a change in the membrane po- crovillus photoreceptors) the apical surface that
tential of the cell. Then we look at how these cells contains the photopigments is elaborated into
are put together into complex photoreceptive or- multiple outfoldings called microvillar projections.
307
Sensory Systems
Rhabdomeric receptors Ciliary receptors
Platyhelminthes
Echinodermata
Vertebrata
Tunicata
Ctenophora
Arthropoda
Nemertea
Mollusca
Annelida
Cnidaria
Bryozoa
Rotifera
Chordata
Lophotrochozoa Ecdysozoa
Protostomia Deuterostomia
Radiata Bilateria
Metazoa
Figure 28 Phylogenetic distribution of ciliary and rhabdomeric

photoreceptors There is no clear pattern in the phylogenetic distribution of ciliary
photoreceptors (shown in orange) and rhabdomeric photoreceptors (shown in blue). Many
groups have both kinds of photoreceptors. Vertebrates have only ciliary photoreceptors, and
arthropods have only rhabdomeric photoreceptors.
In addition to these structural differences, ciliary adult animals. The only known exceptions to the
and rhabdomeric photoreceptor cells also differ in predominance of rhabdomeric eyes among the pro-
that they use distinct signal transduction mecha- tostome invertebrates (worms, molluscs, and
nisms for converting the energy carried by incom- arthropods) are a few species of mollusc, such as
ing photons to a change in the membrane the bay scallop Pecten irradians and the file clam
potential of the receptor cell. Lima scabra, in which the adults have eyes that
Both rhabdomeric and ciliary photoreceptors contain both rhabdomeric and ciliary photorecep-
are widely distributed in most animal groups, but tors. The picture in the deuterostomes (echino-
the pattern of the distributions of these types of derms, such as sea urchins, and chordates, such as
photoreceptors among organisms presents a the vertebrates) is also unclear. Most deutero-
rather confusing picture (Figure 28). The majority stomes have rhabdomeric eyes, similar to those of
of invertebrate groups have rhabdomeric photore- the protostome invertebrates. The major exception
ceptors in their eyes. Some invertebrate groups to this rule is the vertebrates, which have only cil-
(such as the molluscs and the platyhelminths) also iary photoreceptors in their eyes. This pattern is
have some ciliary photoreceptors, but these are also seen in the cnidarians (jellyfish and related
generally present only as small, isolated photore- organisms), which also have only ciliary photo-
ceptors, or in very simple photoreceptive organs receptors. This phylogenetic pattern is difficult to
that are located outside the main eyes, or they are interpret based on what we know about the rela-
present only in larval forms and are absent from tionships among living organisms. A recent discov-
308
Sensory Systems
ery that rhabdomeric photoreceptors in some in-

vertebrates pass through a developmental stage in
which they have cilia suggests the possibility that
all photoreceptor cells are derived from an ances-
tral ciliated cell. Alternatively, the bilateral ances- Outer
segment
tor of the protostomes and deuterostomes may
have already possessed two types of photorecep- Disks
tors, one of which may have been lost in some evo-
lutionary lineages (such as the one leading to the
vertebrates). Until the mechanisms of photorecep-
tion are studied in more animal taxa, particularly
among the invertebrates, the evolution of animal
photoreceptor cells is likely to remain an open
question. Inner
segment
Nucleus
Mammals have two types

of photoreceptor cells
Although all vertebrate photoreceptor cells are
ciliary photoreceptors, in mammals they can be Synaptic
terminals
divided into two subclasses, rods and cones (Fig-
Rod Cone
ure 29). Although rods and cones have different photoreceptors photoreceptors
shapes, they share similar features. Both have an
Figure 29 Structure of mammalian ciliary
outer segment composed of a series of membra- photoreceptors—the rods and cones Although
nous disks that contain the photopigments. A con- they differ in shape, rods and cones have the same structural
necting cilium joins the outer segment to the inner components: an outer segment consisting of a series of disks
segment that contains the nucleus. The other end containing the photopigments, an inner segment containing
the cell body, and synaptic terminals that make connections
of this cell forms synaptic connections with other
with neurons in the retina.
cells of the vertebrate eye.
In addition to their morphological differences,
mammalian rods and cones differ functionally in a relatively higher numbers of rod cells in their eyes
number of respects (Table 1). In comparison to for better vision in dim light.
cones, rods typically have more photopigment Many vertebrates have more than one type of
than do cones, have a much slower response time, cone photoreceptor, each having a slightly different
and integrate signals over a longer period. As a re- photopigment that is maximally sensitive to a partic-
sult, rods have a very high sensitivity compared to ular wavelength of light. As we discuss in detail later
cones, but saturate at relatively low light levels. in the chapter, integrating centers compare the rel-
Because of these differences between rods and ative signals from these receptors to allow detection
cones, rods function best in dim light, while cones of colors. You have probably noticed that in dim light
function best in bright light. In fact, in mammals, (such as at twilight), the world appears in shades of
rods are so sensitive that they can respond even to gray. You use your cones for color vision in bright
a single photon. Many nocturnal mammals have light, and your rods for noncolor vision in dim light.
Table 1 Mammalian rods and cones.

Feature Rods Cones
Class of photoreceptor Ciliary Ciliary
Shape Outer segment rod shaped Outer segment cone shaped
Sensitivity Sensitive to very dim light Sensitive to brighter light
Type of photopigment One type Up to three types in mammals
309
Sensory Systems
There is substantial diversity among verte- chromophore is a derivative of vitamin A, such as

brates in the shape of the rods and cones (Fig- retinal, and the associated protein is a member of
ure 30). In fact, in many species it can be difficult the opsin gene family. Opsins are G-protein-coupled
to distinguish between rods and cones based on receptors that are covalently linked to the chro-
cell shape alone. For example, frogs have several mophore. Depending on the particular photore-
types of rod-shaped photoreceptors in their eyes ceptive cell, the photopigment complex is called
that they use to see colors. Thus, the shape of the by different names, including rhodopsin, iodopsin,
photoreceptor cell is not the important character- porphyropsin, melanopsin, pinopsin, and VA
istic that determines whether it is involved in color opsin, among others. All of these photopigments,
vision or dim-light vision. Instead, the properties of however, consist of a vitamin A-derived chro-
a photoreceptor cell depend on the properties of mophore bound to a G protein in the opsin gene
the photopigment that it contains. family. The sensitivity of the chromophore-opsin
complex to particular parts of the light spectrum
differs among these photopigments, as a result of
Chromophores allow photoreceptors
differences in the amino acid sequence of the opsin
to absorb light
protein. Differences in the spectral sensitivity of
Photopigments consist of a pigment called a chrom- the chromophore-opsin combination underlie color
ophore associated with a specific photoreceptor vision.
protein. In the vast majority of photoreceptors, the Although the specific structures of the pho-
topigments vary among photoreceptors, the gen-
eral pattern of their chemical activation is similar.
In the unactivated state, the chromophore is pres-
ent in the cis conformation. When the chromophore
absorbs the energy of incoming light, it undergoes
a conformational change, rotating the molecule to
an all-trans conformation. For example, absorbing
light converts the chromophore 11-cis retinal to all-
trans retinal (Figure 31). In the cis conformation,
the chromophore binds to opsin, but when it is con-
verted to the trans conformation, it no longer binds
to opsin, and is released in a process known as
Cone Green Red
bleaching. The chromophore is then reconverted
rod rod back to the cis isomer by isomerase enzymes in an
(a) Frog photoreceptors ATP-requiring process that takes several minutes.
In the photoreceptors of vertebrates, the all-trans
retinal is exported from the photoreceptor cell to
nearby epithelial cells where it is converted to 11-
cis retinal and then reimported into the photore-
ceptor, whereas in invertebrates this process
typically takes place within the photoreceptor cell.
The mechanisms of phototransduction

differ among organisms
When the chromophore dissociates from the opsin,
the opsin undergoes a conformational change and
becomes activated. Like other G-protein-coupled
UV Blue Double Green Red Rod receptors, the activated opsin signals to an associ-
cone cone cone cone cone
ated G protein that activates a downstream signal
(b) Turtle photoreceptors transduction cascade. Animal photoreceptors gen-
Figure 30 Structural diversity of vertebrate erally utilize one of two signal transduction cas-
photoreceptors cades: either phospholipase C (PLC) or cGMP. The
310
Sensory Systems
Light
CH3 H CH3 H CH3 H CH3 H CH3

H3C H3C 15 O
C C C 10 C 11 H C C C 10 C11 C 13 C
H 2C 2 1 7 9 H2C 2 1 7 9 C H
6C 8
C C 12C 6C 8
C C 12 C14
15 O
3 5 3 5
H2C 4 C H H C13 14 C H2C 4 C H H H H
C CH3 H3C C H C CH3
H2 H2
H Isomerase
11-cis retinal All-trans retinal
ATP ADP
Figure 31 Isomerization of retinal The molecule 11-cis retinal absorbs a photon of

light and rotates to form all-trans retinal.
opsins found in rhabdomeric photoreceptors, such light causes a slight decrease in cGMP, causing a
as those present in most invertebrates, signal few channels to close, whereas bright light
through a Gq protein that activates a phospholi- causes a larger decrease in cGMP, causing all or
pase C (PLC)-mediated signal transduction cas- most of the Na⫹ channels to close. Thus, the re-
cade (Figure 32a). PLC catalyzes the breakdown of sponse of the cell is graded, depending on the
phosphatidyl-4,5-bisphosphate (PIP2) into two in- light intensity.
tracellular messengers, inositol triphosphate (IP3)
and diacylglycerol (DAG). These signaling mole-
cules initiate signal transduction pathways that
open nonselective cation channels, and Ca2⫹ and
The Structure and Function of Eyes
Na⫹ enter the cell, resulting in a depolarizing re- Although an individual photoreceptor cell can detect
ceptor potential. This depolarizing receptor poten- the relative brightness of a light source, an eye can
tial causes an increase in neurotransmitter release obtain a great deal of additional information from
from the photoreceptor, sending a signal to the an incoming light stimulus. The minimum criterion
nervous system that is ultimately interpreted as for calling a structure an eye, rather than simply a
light. photoreceptor, is the ability to detect the direction
In contrast, the opsins found in ciliary photo- from which light has entered the organ. Eyespots
receptors, such as those in the vertebrates, signal are single cells (or regions of a cell) that contain a
through an inhibitory Gi protein, called transducin, photosensitive pigment and a shading pigment that
initiating a cyclic GMP-mediated signal transduc- helps provide directional information by shading
tion cascade (Figure 32b). Transducin activates a light coming from some directions. For example, the
phosphodiesterase (PDE) enzyme that hydrolyzes eyespot of the protist Euglena is located at its ante-
cGMP to GMP. This decrease in cGMP concentration rior end, and consists of a light-sensitive swelling of
closes a cGMP-gated Na⫹ channel in the photore- the cell membrane that is associated with a red pig-
ceptor membrane, and Na⫹ influx slows or stops. ment. Euglena, which is a photosynthesizer, uses
Reduced Na⫹ influx coupled with continuing K⫹ ef- this eyespot to orient itself toward the light.
flux hyperpolarizes the cell, causing a receptor Eyes, however, are much more complex organs
potential. The hyperpolarization decreases the re- consisting of groups of cells specialized for different
lease of neurotransmitter from the photoreceptor functions, and often include both multiple photore-
cell onto the associated afferent neuron, sending ceptor cells and separate pigment cells. Eyes can
a signal to the nervous system that the brain ulti- provide information such as light direction and con-
mately interprets as light. In the dark, cGMP lev- trasts between light and dark, and some eyes can
els in the cell are high, cGMP binds to the form focused images. Among multicellular animals,
channels, and most of the channels will be open, there are four main types of eyes (Figure 33).
keeping the cell depolarized, and sending a con- Flat-sheet eyes contain a layer of photorecep-
stant signal to the afferent sensory neuron. Dim tor cells that form a primitive retina lined with a
311
Sensory Systems
1 11-cis 3-hydroxy retinal absorbs light

Light and isomerizes into all-trans 3-hydroxy
retinal.
11-cis All-trans
3-hydroxy 3-hydroxy Nonselective 2 All-trans 3-hydroxy retinal dissociates
retinal retinal cation channel from opsin.
1
(TRP)
3 Activated opsin activates a Gq protein.
5
Rhodopsin 3 4
PLC PIP2 DAG 4 Activated Gq activates PLC, converting
2 PIP2 to DAG and IP3.
6
Opsin
Gq protein IP3 Ca2+ and Na+
5 DAG activates a TRP cation channel.
Depolarization 6 Ca2+ and Na+ enter the cell,

depolarizing it.
(a) Phototransduction in rhabdomeric photoreceptors
1 11-cis retinal absorbs light and

Light isomerizes into all-trans retinal.
2 All-trans retinal dissociates from opsin.

11-cis All-trans
retinal retinal Na+
1 3 Activated opsin activates the Gi
Na+ channel protein transducin.
Rhodopsin 3 5 4 Transducin activates PDE,

PDE 4 which converts cGMP to GMP.
2
cGMP
Opsin GMP 6 5 The decreased cGMP closes
Gi protein a Na+ channel.
transducin
Hyperpolarization 6 Na+ entry decreases,
hyperpolarizing the cell.
(b) Phototransduction in vertebrate photoreceptors
Figure 32 Phototransduction in the invertebrates and vertebrates
pigmented epithelium. These eyes provide some of the light from entering the eye so that an incom-
sense of light direction, and may allow the detec- ing point light source illuminates a single point on
tion of contrasts between light and dark. Many an- the retina, forming an image. This design is simi-
imal groups have eyes of this type, although they lar to a primitive type of camera called a pinhole
are most often seen in larval forms or as accessory camera. Pinhole camera eyes can form images, al-
eyes in adults. However, the limpet Patella has a though the resolution is poor and the image is dim.
simple patch of pigmented cells that serve as its In order to form a crisp image, the aperture (pin-
primary eyes. hole) must be small, but a small aperture lets in
Cup-shaped eyes (Figure 33b) are similar to only a small amount of light, resulting in a dim im-
flat-sheet eyes, except that the retinal sheet is age. Thus, there is a compromise between image
folded to form a narrow aperture. These eyes pro- clarity and image intensity.
vide much better discrimination of light direction Vesicular eyes (Figure 33c) and modern cam-
and intensity, and allow improved detection of eras solve this conflict by inserting a lens into the
contrasts between light and dark. The most ad- pinhole aperture. A lens takes multiple sources of
vanced cup-shaped eyes, such as those of the light and refracts them, focusing the light from a
Nautilus, a cephalopod, have extremely small, single source onto a single point on the retina. The
pinhole-sized openings. The pinhole blocks most challenge in developing a good vesicular eye
312
Sensory Systems
number of ommatidia in a compound eye varies

Photoreceptor cells
greatly among species. For example, worker ants
Retina of the genus Pomera have only a single ommatid-
Pigment layer
ium per eye, while the eye of the dragonfly con-
tains over 25,000 ommatidia arranged in a
Primary afferent neurons hexagonal pattern. The structure of an ommatid-
ium also varies among species, although it gener-
(a) Flat-sheet eye ally consists of a modified region of the cuticle
called the cornea overlying a crystalline cone that
Retina
forms a lens. Immediately below this lens is a
group of photoreceptive cells, called retinular
Pigment layer cells, in a tubular arrangement. The retinular cells
are rhabdomeric photoreceptor cells, as is typical
Photoreceptor cells for invertebrates. The microvilli of these photore-
ceptors project toward a central area called the
Afferent neurons rhabdom. Thus, in cross-section, the ommatidium
(b) Cup-shaped eye resembles a slice through an orange.
Compound eyes form images in two rather dif-
Lens ferent ways. Apposition compound eyes, which are
found in many diurnal insects, consist of omma-
Retina
tidia that are each surrounded by a pigment cell. In
an apposition compound eye each ommatidium op-
Photoreceptor cells
erates essentially independently, and detects only a
small part of the world directly in front of the om-
matidium. However, the afferent neurons leading
Afferent neurons
from the eye make many interconnections, so ani-
(c) Vesicular eye mals with apposition compound eyes are able to
generate an integrated image. In contrast, super-
position compound eyes have ommatidia that work
together to produce a bright, superimposed image
on the retina. Eyes of this type, found in nocturnal
insects and crustaceans, function well in dim light.
Photoreceptor Retina
Compound eyes do not provide the resolving power
cells of the camera eyes of vertebrates, but can still pro-
Afferent neurons
(d) Convex eye
vide quite good visual discrimination.
There are two ways to increase the resolving
Figure 33 Structure of the major types of power of a compound eye: reducing the size of
animal eyes
each ommatidium or increasing the number of
ommatidia. However, diffraction due to the wave
is that the lens must fit precise specifications in or- properties of light limits the minimum size of an
der to provide a clear image. However, even a bad ommatidium. Once this size is reached, the only
lens is better than no lens at all, and provides an way to increase visual acuity is to increase the
improvement over a pinhole camera-type eye. number of ommatidia, and thus the size of the
Convex eyes (Figure 33d) are present in many compound eye. In fact, in order to have the aver-
annelids, molluscs, and arthropods. In these eyes, age resolving power of the human eye, an insect
the individual photoreceptors radiate outward eye would have to be nearly a meter in diameter.
from the base, forming a convex, rather than a Although insect eyes have limited resolving
concave, light-gathering surface. The most com- power, they are very good at capturing images
plex convex eyes are the compound eyes of the from many directions. For example, a dragonfly
arthropods (Figure 34). Compound eyes are com- can see almost 360° around itself, except for a
posed of many ommatidia arranged radially to small blind spot caused by its body. In addition, in-
form the convex light-gathering surface. The sects generally have very good close-up vision,
313
Sensory Systems
outer surface of the mammalian eye

consists of the sclera, a tough layer
Cornea
of connective tissue that makes up
the “white” of the eye in humans,
and the cornea, a transparent layer
that allows light to enter the eye. At
Crystalline the front of the eye, just inside the
cone
cornea, are the iris, the ciliary
Ommatidium body, and the lens. The iris consists
Afferent nerve of two layers of pigmented smooth
fibers muscle surrounding an opening
(a) Photo of compound eye (b) Structure of compound eye called the pupil. The iris can con-
strict or dilate, controlling the
Cornea
amount of light that enters the eye.
Crystalline The iris dilates in dim light, increas-
cone
ing the size of the pupil, and allow-
ing more light to enter the eye. In
Retinular
cell Retinular
bright light, the iris constricts, re-
cell ducing the size of the pupil, and lim-
iting the amount of light that enters
the eye. The lens is held in place be-
Rhabdom Microvilli of
(microvilli of
hind the pupil by suspensory liga-
retinular cell
retinular cells) ments that are attached to the ciliary
body, which contains the ciliary
muscles. The iris and ciliary body
(c) Structure of an ommatidium (d) Cross-section through an ommatidium divide the eye into two compart-
ments. The anterior chamber con-
Figure 34 Structure of an insect compound eye and ommatidium tains a fluid called the aqueous
(a) The compound eye of Drosophila melanogaster. (b) A compound eye is composed of
a cornea and many ommatidia. (c) Each ommatidium consists of a cornea, a
humor. Aqueous humor is secreted
crystalline cone, and several rhabdomeric photoreceptors called retinular cells. by the ciliary body and circulates
(d) The retinular cells are arranged radially, with their microvilli pointing inward to into the anterior chamber via the
form a structure called the rhabdom. pupil. The lens is suspended in the
posterior chamber, which contains a
and they can see objects for which we would need gelatinous mass called the vitreous humor. The
a microscope. However, most insects can see only vitreous humor assists in stabilizing the eye and
a few millimeters away from their body. Dragon- provides support for the retina. Lining the inside
flies have the best distance vision among insects, surface of the eye is the retina, which contains the
and can see objects up to a meter away. photoreceptor cells and several layers of interneu-
Because of the apparent complexity and enor- rons that help to process the incoming visual sig-
mous diversity of eyes, the evolution of eyes has nals. Immediately under the retina is the retinal
been a topic of great interest to biologists. Recent pigment epithelium, which contains the cells that
discoveries in molecular developmental biology regenerate all-trans retinal back into the 11-cis
are providing some new insights into this classic conformation following light absorption. Just un-
problem (see Box 2, Genetics and Genomics: Mol- der the retinal pigment epithelium is a highly pig-
ecular Similarity of Diverse Eyes). mented layer of tissue called the choroid. The
choroid contains blood vessels, providing nourish-
ment to the eye. In most diurnal animals, such as
The structure of the vertebrate eye relates humans, the choroid also absorbs light that
to its function reaches the back of the eye so that it is not re-
The structure of the vertebrate eye allows the for- flected, which might cause distortion of the visual
mation of a bright, focused image (Figure 35). The image. The choroids of nocturnal animals such as
314
Sensory Systems

Molecular Similarity of Diverse Eyes
Although the structure of eyes appears to cascade that results in eye formation, and acting as the
differ greatly among animals, ranging from a master control gene for eye development. Since homo-
simple flat sheet to complex camera or compound eyes, logues of pax-6 are found not just in Drosophila, which
at a molecular level the genes that control eye formation has compound eyes, but also in vertebrates, which have
are surprisingly similar. For example, the gene pax-6, vesicular eyes, it is likely that all eyes share a common
which codes for a transcription factor, has been isolated ancestor. This ancestral eye may have been just a single
from humans, mice, chickens, zebrafish, sea urchins, or a few photoreceptive cells whose development was
and Drosophila. Loss-of-function mutations in this gene controlled by pax-6. In fact, a homologue of pax-6 is ex-
cause reduced or absent eye structures in both verte- pressed in flatworms, which have a primitive cup-
brates and invertebrates. In humans, mutation of the shaped eye consisting of a group of rhabdomeric
pax-6 gene causes the inherited disease aniridia, in photoreceptor cells surrounded by pigment cells.
which the iris of the eye is missing or misformed. In
Drosophila, mutation of the pax-6 gene causes the mu- References
tant phenotype called eyeless. Thus, the pax-6 gene is re- q Callaerts, P., A. M. Munoz-Marmol, S. Glardon, E. Castillo,
sponsible for the development of the eye in a wide variety H. Sun, W. H. Li, W. J. Gehring, and E. Salo. 1999. Isolation and
of animals. In Drosophila, ectopic expression of pax-6 expression of a Pax-6 gene in the regenerating and intact Pla-
narian Dugesia(G) tigrina. Proceedings of the National Academy of
(turning the gene on in tissues where it is not normally
Sciences USA 96: 558–563.
present) results in the formation of compound eyes in
q Gehring, W. J. 2002. The genetic control of eye development and
various parts of the body, including the legs, the anten-
its implications for the evolution of the various eye-types.
nae, and the wings. These ectopic eyes have been shown International Journal of Developmental Biology 46: 65–73.
to respond to light, although they are not functional eyes
q Salo, E., D. Pineda, M. Marsal, J. Gonzalez, V. Gremigni, and
because they are not correctly wired into the brain. Nev- R. Batistoni. 2002. Genetic network of the eye in Platyhelminthes:
ertheless, these experiments demonstrate that pax-6 Expression and functional analysis of some players during pla-
functions like an on switch, initiating a developmental narian regeneration. Gene 287: 67–74.
cats are slightly different from those of humans.

They contain a layer called the tapetum that re-
Vitreous
flects light instead of absorbing it, amplifying the
humor light and allowing noctural animals to see better
Retina than diurnal animals in dim light. Light reflected
Lens
off the tapetum can make a cat’s eyes appear to
Choroid
Iris glow in the dark.
Pupil Fovea
Optic
Cornea nerve The lens focuses light on the retina
Aqueous Both the cornea and lens have a convex shape,
humor and thus act as converging lenses that focus the
Optic light on the retina (Figure 36). Converging lenses
Ciliary body
disk
work by bending light rays toward each other, a
Sclera process called refraction. Light refracts as it
passes through objects of differing densities. In
terrestrial vertebrates, the degree of refraction is
Figure 35 Structure of a mammalian eye Light
entering the eye passes through the cornea, the aqueous
much greater between the air and the cornea than
humor, the pupil, the lens, and the vitreous humor before between the cornea and the lens because of the
striking the retina. large difference in density between the air and
315
Sensory Systems
Convex
lens
Focal point
Light
from
distant
source
Focal length
(a) Light rays from a distant object are (b) Light rays from a nearby object are (c) Lens changes shape, altering focal
parallel when they strike the eye, not parallel. Focal length increases length and bringing image of nearby
and focal length is short. and image is not focused on object into focus on the retina in the
the retina. process of accommodation.
Figure 36 Image formation and accommodation by the mammalian eye
corneal tissue. Thus, the cornea of terrestrial ver- for nearby and distant images differ. In order to
tebrates plays the greatest role in focusing the im- produce focused images of objects at various dis-
age, whereas the lens only fine-tunes the focus. tances, the eye must ensure that the focal point
You can observe this effect for yourself; when you falls on the retina, a process termed accommod-
open your eyes underwater, you will find that it is ation. Because the location and shape of the
difficult to bring objects into focus, because the cornea are fixed, the cornea does not participate
cornea has a similar density to water and no longer in accommodation. Instead, the lens must either
refracts light in the same way as it does in the air. change position relative to the retina, or change
The cornea is less important than the lens for focus- shape.
ing images in the eyes of aquatic vertebrates be- Some polychaete worms change focal length
cause of this effect. The importance of the cornea in by changing the volume of fluid in the eye, altering
humans can be demonstrated by the success of laser the size of the eye and thus the distance between
eye surgery for correcting some vision problems. the lens and the retina. Many invertebrates and
The point at which the light waves converge vertebrates alter focal length by moving the lens
after passing through a lens is called the focal forward or backward. In contrast, lizards, birds,
point. The distance from the center of a lens to its and mammals alter their focal length by changing
focal point is called the focal length. A sharp im- the shape of the lens (Figure 36). To focus on
age can be formed only at the focal point of a lens. nearby objects, the ciliary muscles contract,
Thus, incoming light rays must converge at the which increases their width and loosens the ten-
retina, not behind it or in front of it, in order to sion on the suspensory ligaments, causing the
produce a clear image. The focal length of an im- lens to become more rounded. To focus on distant
age changes, depending on the distance between objects, the ciliary muscles relax. This reduces
the object and the eye. As shown in Figure 36a, the width of the ciliary muscles, increasing the
light rays reflected off a distant object are nearly tension on the suspensory ligaments, which pulls
parallel when they pass through the lens, but light on the lens and flattens it. A more spherical lens
rays reflected off a nearby object are not parallel aids in focusing on nearby objects, whereas a
when they pass through the lens (Figure 36b). As flatter lens brings distant objects into focus on the
a result of this difference in angle, the focal lengths retina.
316
Sensory Systems
Vertebrate retinas have multiple layers Because the photoreceptors of the vertebrate
retina are located in its deepest layer, light entering
In addition to containing the photoreceptor cells
the eye must travel through the ganglion and bipo-
that transduce incoming light energy into an elec-
lar cells before reaching the photoreceptor cells.
trical signal, vertebrate retinas contain many in-
The only exception to this rule is an area called the
terneurons that play an important role in the
fovea or the visual streak. The fovea is a circular re-
processing of visual signals (Figure 37a). The rods
gion located roughly in the middle of the eye. Most
and cones are actually located at the back of the
nonmammalian vertebrates, as well as some mam-
retina, oriented with their tips embedded in the
mals (including humans and other primates), have
pigment epithelium at the back of the eye. The
a fovea in each eye. In contrast, the majority of
rods and cones form synapses with a layer of
mammals, and some nonmammalian vertebrates,
bipolar cells, and these bipolar cells in turn form
have a visual streak, which is a narrow strip along
synapses with a layer of retinal ganglion cells. In
the retina arranged in the plane of the horizon. In
the same layers as the bipolar and ganglion cells
both the fovea and the visual streak, the overlying
are two additional classes of interneuron: the
bipolar and ganglion cells are pushed to one side,
horizontal cells and the amacrine cells. The axons
allowing light to strike the photoreceptors without
of the ganglion cells run along the surface of the
passing through several layers of neurons. As a re-
retina, joining together to form the optic nerve,
sult, vision is sharpest in these regions.
which exits the retina at a point slightly off the
The retina of cephalopods is arranged rather
center of the retina. This area, called the optic
differently than the retina of vertebrates. In the
disk, contains no photoreceptor cells, causing a
cephalopods, the photoreceptors are located on
“blind spot.”
Retina
Retina
Lens Optic
Lens
nerve
Optic nerve
Light Light
To optic
nerve
Amacrine Horizontal Pigment Photoreceptor Supporting To optic
cells cell epithelium cell cell nerve
Light
Light
Outer segment Cell body of

of photoreceptor photoreceptor
Ganglion Bipolar Photoreceptors cell cell
cells cells (rods and cones)
(a) Vertebrate eye and retina (b) Cephalopod eye and retina
Figure 37 Organization of the retina in the vertebrate retina. (b) The cephalopod retina consists of a
vertebrates and cephalopods (a) In the vertebrate single layer of photoreceptor and supporting cells. Light
retina, the photoreceptors are located toward the back. Light entering the eye strikes the photoreceptors directly without
must pass through several layers of cells before striking the passing through multiple retinal layers. There are no
photoreceptors. The middle layers of the retina also contain interneurons, and little or no signal processing occurs within
interneurons that are important for signal processing within the retina.
317
Sensory Systems
the surface of the retina, rather than at the back Information from rods and cones
(Figure 37b). Supporting cells are located between is processed differently
the photoreceptor cells, but there are no additional
The vertebrate retina processes information com-
layers of cells. The axons of the photoreceptors
ing from rods and cones differently (Figure 38). Rod
come together to form the optic nerve, rather than
signaling pathways are organized using the princi-
forming synapses with interneurons within the
ple of convergence. Many rods synapse with a sin-
retina. Thus, the cephalopod retina has far fewer
gle bipolar cell, and many of these bipolar cells can
parts than a vertebrate retina, and little signal pro-
synapse with a ganglion cell. As a result, as many as
cessing occurs in the retina itself.
100 rods may connect with a single retinal ganglion
cell. In contrast, a cone located within
the fovea connects to a single bipolar
cell, and that bipolar cell connects to a
single ganglion cell. Thus, a single
To optic Pigment pathway carries a signal from a cone
nerve epithelium
cell to the visual centers of the brain.
Toward the edge of the retina, cones
participate in somewhat more conver-
gent pathways, but never to the extent
seen with rods. These differences in
wiring result in differences in the size
of the receptive fields of retinal gan-
glion cells. A retinal ganglion cell that
is associated with only one or a few
photoreceptors has a small receptive
field, processing information from only
a small area of the retina. In contrast,
Ganglion Bipolar Rod
cell cell a retinal ganglion cell that is associ-
(a) Signal processing from rod photoreceptors ated with many photoreceptors has a
large receptive field, and processes
To optic Pigment information from a larger area of the
nerve epithelium
retina. Thus, retinal ganglion cells
that are associated with cones located
in the fovea have very small receptive
fields and can provide a detailed,
high-resolution image. In contrast,
the receptive field of a retinal gan-
glion cell that receives inputs from
rod photoreceptors is much larger,
and thus rods provide less detailed
images.
Ganglion Bipolar Cone

cell cell
(b) Signal processing from cone photoreceptors Signal processing in the retina
enhances contrast
Figure 38 Convergence in the vertebrate retina (a) The signaling
pathways of rods show convergence. Many rods can form synapses with one bipolar Vertebrate retinas are organized such
cell, and several bipolar cells may form synapses with a single ganglion cell. Thus, that they enhance the perception of
the receptive fields of these retinal ganglion cells include input from many borders and contrast, using the process
photoreceptor cells. (b) The signaling pathways of cones in the fovea do not
converge. A single cone forms a synapse with a single bipolar cell, which forms
of lateral inhibition that we discussed
synapses with a single ganglion cell. Thus, the receptive fields of these ganglion at the beginning of this chapter. In fact,
cells include input from a single photoreceptor cell. a point light source causes a greater re-
318
Sensory Systems
sponse in a retinal ganglion cell than does evenly shone onto photoreceptors in the center region of
distributed diffuse illumination of the same inten- the receptive field, the energy from the incoming
sity. This phenomenon occurs because the recep- light converts 11-cis retinal to all-trans retinal, ac-
tive fields of retinal ganglion cells have a tivating the G protein transducin, which decreases
center-surround organization, consisting of a cen- cGMP within the photoreceptor cell. The decrease
tral region surrounded by a concentric ring that in cGMP closes Na⫹ channels, hyperpolarizing the
each have different responses to light (Figure 39). cell. This hyperpolarizing graded potential re-
For example, an “on-center” retinal ganglion cell duces the release of the neurotransmitter gluta-
increases action potential frequency in response to mate from the photoreceptor cell. Glutamate is an
illumination of the center of the receptive field, and inhibitory neurotransmitter for the bipolar cell, so
decreases action potential frequency in response to a decrease in the inhibitory neurotransmitter glu-
illumination of the surround region of the receptive tamate stimulates the bipolar cell, causing it to de-
field. An “off-center” retinal ganglion cell shows the polarize. The depolarization increases the release
opposite response. The horizonatal and amacrine of neurotransmitter from the bipolar cell, stimu-
cells of the retina play the major role in establish- lating the ganglion cell to depolarize.
ing the center-surround organization of a retinal Now let’s look at what happens when a more
ganglion cell. diffuse light is shone onto the receptive field such
To see how this works, let’s trace the events in that it illuminates photoreceptors in both the center
the retina when light strikes the receptive field of and surround regions. In addition to forming
a retinal ganglion cell with an on-center organiza- synapses with bipolar cells, photoreceptors in the
tion (Figure 39, left side). When a bright light is surround region of the receptive field form synapses
with horizontal cells (Figure 40). When stimulated,
these horizontal cells inhibit the activity of the
Ganglion cell Ganglion cell
with ON-center with OFF-center bipolar cells that are connected to the photorecep-
receptive field receptive field tors at the center of the receptive field. Thus, bipo-
lar cells that form synapses with photoreceptors in
ON OFF OFF ON
Illumination Increases action Decreases action Photoreceptor

of center potentials in potentials in cell
only ganglion cell ganglion cell
Light
Illumination Decreases action Increases action
of surround potentials in potentials in
only ganglion cell ganglion cell
Horizontal
cell
Diffuse Weak response Weak response
illumination in ganglion cell in ganglion cell
of center
and surround Bipolar
cell
Figure 39 Receptive fields of retinal ganglion

cells Retinal ganglion cells have complex receptive fields
that are divided into regions with different responses to light.
Ganglion cells with an on-center receptive field fire action Ganglion
potentials at higher frequency in response to light focused on cell
the center of the receptive field and fire action potentials at a
decreased frequency in response to light focused on the
surrounding region of the receptive field. When light strikes To optic nerve
both the center (on) region and the surround (off) region at
the same time, the two effects partially cancel out and the Figure 40 Lateral inhibition in the vertebrate
frequency of action potentials increases only slightly. The retina Photoreceptors communicate with both bipolar
opposite pattern holds for retinal ganglion cells with an off- cells and horizontal cells. Excited horizontal cells inhibit
center organization. neighboring bipolar cells—the process of lateral inhibition.
319
Sensory Systems
the center of the receptive field receive two conflict- and left eyes, in an area called the binocular zone.
ing inputs: a stimulatory input from the center photo- Figure 41 illustrates the visual field of a human.
receptors and an inhibitory input from the surround Human eyes are on the front of the head, and the
photoreceptors (via the horizontal cells). These two binocular zone is large.
conflicting inputs cause the bipolar cell to send a Each part of the retina detects a different por-
much weaker signal to the retinal ganglion cell, re- tion of the visual field. Light from the left part of
ducing its response to diffuse light compared with a the visual field strikes the right part of the retina
point of light in the center of the receptive field. of each eye, whereas light from the right part of
Similar processes occur for retinal ganglion the visual field strikes the left part of the retina of
cells with an off-center organization, but in this each eye. In fact, we can divide the human retina
case, glutamate released from the photoreceptor down the middle (roughly at the fovea) and define
cells acts as an excitatory neurotransmitter for two regions of each retina: the temporal half (to-
bipolar cells connected to photoreceptors in the ward the outside of the face) and the nasal half (to-
center of the receptive field. When light strikes ward the center of the face). The temporal retina
these photoreceptors, it causes the photoreceptor of the right eye detects the left visual field, and the
to hyperpolarize and decrease the release of gluta- nasal retina detects the right visual field. In con-
mate, just as in the case of a photoreceptor in an trast, the temporal retina of the left eye detects the
on-center receptive field. In the case of an off- right visual field, and the nasal retina of the left
center receptive field, however, this decrease in eye detects the left visual field.
glutamate hyperpolarizes the bipolar cell and re- The two optic nerves carrying information
duces the release of neurotransmitter onto the reti- from the right and left eyes converge in a region
nal ganglion cell, causing the frequency of action called the optic chiasm (Figure 41). Most of the
potentials in the retinal ganglion cell to decline. The neurons then form synapses in a part of the brain
difference in the response of the bipolar cell is called the lateral geniculate nucleus, which in
caused by the presence of a different isoform of the turn sends processes to the visual cortex, which
glutamate receptor in bipolar cells associated with is responsible for the final processing of visual in-
on-center and off-center receptive fields. formation.
To add another layer of complexity, bipolar Neurons coming from the temporal retina of
cells do not always form synapses directly with the right eye send projections to the right lateral
ganglion cells. Instead, bipolar cells form electrical geniculate nucleus, whereas neurons coming from
synapses with amacrine cells. Depolarization of the temporal retina of the left eye send projections
the bipolar cell is communicated directly to the to the left lateral geniculate nucleus. In contrast,
amacrine cell via gap junctions. The amacrine cell neurons coming from the nasal retinas of the right
integrates and modifies the inputs from several and left eyes cross over at the optic chiasm to form
bipolar cells, ultimately altering the release of neu- synapses with the lateral geniculate nucleus on the
rotransmitter from the amacrine cell onto the gan- opposite side of the brain. As a result, the right
glion cell. These extremely complex relationships half of the brain processes signals from the left
are particularly prevalent in the highly convergent part of the visual field, and the left half of the brain
pathways involved with rod photoreceptors. processes signals from the right half of the visual
field. The right and left sides of the visual field
overlap in the binocular zone, and thus signals
The brain processes the visual signal from the binocular zone are processed on both
We can define a region called the visual field, sides of the brain. Animals can compare the prop-
which consists of the entire area that can be seen erties of the images in the binocular zone coming
without moving the eyes. Depending on the posi- from each eye to provide information such as the
tion of the eyes on the head, each eye sees a some- distance of an object from the body. This is one of
what different part of the visual field. In animals the processes that underlies depth perception.
with their eyes on the sides of their heads, there is In general, the degree of crossing of neurons in
little overlap between the visual fields of the right the optic chiasm is related to the degree of overlap
and left eyes, whereas in animals with eyes placed between the left and right visual fields. In fishes
toward the front of their heads there is a great deal and amphibians with eyes located at the extreme
of overlap between the visual fields of the right
320
Sensory Systems
sides of the head, the left and right vi- Visual field
sual fields do not overlap. These ani-
Binocular zone
mals lack a binocular zone, and most of
the neurons in the optic nerve from the
right eye send projections to the left side
of the brain, whereas the optic nerve
from the left eye sends projections to the
right side of the brain. Similarly, in
mice, which also have a limited overlap
between their right and left visual fields,
about 97% of the fibers cross over to the
other side of the brain, while only 3% of
the fibers are uncrossed. Although ani-
mals (such as fish and rodents) with
eyes on each side of the head tend to
have poor depth perception, these ani-
mals have excellent panoramic vision,
often having an almost 360° view of the
world. Humans have a large binocular
zone, and about 60% of the fibers in the
Optic nerve
optic nerve cross over to the other side
of the brain at the optic chiasm, while
40% of the fibers are uncrossed. This
cross-fiber organization plays a part in Optic chiasm
generating stereopsis, in which com-
parison of the information by the two Optic tract
eyes assists in depth perception. In gen- Lateral geniculate

eral, animals with superior stereopsis nucleus of brain
tend to have roughly equal amounts of
crossed and uncrossed fibers, allowing
easy comparison of signals from each
eye on both sides of the brain. Owls,
which have eyes at the front of their
heads, and excellent depth perception, Visual cortex
are an exception to this rule because all of brain
of their optic neurons cross at the optic
chiasm. The two sides of an owl’s brain Figure 41 Visual processing In humans, about half of the neurons
coming from each eye cross over each other in the optic chiasm. Neurons sending
communicate with each other in other signals from the right side of the field of view from both the left and right eyes
parts of the visual pathway, allowing send processes to the left half of the brain, whereas neurons sending signals from
both sides of the brain to process im- the left side of the field of view from both the right and left eyes send processes to
ages from both eyes, and providing the the right side of the brain. Thus, each side of the brain receives information from
both eyes. Comparing these two views provides stereopsis, which enhances depth
necessary conditions for good depth
perception.
perception.
Color vision requires multiple types lengths. Animals accomplish this by having more
of photoreceptors than one type of photoreceptor cell, each contain-
In addition to detecting shapes and movements, ing a photopigment that is sensitive to light of spe-
many animals are capable of detecting the wave- cific wavelengths. Humans can distinguish about
length of incoming light, a phenomenon we experi- 1500 wavelengths between 400 nm (blue) and
ence as color. In order to detect colors, an animal 700 nm (red), differences in wavelength of about
must be able to distinguish among different wave- 0.2 nm. This might suggest that humans would
321
Sensory Systems
need several thousand different photopigments matic (depending on the species). It is difficult for us
and photoreceptor cells; however, humans have to understand the visual world of a pentachromatic
only three different cone photoreceptors, with max- animal. The additional photoreceptors likely allow
imum sensitivities of approximately 440 nm (blue), these species to discriminate among colors that ap-
530 nm (green), and 565 nm (red) (Figure 42). Light pear the same to humans, and some species can de-
of a given wavelength stimulates more than one tect light in the ultraviolet (UV) or infrared ranges
type of cone, but to different degrees. The retina that humans cannot detect. Most mammals are
and brain then compare the output from each type dichromats, having only middle (green) and short
of cone and infer the color of the stimulus. (blue) wavelength cones (in addition to rods) in
Each cone photoreceptor is maximally sensi- their retinas. Since dichromats lack the “red” cone,
tive to a particular wavelength of light, but can these animals cannot distinguish between red col-
also be stimulated by light of other wavelengths. ors and green colors, similar to a human that is
So how can the brain distinguish between a low- red/green color-blind. Many marine mammals and
intensity stimulus at the peak wavelength and a a few nocturnal rodents and carnivores have sec-
strong stimulus at another wavelength? Clearly, a ondarily lost one of these pigments and become
single cone photoreceptor cannot provide infor- monochromats that cannot distinguish colors at all.
mation about the wavelength of incoming light. Because ancient reptile-like creatures with at
The outputs of all types of cones must be used to least trichromatic color vision are the probable an-
estimate the wavelength of the incoming light. The cestors of the mammals, we can infer that mam-
first stage of this processing occurs in the horizon- mals must have lost one or more of the ancestral
tal and ganglion cells of the retina, where lateral photopigment genes. Mammals are thought to
inhibition by horizontal cells plays an important have evolved primarily as nocturnal creatures
role in the initial processing of color information. (first appearing during the time of the dinosaurs),
This system, called trichromatic color vision, al- and at that time some of the genes needed for
lows humans to see a wide range of colors using color vision may have been lost because they were
only three types of cone photoreceptors. not needed for vision in dim light. Trichromacy
Birds, reptiles, and shallow-water fishes can be was subsequently restored only in the primates.
trichromatic, tetrachromatic, or even pentachro- Interestingly, however, trichromatic color vision
appears to have evolved independently in the Old
Red World primates and the New World primates (see
Rods cones Box 3, Evolution and Diversity: The Evolution of
Blue Green
cones cones Trichomatic Color Vision in Primates).
100
Absorbance (% of maximum)
2 CONCEPT CHECK
75
14. Compare and contrast phototransduction in
rhabdomeric and ciliary photoreceptors.
50 15. What are the advantages of a vesicular eye
compared to a pinhole-type eye?
25 16. Would you expect laser eye surgery (which
affects the shape of the cornea) to be effective in
an aquatic vertebrate? Why or why not?
17. Explain how lateral inhibition enhances contrast
400 430 500 530 560 600
at the retina.
Wavelength (nm)
Figure 42 The absorbance spectra of human

rods and cones Humans typically have one type of rod
photopigment and three types of cone photopigment.
Although the absorbance spectra of the photopigments
Thermoreception
overlap, each has a unique absorbance maximum. By
comparing the signals coming from each type of
Animals have central thermoreceptors, located in
photoreceptor, the brain can distinguish over 1000 different the hypothalamus of the brain, that monitor their
wavelengths of light. internal temperature, and peripheral thermore-
322
Sensory Systems

The Evolution of Trichromatic Color Vision in Primates
Mammals generally have much worse opsin, a “green” opsin, and a “red” opsin. Recall that the
color vision than other vertebrates, and many “green” opsin gene is found on the X chromosome. Male
species are entirely color-blind. Primates are one of the primates have only one copy of the X chromosone, and
few exceptions to this rule. All of the Old World primates one copy of the Y chromosome. Thus, males of this
(humans, apes, and Old World monkeys) have trichro- species are always homozygous for the “green” opsin
matic color vision similar to that found in humans. In con- gene, and are functionally dichromatic. In these
trast, the New World monkeys vary greatly in their ability species, males are red/green color-blind, while females
to see colors. Most species are dichromatic, a few species can be either color-blind or trichromats, depending on
have trichromatic females but dichromatic males, and whether they are heterozygous for this gene.
only the howler monkeys are true trichromats. The genet- Of all the New World primates, only the howler mon-
ics of these different visual systems have now been keys deviate from this system. In howler monkeys, the
worked out, and their evolution has been studied in detail. “green” opsin gene has been duplicated, similar to the
Humans and the other Old World primates have three situation in the Old World primates. Thus, both male and
opsin genes in the genome, one coding for a blue- female howler monkeys are true trichromats, and have
sensitive photopigment, one coding for a green-sensitive color vision similar to that in humans. Because the New
photopigment, and one coding for a red-sensitive pho- World monkeys diverged from the Old World monkeys
topigment. The “green” and “red” opsins are coded by prior to the evolution of the primates, the gene duplica-
very similar DNA sequences, and differ by only 11 amino tion in the howler monkeys is independent from that
acids. This degree of differentiation suggests, based on shared by all of the Old World primates. It also appears
the approximate mutation rate of genes in the verte- to be somewhat more recent, since the “green” and
brates, that these genes began to diverge from each “red” opsins of the howler monkeys differ from each
other about 40 million years ago. It appears that an another by only eight amino acids. Thus, true trichromacy
cestral “green” opsin gene was duplicated at that time, has evolved at least twice in the primates, once in the lin-
during the early evolution of the Old World primates, and eage leading to the Old World primates, and once in the
the two genes began to diverge. In humans, these two ancestors of the howler monkeys. Multiple independent
genes are located very close together on the X chromo- evolution of a phenotypic trait strongly suggests that this
some, further suggesting that they arose through an an- trait has been selected over evolutionary time for some
cestral duplication in this part of the genome. important function. For example, being able to distin-
Some species of New World primate, such as the owl guish many shades of red and green might allow pri-
monkey, a nocturnal animal, are monochromats and are mates to easily find ripe fruit in a background of leaves.
thus color-blind. But most other species of New World
References
monkeys have a form of trichromatic color vision. These
q Dominy, N. J., and P. W. Lucas. 2001. Ecological importance of
monkeys have only two opsin genes in their genome—a trichromatic vision to primates. Nature 410: 363–366.
“blue” opsin and a “green” opsin. As in the Old World
q Dulai, K. S., M. von Dornum, J. D. Mollon, and D. M. Hunt. 1999.
primates, the “green” opsin gene is found on the X chro- The evolution of trichromatic color vision by opsin gene duplica-
mosome, but in this case the gene has not been dupli- tion in New World and Old World primates. Genome Research 9:
cated. Instead, in some species of New World monkeys, 629–638.
two different alleles of this one gene are present in the q Jacobs, G. H. 1996. Primate photopigments and primate color vi-
population. One of the alleles is sensitive to green light, sion. Proceedings of the National Academy of Sciences USA 93:
and the other is more sensitive to red light. An individ- 577–581.
ual that is heterozygous for these alleles (that has one q Orsorio, B., and M. Vorobyev. 1996. Colour vision as an adaptation
copy of the “green” allele and one copy of its “red” vari- to frugivory in primates. Proceedings of the Royal Society of Lon-
ant) is functionally trichromatic, expressing a “blue” don (Series B: Biological Sciences) 263: 593–599.
ceptors that monitor environmental temperature. stimuli. In mammals, warm-sensitive neurons start
There are three types of peripheral thermo- to fire action potentials when the skin temperature
receptors: warm-sensitive thermoreceptors, cold- is raised above 30°C, and firing frequency increases
sensitive thermoreceptors, and thermoreceptors with increasing temperature up to a saturating
that are specialized for detecting painfully hot value. In contrast, cold receptors are extremely
323
Sensory Systems
sensitive to small (0.5°C) decreases in tempera- Other snakes such as the boa constrictor have
ture, but they respond mostly to temperature labial pits along the upper and lower jaws. Pit
change, rather than the absolute value of the tem- organs and labial pits are extremely sensitive
perature. The thermal nociceptors detect painful thermoreceptors that allow snakes to detect mam-
heat and burns, and start to fire only at higher, malian prey and to select thermally appropriate
painful temperatures (starting at around 45°C in habitats. The thermoreceptive neurons in the pit
mammals). These neurons increase their firing fre- organs can detect temperature changes as small
quency in parallel with increasing pain sensation. as 0.003°C (compare this to the 0.5°C discrimina-
Thermoreception begins when specific ther- tion of human thermoreceptors). Little is known
moreceptor proteins in the free nerve endings of about the transduction mechanisms of pit organs.
thermoreceptor neurons are activated. These re- However, like the thermoTRP neurons in humans,
ceptors, which are found in both vertebrates and pit organ thermoreceptors are sensitive to cap-
invertebrates, are called thermoTRPs and, like saicin, suggesting the possibility of a similar mech-
some mechanoreceptors, are members of the TRP anism.
family of ion channels. Individual thermoTRPs are
specialized to detect distinct temperature ranges;
some thermoTRPs are activated by heat, others by Magnetoreception
cold. Capsaicin, the “hot” ingredient in peppers,
stimulates warm-sensitive neurons, while men- Magnetoreception, or the ability to detect mag-
thol, the ingredient that makes mints taste “cool,” netic fields, is widely distributed throughout the
stimulates cold-sensitive neurons. Further study animal kingdom. Migratory birds, homing salmon,
of the responses of thermoreceptors to these and many other organisms use the Earth’s mag-
chemicals should lead to clues about the gating netic field to help them navigate, although humans
properties of the thermoTRPs. apparently lack this sense. Magnetoreception has
Some animals have highly specialized sensory been extensively studied, but the mechanisms of
organs that allow them to detect heat radiating magnetoreception are not understood for any an-
from objects at a distance. For example, pit vipers imal, and it remains the most elusive of sensory
(a group that includes rattlesnakes) have special- modalities.
ized pit organs that are found between the eye In one intriguing study, scientists identified
and nostril on either side of the head (Figure 43). specific neurons in the olfactory epithelium of
rainbow trout that respond to magnetic fields.
These neurons contain particles that resemble
magnetite when examined under a microscope.
Magnetite is a natural mineral that responds to
magnetic fields, and thus could be the basis for
magnetoreception in animals. The magnetite par-
ticles in trout olfactory neurons are arranged in a
chain within the cell, similar to a compass needle,
strongly suggesting that trout use a magnetite-
based mechanism for detecting magnetic fields. A
similar mechanism is used by some species of bac-
teria that can orient themselves in a magnetic
field. However, the mechanism by which magne-
toreceptive sensory neurons in trout respond to
changes in the position of the magnetite is still un-
known. Not all animals that can respond to mag-
netic fields have detectable magnetite crystals, so
Figure 43 Pit organs of snakes The pit organs of
this fer de lance pit viper are clearly visible between the it is unlikely that this mechanism is found in all
nostril and the eye. magnetoreceptors.
324
Sensory Systems
Integrating Systems Sensory Systems and Circadian Rhythms

Circadian rhythms are predictable daily variations in phys- The suprachiasmatic nucleus communicates its
iological parameters that are linked with the daily cycle of circadian signal to other parts of the hypothalamus in-
light and dark. Almost every aspect of behavior and phys- cluding the paraventricular nucleus, the ventromedial
iology undergoes a circadian rhythm, including processes nucleus, and the periventricular nucleus. These nuclei
such as metabolic rate, activity, and digestion. Circadian are involved in regulating a large number of important
rhythms persist even when an organism is kept in con- physiological processes. The ventromedial nucleus reg-
stant darkness; however, without environmental cues ulates appetite and feeding behavior. The paraventricu-
these rhythms tend to be somewhat longer or shorter lar nucleus synthesizes the hormones vasopressin (also
than 24 hours—giving rise to the name circadian (circa ⫽ called antidiuretic hormone or ADH) and oxytocin. Vaso-
about; dies ⫽ day). External environmental cues, such as pressin regulates kidney function, whereas oxytocin
the pattern of light and dark, help to keep this intrinsic cir- influences milk ejection from the breast and the con-
cadian clock in sync with the natural environment. traction of the uterus in mammals, and sexual behavior
In mammals, the circadian clock is located within a and pair-bonding in other animals. The periventricular
part of the brain called the hypothalamus, or more nucleus secretes a large number of releasing hormones
specifically within the suprachiasmatic nucleus, a that regulate the hormones of the anterior pituitary. The
grouping of about 10,000 neurons within the hypothala- pituitary hormone prolactin is best known for its effects
mus (Figure 44a). Very little light penetrates so deeply on reproduction in mammals. It stimulates the growth
within the brain, so for many years scientists assumed of the mammary glands, causes milk production, and in
that rod and cone photoreceptors must somehow com- some species it is important for maintaining pregnancy
municate the incoming light information to the and stimulating reproductive behaviors such as nest
suprachiasmatic nucleus. This assumption was sup- building. Prolactin is also involved in a host of other
ported by the observation that mammals that lack eyes physiological processes, including (1) water and elec-
cannot reset their circadian clocks in response to light trolyte balance, (2) growth and development, and (3) im-
cues. However, genetically defective mammals that mune function. Thyroid-stimulating hormone (TSH)
lack rods and cones but have otherwise intact eyes dis- released by the pituitary causes the release of thyroid
play normal circadian rhythms that respond to light hormones from the thyroid gland. Thyroid hormones
cues, suggesting that the rods and cones cannot be the play an important role in the regulation of metabolic
source of the light input to the circadian clock. rate. Adrenocorticotropic hormone (ACTH) causes the
We now know that retinal ganglion cells play the release of corticosteroids from the adrenal cortex. Cor-
critical role in sending light signals to the suprachias- ticosteroids, or the stress hormones, regulate many bi-
matic nucleus. Retinal ganglion cells make synaptic con- ological processes, particularly those involved in
nections with neurons in the suprachiasmatic nucleus, carbohydrate metabolism. Growth hormone (GH) re-
providing a direct neural pathway between the sensory leased from the pituitary stimulates a variety of anabolic
receptor cell (the retinal ganglion cell) and the integrat- processes, and regulates the release of insulin-like
ing centers of the central nervous system. The nature of growth factor from the liver, which in turn plays a role in
photoreceptor protein in these cells is still somewhat regulating growth. Finally, follicle-stimulating hormone
disputed, but most evidence points to an opsin-related (FSH) and luteinizing hormone (LH) regulate the pro-
protein called melanopsin. duction of the sex hormones (androgens and estro-
The suprachiasmatic nucleus then communicates gens). By modulating the activity of the hypothalamus,
its rhythmic signal to other parts of the brain and to which influences pituitary function, the circadian clock
many physiological systems (Figure 44b). At present, can influence almost every function of the body.
most evidence suggests that the suprachiasmatic nu- The suprachiasmatic nucleus also sends signals to
cleus communicates with the rest of the body by secret- the pineal gland, in a neighboring part of the brain. The
ing neuropeptides. For example, if you destroy the pineal gland secretes the hormone melatonin into the
neurons in the suprachiasmatic nucleus, circadian cerebrospinal fluid and the blood in a circadian rhythm.
rhythms disappear, but if you transplant suprachias- In humans, melatonin secretion is high at night and low
matic nucleus neurons from another animal, the circa- during the day. Most tissues of the body have receptors
dian rhythms return, even though the neurons do not for melatonin, so although the effects of this hormone
form synaptic connections with other parts of the brain.
325
Sensory Systems
Hypothalamus Pineal
gland
Pineal gland Paraventricular
nucleus
Melatonin
Supraoptic
nucleus
Suprachiasmatic Periventricular
nucleus nucleus
Eye Optic Pituitary Ventromedial

nerve gland nucleus
(a)
Input from retinal
ganglion cells
Hormone
release
Anterior pituitary Posterior pituitary
Prolactin TSH ACTH GH FSH LH Vasopressin Oxytocin
Thyroid Adrenal Liver Gonads

gland cortex
Thyroid Cortisol IGF Androgens Estrogens

hormone
(b) Breast Many tissues Kidney Breast, Many

uterus tissues
Figure 44 The role of light input in circadian pituitary, and affecting the secretion of releasing hormones
rhythms in mammals (a) The organs involved in into the pituitary portal system. The releasing hormones in
circadian rhythms in mammals. (b) The endocrine system and turn affect the secretion of the pituitary hormones, which go on
circadian rhythms. A light signal from the retinal ganglion cells to have direct effects on a variety of tissues, as well as
entrains the circadian clock in the suprachiasmatic nucleus influencing the release of hormones from other endocrine
(SCN) of the hypothalamus. The SCN sends a signal to the glands. Melatonin from the pineal gland also enters the
pineal gland, altering the release of melatonin on a circadian bloodstream and has effects on many tissues. (TSH ⫽ thyroid-
cycle. Melatonin and secreted proteins from the SCN affect the stimulating hormone; ACTH ⫽ adrenocorticotropic hormone;
other hypothalamic nuclei, causing circadian changes in the GH ⫽ growth hormone; FSH ⫽ follicle-stimulating hormone;
release of vasopressin and oxytocin from the posterior LH ⫽ luteinizing hormone; IGF ⫽ insulin-like growth factor).
are not yet fully understood they are likely to be wide- In most nonmammalian vertebrates, the pineal
spread. The suprachiasmatic nucleus and parts of the gland is directly sensitive to light and contains its own
anterior pituitary have particularly high levels of mela- biological clock. In these animals, the pineal organ rests
tonin receptors, so melatonin likely plays a role in feed- on top of the brain, and in some species the skull over
back regulation of the circadian clock. In fact, the pineal gland is very thin, allowing substantial light to
administration of melatonin can shift the circadian penetrate to the pineal organ. In fact, in some extinct
clock, or improve entrainment to environmental cues. vertebrates, the pineal organ apparently formed a third
Because of these effects, melatonin is increasingly used eye with a lens to focus light. In living organisms, only
as a nutritional supplement to reduce the severity of jet the lamprey and some lizards retain the remnants of
lag, although its effectiveness is controversial. this third eye.2
326
Sensory Systems
Summary
General Properties of Sensory Reception which are separate senses in the vertebrates.
k Sensory receptors transduce the energy from These distinctions are not as clear in the
incoming signals into changes in membrane po- invertebrates.
tential that can be communicated to other parts
k Vertebrate olfactory receptors are bipolar neu-
of the nervous system.
rons that express odorant receptor proteins
k Sensory receptors can be classified based on that signal through an associated G protein.
the type of stimulus that the receptor detects
k The olfactory G protein (Golf) signals via an
(the stimulus modality).
adenylate cyclase signal transduction cascade.
k Chemoreceptors sense environmental chemi-
k Each olfactory neuron expresses one of several
cals in both the internal and external environ-
thousand odorant receptor genes, each of
ments. Mechanoreceptors sense pressure
which is sensitive to a unique combination of
changes. Photoreceptors detect light. Magne-
odorants.
toreceptors detect magnetic fields. Electrore-
ceptors detect electrical currents, and k The combinatorial odorant code allows verte-
thermoreceptors detect temperature. brates to discriminate among hundreds of thou-
sands of different odors using fewer than a
k Most receptors have an adequate stimulus, a
thousand different odorant receptor proteins.
specific stimulus that maximally excites the re-
ceptor, although other stimuli can excite these k Vertebrates also use G-protein-coupled receptors
receptors, if they are sufficiently large. to detect pheromones, but pheromone detection
occurs in the vomeronasal organ, not the olfac-
k Some polymodal receptors, including many
tory epithelium, and the G protein signals via a
pain receptors (nociceptors), have fairly broad
phospholipase C signal transduction cascade.
specificity and can detect more than one type of
stimulus. k Invertebrate olfactory receptors also use odor-
ant receptor proteins coupled to a G protein for
k Some sensory receptors are epithelia-derived
signal transduction, but the genes for these re-
cells. Incoming stimuli cause a receptor poten-
ceptors are not homologous to the vertebrate
tial in these cells that causes the release of neu-
odorant receptors.
rotransmitter onto an afferent neuron.
k The vertebrate gustatory system detects five
k Some sensory receptors are neurons. Incoming
broad classes of chemical (sweet, umami, salty,
stimuli cause a generator potential in these cells
sour, and bitter).
that triggers action potentials in the axon.
k Vertebrate taste receptors are epithelial cells that
k For many receptors, receptor location can en-
form synapses with bipolar sensory neurons that
code stimulus modality and location.
use diverse signal transduction mechanisms, in-
k Action potential frequency encodes stimulus cluding ion channels and G-protein-coupled re-
intensity. ceptors.
k The beginning or ending of groups of action po- k Insect taste receptors are bipolar sensory neu-
tentials can encode stimulus duration. rons that signal through G-protein-coupled
receptors.
k Range fractionation and logarithmic encoding
can extend the dynamic range of a sense organ. Mechanoreception
k Mechanoreceptors detect physical stimuli using
Chemoreception stretch-sensitive ion channels.
k Chemoreception is the process of detecting chem-
k Baroreceptors detect changes in blood pres-
icals in the internal and external environments.
sure. Tactile (touch) receptors detect mechani-
k External chemoreception can be divided into cal stimuli on the body surface. Proprioceptors
olfaction, pheromone sensing, and gustation, monitor the position of the body.
327
Sensory Systems
k Vertebrate tactile receptors are isolated sensory tion cascade that causes the cell to depolarize in
cells within the skin. response to light.
k Insect tactile receptors are grouped into com- k In a ciliary photoreceptor, the G protein signals
plex mechanosensory organs called sensilla. via phosphodiesterase, causing the cell to hy-
perpolarize in response to light.
k Arthropods use statocysts as the organ of equi-
librium. A variety of different structures involv- k In most animals, photoreceptors are grouped in
ing modified chordotonal organs can be used as complex photoreceptors such as eyes that range
organs of hearing. in complexity from a simple flat sheet to com-
plex vesicular eyes.
k The ears are the organs of both equilibrium and
hearing in the vertebrates. k Despite the diversity of eye structure, the same
genes are involved in the development of eyes in
k Vertebrate inner ears contain specialized hair
all animals.
cells with ciliary projections that pivot in re-
sponse to changes in pressure, opening a k A vesicular eye can focus images on the retina
mechanosensitive ion channel that transduces of objects at varying distances, a process called
the mechanical stimulus into a change in mem- accommodation.
brane potential.
k In the vertebrates, accommodation occurs via
k The hair cells associated with the semicircular changes in the shape of the lens. The vertebrate
canals are involved in the sense of equilibrium. retina performs substantial processing of the vi-
sual signal.
k The hair cells of the lagena, cochlear duct, or
cochlea (depending on the species) are involved k Comparison of signals from multiple photore-
in hearing. ceptors with different photopigments allows
color vision.
k The middle ear of terrestrial vertebrates ampli-
fies sounds. Thermoreception
k Thermoreceptors may be warm sensitive, cold
Photoreception
sensitive, or hot/pain sensitive.
k Photoreception involves the transduction of the
energy carried by light into a depolarization of k Thermoreceptor proteins are in the transient
a photoreceptor cell. receptor potential (TRP) family of ion channels.
k Animals have two classes of photoreceptor cells k Some chemicals (including capsaicin, from hot
(ciliary and rhabdomeric photoreceptors). peppers) can stimulate temperature-sensitive
TRP channels.
k Both types contain similar photoreceptor chro-
mophores that are made up of the protein opsin k Some animals have specialized organs for de-
and a pigment derived from vitamin A (such as tecting temperature, such as the pit organs of
retinal). vipers.
k When light strikes the pigment in a chro- Magnetoreception

mophore, the pigment isomerizes and dissoci- k Magnetoreception is present in many organ-
ates from opsin, changing opsin’s conformation isms, but is poorly understood.
and signaling to an associated G protein.
k Some magnetoreceptors contain particles of
k In a rhabdomeric photoreceptor, the G protein magnetite, a mineral that responds to magnetic
signals via a phospholipase C signal transduc- fields.
328
Sensory Systems
Review Questions
1. What is the difference between a sense organ 8. Compare and contrast the signal transduction
and a sensory receptor? mechanisms used by gustatory receptors to
2. What are the primary stimulus modalities de- detect the primary types of tastants.
tected by animal sensory receptors? 9. Using the vertebrate ear as an example, out-
3. What is a receptor potential? How does it dif- line some of the ways in which sensory sys-
fer from a generator potential? tems amplify environmental stimuli.
4. Explain labeled-line coding and give an exam- 10. Outer hair cells respond to sounds, but they do
ple of the kinds of sensory information that not make synaptic connections with afferent
can be encoded by this method. neurons that carry sound information to the
brain. What is their role in hearing?
5. What is the relationship between the intensity
of a stimulus and the response of the primary 11. Compare and contrast the rods and cones of
afferent neuron? How do neurons encode mammals. Does this distinction apply to all
changes in stimulus intensity? vertebrates?
6. Many sensory systems encode stimuli loga- 12. Explain the role of the following types of cells
rithmically. Compare and contrast this ap- in the mammalian retina, using one or two
proach with range fractionation. sentences for each answer: rods, cones, hori-
zontal cells, bipolar cells, amacrine cells, reti-
7. What is sensory adaptation?
nal ganglion cells.
Synthesis Questions
1. Mechanoreceptors do not depolarize in re- 5. Why do the inner ears of most vertebrates have
sponse to light, no matter how intense the three semicircular canals and not just one?
stimulus, but the eye responds to a mechani- 6. Peripheral vision is the ability to detect objects
cal stimulus (such as pressing on the eyeball) outside the center of the visual field. Vertebrates
if the stimulus is sufficiently large. Why might vary in the extent of their peripheral vision.
this be? What differences would you expect in the retina
2. Do taste receptors use labeled-line coding? of an animal with excellent peripheral vision,
Why or why not? compared to one with poor peripheral vision?
3. Receptors for fine touch are typically located 7. Humans have only three types of cone pho-
in the shallow layers of the skin, while recep- toreceptors, but can distinguish thousands of
tors for stronger touch stimuli are typically lo- colors. How is this possible?
cated in deeper layers. Why might this be so? 8. What predictions could you make about what
4. Hair cells have prominent cilia on their apical would happen to vision in an individual with a
surface. Why do these cilia increase the sensi- degenerative disease that destroyed the hori-
tivity of a hair cell to mechanical stimuli? zontal cells of the retina?
1. You are studying a sensory receptor and find (a) Graph the results for generator potential
that the amplitude of the receptor (generator) amplitude and action potential frequency.
potential increases linearly with the log of the (b) What do these results tell you about how
stimulus intensity. The generator potential re- this receptor encodes stimulus intensity?
sults in a train of action potentials whose fre- 2. One way in which the vertebrate auditory sys-
quency increases linearly with increasing tem detects the location of a sound is to com-
generator potential (above the threshold pare the time at which a sound reaches one
value). You also observe that above a certain ear to the time at which that sound reaches the
level, additional increases in stimulus inten- other ear.
sity do not result in increases in action poten- (a) How long would it take for a sound reach-
tial frequency. ing the left side of the head to reach the
329
Sensory Systems
right ear, assuming that the distance be- ceptor, but in which each receptor can detect
tween the ears is approximately 12 cm several odorants. You are a scientist working
and that the speed at which a sound trav- on a little-known vertebrate, the schmoo,
els through the head is approximately and have discovered 100 functional olfactory
1000 m/s? G-protein coupled receptors in the schmoo
(b) Neurotransmission takes approximately genome. Assuming a simple combinatorial
10–20 milliseconds. Using this informa- code, how many potential odorants could a
tion and the value you calculated in part a, schmoo distinguish if each receptor could de-
what are the implications for the localiza- tect 3 different odorants. What if each recep-
tion of a sound? tor could detect 5 different odorants? What is
3. The vertebrate olfactory system uses a combi- the minimum number of genes required to dis-
natorial coding scheme in which each odorant criminate among 10,000 different odorants if
receptor cell expresses only a single allele of a each receptor can detect 2 different odorants?
single gene of a G-protein-coupled odorant re-
For Further Reading

See the Additional References section at the end The following reviews report recent findings
of the chapter for more readings related to the regarding the sense of taste.
topics in this chapter. Gilbertson, T. A., and J. D. Boughter, Jr. 2003.
Taste transduction: Appetizing times in
gustation. Neuroreport 14: 905–911.
General Properties of Sensory Reception
Reed, D. R., T. Tanaka, and A. H. McDaniel.
This excellent book summarizes the mechanisms 2006. Diverse tastes: Genetics of sweet and
by which sensory receptors transduce incoming bitter perception. Physiology and Behavior 88:
sensory stimuli. The book is comprehensive but 215–226.
accessible, and includes examples from both
vertebrates and invertebrates. This book is an This interesting review discusses the evolution of
ideal “next step” for students who want more olfaction, pheromone detection, taste, and the
information about sensory systems than can be sense of vision in mammals, with a focus on the
presented in a single chapter in a physiology primates.
textbook.
Liman, E. R. 2006. Use it or lose it: Molecular
Fain, G. L. 2003. Sensory transduction. evolution of sensory signaling in primates.
Sunderland, MA: Sinauer Associates. Pflugers Archiv: European Journal of
Physiology 453: 125–131.
Chemoreception Mechanoreception
These reviews discuss the mechanisms of These reviews discuss the mechanisms of
olfaction and the evolution of olfactory systems in mechanoreception and the discovery of the
animals. molecules involved in transducing mechanical
Breer, H. 2003. Sense of smell: Recognition and stimuli into changes in membrane potential.
transduction of olfactory signals. Biochemical Ernstrom, G. G., and M. Chalfie. 2002. Genetics
Society Transactions 31: 113–116. of sensory mechanotransduction. Annual
Eisthen, H. 2002. Why are olfactory systems of Review of Genetics 36: 411–453.
different animals so similar? Brain, Behavior, Gillespie, P. G., and R. G. Walker. 2001. Molecular
and Evolution 59: 273–293. basis of mechanosensory transduction. Nature
Malnic, B., J. Hirono, T. Sato, and L. B. Buck. 413: 194–202.
1999. Combinatorial receptor codes for odors. Goodman, M. B., and E. M. Schwarz. 2003.
Cell 96: 713–723. Transducing touch in C. elegans. Annual
Menashe, I., and D. Lancet. 2006. Variations in Review of Physiology 65: 429–452.
the human olfactory receptor pathway. Nicolson, T. 2005. Fishing for key players in
Cellular and Molecular Life Sciences 63: mechanotransduction. Trends in Neuroscience
1485–1493. 28: 140–144.
330
Sensory Systems
This comprehensive review by LeMasurier and Thermoreception

Gillespie provides an excellent introduction to the These reviews discuss the recently discovered
structure and function of the mammalian inner TRP channels that are involved in temperature
ear and its role in sound transduction. sensing.
LeMasurier, M., and P. G. Gillespie. 2005. Hair- Dhaka, A., V. Viswanath, and A. Patapoutian.
cell mechanotransduction and cochlear 2006. TRP ion channels and temperature
amplification. Neuron 48: 403–415. sensation. Annual Review of Neuroscience 29:
135–161.
This review discusses the role of the outer hair
cells in the mammalian ear, and the role of the Jordt, S. E., D. D. McKemy, and D. Julius. 2003.
prestin gene as part of their molecular motors. Lessons from peppers and peppermint: The
molecular logic of thermosensation. Current
Geleoc, G. S. G., and J. R. Holt. 2003. Auditory Opinion in Neurobiology 13: 487–492.
amplification: Outer hair cells pres the issue.
Trends in Neuroscience 26: 115–117. Patapoutian, A., A. M. Peier, G. M. Story, and V.
Viswanath. 2003. ThermoTRP channels and
This paper is the first report of the identification beyond: Mechanisms of temperature sensation.
of a mechanosensory channel in vertebrate hair Nature Reviews: Neuroscience 4: 529–539.
cells. Magnetoreception
Sidi, S., R. W. Friedrich, and T. Nicolson. 2003. This paper reports a possible mechanism for
NompC TRP channel required for vertebrate magnetoreception in vertebrates.
sensory hair cell mechanotransduction.
Science 301: 96–99. Diebel, C. E., R. Proksch, C. R. Green, P. Neilson,
and M. M. Walker. 2000. Magnetite defines a
Photoreception vertebrate magnetoreceptor. Nature 406:
These reviews discuss the evolution of eyes and 299–302.
visual pigments in a variety of organisms.
This comprehensive review outlines the two
Arendt, D. 2003. The evolution of eyes and mechanisms currently proposed to underlie
photoreceptor cell types. International Journal magnetoreception in the vertebrates.
of Developmental Biology 47: 563–571.
Wiltschko, R., and W. Wiltschko. 2006.
Briscoe, A. D., and L. Chittka. 2001. The Magnetoreception. BioEssays 28:157–168.
evolution of color vision in insects. Annual
Review of Entomology 46: 471–510. Circadian Rhythms
Fernald, R. D. 2006. Casting a genetic light on These reviews highlight some of the recent
the evolution of eyes. Science 313: 1914–1918. findings regarding circadian rhythms in
Fernald, R. D. 2000. Evolution of eyes. Current mammals and other animals.
Opinion in Neurobiology 10: 444–450. Macchi, M. M., and J. N. Bruce. 2004. Human
Hisatomi, O., and F. Tokunaga. 2002. Molecular pineal physiology and functional significance
evolution of proteins involved in vertebrate of melatonin. Frontiers in Neuroscience 25:
phototransduction. Comparative Biochemistry 177–195.
and Physiology, Part B: Biochemistry and Panda, S., and J. B. Hogenesch. 2004. It’s all in
Molecular Biology 133: 509–522. the timing: Many clocks, many outputs.
Yokoyama, S., and R. Yokoyama. 1996. Adaptive Journal of Biological Rhythms 19: 374–387.
evolution of photoreceptors and visual Peirson, S., and R. G. Foster. 2006. Melanopsin:
pigments in vertebrates. Annual Review of Another way of signaling light. Neuron 49:
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Baylor, D. 1996. How photons start vision. Proceedings of the Julius, D., and A. I. Basbaum. 2001. Molecular mechanisms
National Academy of Sciences, USA 93: 560–565. of nociception. Nature 413: 203–210.
Buck, L. B. 2000. The molecular architecture of odor and Kirschvink, J. L., M. M. Walker, and
pheromone sensing in mammals. Cell 100: 611–618. C. E. Diebel. 2001. Magnetite-based magnetoreception.
Burighel, P., N. J. Lane, G. Fabio, T. Stefano, G. Zaniolo, M. D. Current Opinion in Neurobiology 11: 462–467.
Carnevali, and L. Manni. 2003. Novel, secondary sensory Martin, V. 2002. Photoreceptors of cnidarians. Canadian
cell organ in ascidians: In search of the ancestor of the Journal of Zoology 80: 1703–1722.
vertebrate lateral line. Journal of Comparative Neurology Smotherman, M. S., and P. M. Narins. 2000. Hair cells,
461: 236–249. hearing, and hopping: A field guide to hair cell physiology
Fay, R. R., and A. N. Popper. 2000. Evolution of hearing in in the frog. Journal of Experimental Biology 203:
vertebrates: The inner ear and processing. Hearing 2237–2246.
Research 149: 1–10. Tobin, D. M., and C. I. Bargmann. 2004. Invertebrate
Fernald, R. D. 2004. Evolving eyes. International Journal of nociception: Behaviors, neurons and molecules. Journal of
Developmental Biology 48: 701–705. Neurobiology 61: 161–174.
Field, G. D., A. P. Sampath, and F. Rieke. 2005. Retinal Yamamoto, T., K. Taskai, Y. Sugawara, and A. Tonosaki.
processing near absolute threshold: From behavior to 1965. Fine structure of the octopus retina. Journal of Cell
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Credits
247 Oliver Meckes/Nicole Ottawa/Photo Researchers, Inc.
248 Paul Johnson/Nature
Picture Library.
249 Photo Researchers, Inc., Eye of Science/Photo
Researchers, Inc.
249 Photo Researchers, Inc., SPL/Photo Researchers, Inc.
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Biological Supply Company/Phototake.
298 imagebroker/Alamy.
332
333
Functional Organization of Nervous Systems
The ancient Egyptians and Greeks considered the brain to be anatomists and physiologists felt that the brain was not sub-
of little importance; when preparing a mummy for burial, divided into functional regions, but instead worked together
the Egyptians would carefully preserve the heart but discard as a whole, without any regional specialization.
the brain, because they believed the heart to be the seat of By the 19th century, however, detailed observations of
consciousness. The Greek philosopher Aristotle, working in patients suffering from brain injuries, tumors, or strokes
the 4th century B.C., thought that the brain acted as a sort of led physiologists to the conclusion that parts of the brain
cooling system for the spirit (or soul), but that the soul was were specialized for particular functions. One of the most
located in the heart. Five hundred years later, the Greek famous cases of this time was that of Phineas Gage. Gage,
physician Galen disputed this finding, and concluded that a railway worker, was injured on September 13, 1848, when
mental activity occurred within the brain because of his ob- a blasting charge that he was preparing accidentally ex-
servations of the effects of head injuries in Roman gladia- ploded and drove a tamping iron into his skull. (A tamping
tors. However, in subsequent centuries, physiologists and iron is a tool similar to a crowbar that is used to compact an
anatomists made little progress beyond the observations of explosive charge into a borehole.) The resulting blast blew
Galen in understanding the workings of the brain. The hu- the tamping iron out of the borehole and into Mr. Gage’s left
man brain appears to be rather uniform, composed of a soft cheek. It passed all the way through his head, exiting from
amorphous tissue. Indeed, because of its gelatinous ap- the top of his skull and landing over 25 yards away. Mr. Gage
pearance, up until the middle of the 17th century most survived the accident, but his brain injuries left his person-
334
A computer-generated representation of the 1848 Phineas Gage accident.
A London taxi driver.
ality changed. Before the accident he had been efficient, netic field, just as a compass aligns with the Earth’s mag-
well balanced, and highly intelligent. After the accident, he netic field. The MRI machine then sends out a pulse of ra-
was reported to be irritable, profane, and unable to make dio energy. This pulse briefly knocks the hydrogen atoms
decisions. He was still functional in many respects, but his out of alignment. As the hydrogen atoms return to their
personality was profoundly altered. Cases like that of aligned position they emit energy, which the MRI machine
Phineas Gage, and of patients with strokes or other brain can detect and interpret. Because the amount of water
damage, helped anatomists assign functions to various (and hence hydrogen atoms) varies in different structures
parts of the brain, and provided increasing insights into the of the brain, an MRI machine can provide detailed brain
way the brain works. images. Functional MRI is a simple modification of this
In this century, brain-imaging technology is revolu- technique. Parts of the brain that are working harder re-
tionizing the way in which physiologists study the functions quire more oxygen than parts of the brain that are resting,
of the brain and has revealed an astonishing level of plas- and thus tend to deplete the oxygen from the blood. It turns
ticity. For example, scientists have been able to determine out that the MRI signal is a little different between oxy-
that the brains of taxi drivers working in London, England, genated and deoxygenated blood, so the MRI signal
differ from those of other people. In order to get a license changes as a subject uses different parts of the brain. If you
to drive a taxi in London, drivers must pass a difficult test make a series of MRI images while asking a subject to per-
that assesses their ability to find their way. The streets of form a mental task, you generate a so-called fMRI image, in
London are not laid out in a grid pattern, which makes nav- which you can observe changes in blood flow (and thus
igating in London without a map difficult. London taxi drivers changes in activity) in different parts of the brain. For exam-
have an enlarged hippocampus, a part of the brain known ple, listening to music activates a part of the brain involved in
to be involved in spatial relationships and memory. processing incoming auditory information, whereas speak-
But are these differences the result of training, or are ing activates different parts of the brain. Studies using fMRI
people with these unusual brain structures simply at- are revealing the truly dynamic nature of the brain. For ex-
tracted to professions in which they can excel? A new tech- ample, there are observable changes in the brains of adults
nique called functional magnetic resonance imaging when they are taught a new alphabet.
(fMRI) is providing a way to address this question. Func- As for the London taxi drivers, recent studies have
tional MRI is a modification of the MRI technique that was shown that the differences in their brain structure and ac-
developed in the late 1970s. An MRI machine emits a pow- tivity are a result of practice, not an accident of birth. The
erful magnetic field that can be directed at the brain (or at brain can alter its structure and function in response to
other parts of the body). This magnetic field causes the hy- training, and thus there is a physiological basis for the
drogen atoms in water molecules to realign with the mag- adage, “Practice makes perfect.”2
335
Overview muscles, glands, and internal organs. Thus, the

nervous system acts to sense environmental in-
The nervous system is one of the body’s homeo- formation, integrate this information, and coor-
static control systems, helping to regulate physi- dinate the response.
ological processes and coordinate behavior. But In this chapter we first examine the evolution
how do the many individual neurons that make of nervous systems and their organization. We
up the nervous system work together to perform then take a closer look at the functions of the prin-
these complex tasks? Like other homeostatic con- cipal integrating centers of vertebrates—the
trol systems, the nervous system contains sen- brain and spinal cord—using mammals as an ex-
sors, integrating centers, and output pathways ample. Next, we focus on the peripheral nervous
(Figure 1). Sensory receptors detect incoming system, looking at the organization of the efferent
stimuli and convert the signal to a change in pathways that carry signals to effector organs. Fi-
membrane potential. Afferent sensory neurons nally, we end the chapter with a consideration of
carry these signals to one or more integrating the integrated functions of the nervous system,
centers, such as a brain or ganglion. Integrating addressing how sensory receptors, afferent neu-
centers typically contain many interneurons, rons, integrating centers, and efferent pathways
which (as the name suggests) form synaptic con- work together to allow organisms to perform
nections among neurons. The more interneurons complex behaviors and maintain physiological
that are added to a neural pathway, the greater homeostasis.
the possibilities for interconnections, and the
greater the ability to integrate information. The
complex behavioral and physiological control Organization of Nervous
systems of animals result from these multistep Systems
neural pathways, which find their most elaborate
form in large integrating centers such as the mam- Most nervous systems are organized into three
malian brain. For example, an average human functional divisions: the afferent sensory division;
brain contains more than 100 billion neurons con- integrating centers; and the efferent division. Only
nected via trillions of synapses. Integrating cen- the cnidarians (a phylum that includes jellyfish
ters ultimately send an output signal via efferent and sea anemones, among others) have nervous
neurons to effector organs, including skeletal
Central Integrating center

nervous (e.g., brain, ganglia)
system Interneuron
Afferent neuron Efferent neuron
Peripheral
nervous
system
Sensory receptors Effector organs

Incoming (e.g., mechanoreceptors, (e.g., muscles, glands)
Output
stimulus photoreceptors)
Sensors Integrating Output

centers pathways
Figure 1 An overview of the nervous system The of action potentials to integrating centers such as the brain or
nervous system contains sensors, integrating centers, and ganglia. Interneurons within the integrating centers process
output pathways. Sensory receptors convert the energy from the information and send out signals via efferent neurons to
incoming stimuli of various kinds to changes in the membrane effectors such as the muscles and internal organs, resulting in
potential. Afferent neurons conduct these signals in the form changes in behavior or physiological processes.
336
systems that depart from this general plan. cnidarian neurons are not specialized but can
Cnidarians are radially symmetrical animals with function as sensory neurons, interneurons, or ef-
nervous systems that are interconnected into a ferent neurons, and can communicate synaptically
large web (or nerve net) with neurons distributed at several points along their length. Cnidarian neu-
throughout the body (Figure 2a). In general, rons often form en passant synapses, allowing in-
formation to be passed in either direction across
Mouth the synapse. In fact, many cnidarian neurons are
Tentacles functionally bipolar in that a stimulus at any point
on the organism triggers an impulse that radiates
out from the stimulus site in every direction.
Despite having a seemingly simple nervous
Nerve net organization and no obvious single integrating
center, cnidarians can perform some rather com-
plex behaviors. For example, the sea anemone
Calliactis parasitica attaches its tentacles onto a
mollusc shell and somersaults onto the shell (Fig-
(a) ure 2b), a behavior that involves detecting a shell,
using its tentacles to grab onto the shell, detach-
ing its foot from the substrate, making coordi-
1 The tentacles of the nated movements of the whole body to somersault
sea anemone up onto the shell, and reattaching its foot onto the
encounter a whelk
shell. shell. Thus, the apparent simplicity of the cnidar-
ian nerve net must hide substantial complexities.
In some species the nerve net is broken down
into several pathways with characteristic conduc-
tion speeds that control different behavioral re-
2 The sea anemone sponses. In addition, in some species neurons are
grasps the shell with
its tentacles. concentrated around the oral opening, or into
clusters in other locations. These groupings of
neurons may act as integrating centers, providing
additional layers of functional complexity to the
nervous system. In fact, in many species of cnidar-
ians epithelial cells can also generate action poten-
3 The sea anemone tials, and are connected via gap junctions, adding
releases its foot from
the substrate. yet another layer of complexity.
Evolution of Nervous Systems

Unlike the cnidarians, most animals are
4 The anemone
performs a somersault, bilaterally symmetrical; they have an anterior
attaching its foot to the and a posterior end and a right and left side. In bi-
whelk shell and
releasing its tentacles. laterally symmetrical organisms, sense organs
tend to be concentrated at the anterior end of the
body, close to the mouth, and the relatively un-
(b) structured netlike organization of the cnidarian
Figure 2 The nervous system of cnidarians (a) nervous system is replaced by more complex
Cutaway view of a sea anemone, showing the nervous groupings of neurons. For example, bilaterally
system. The cnidarian nervous system is diffuse, composed symmetrical animals typically have one or more
of a loosely organized nerve net. (b) Shell-climbing behavior
ganglia, which are groupings of neuronal cell
in a sea anemone, Calliactis parasitica. Despite their
seemingly simple nervous systems, cnidarians can perform
complex behaviors.
337
bodies interconnected by synapses. Ganglia func- Axon

tion as integrating centers for the nervous system.
In many species, the ganglia in the anterior region Myelin sheath
of the body are grouped together into larger clus- Endoneurium

ters forming a brain, a complex integrating cen-
ter. Within the brain, groupings of neuronal cell
bodies are termed nuclei, which are the functional
equivalent of ganglia, and groupings of neuronal
axons are called tracts. Outside of the integrating Perineurium
centers, the axons of afferent and efferent neurons
are usually organized into structures called nerves, Fascicle
which are the functional equivalent of the tracts in
the integrating centers.
Figure 3 illustrates the structure of a verte- Blood vessels
brate nerve, which consists of parallel bundles of
myelinated and unmyelinated axons enclosed in
several layers of connective tissue. Within a nerve,
individual axons and their myelin sheaths (if pres- Epineurium
ent) are surrounded by the endoneurium. Many
axons are bundled together into structures called
fascicles by another layer of connective tissue, the
perineurium. Several fascicles and blood vessels
are grouped together, enclosed by a fibrous layer
of connective tissue called the epineurium, form-
Nerve
ing the nerve. Most nerves contain axons of both
afferent and efferent neurons, and are thus
termed mixed nerves, although there are some
purely afferent or purely efferent nerves.
Figure 3 The structure of a vertebrate nerve A

Bilaterally symmetrical animals exhibit nerve is composed of groups of axons from many neurons
cephalization surrounded by successive layers of connective tissue (the
endoneurium, perineurium, and epineurium).
The pattern of locating sense organs and nervous
integrating centers at the anterior end of the body,
known as cephalization, becomes increasingly ap- formation between the tissues and the various inte-
parent in more complex nervous systems. The de- grating centers. Similarly, the arthropod nervous
gree of cephalization varies greatly among the system contains a brain, a ventral nerve cord, and
bilaterally symmetrical invertebrates, although a large ganglion within each body segment. The
most species have a well-developed brain, several nervous system varies greatly in complexity among
ganglia, and one or more nerve cords (Figure 4). In the molluscs, although most species have dual
the invertebrates, bundles of axons that connect nerve cords and a series of large ganglia, including
ganglia or run between a ganglion and the brain are the cerebral ganglia (which innervate the head and
called connectives or commissures. Flatworms are neck), the buccal ganglia (which innervate the
the simplest of the bilaterally symmetrical animals. mouth and stomach), and the pedal ganglia (which
Some species of flatworms lack an obvious brain, innervate the foot). In the cephalopod molluscs (a
while others have a well-developed brain that al- group that includes octopus and squid), the anterior
lows them to perform complex behaviors and even pairs of ganglia are greatly expanded and placed
learn tasks such as navigating a maze. Nemertine, close together to create a tightly packed mass that
nematode, and annelid worms have a more struc- lies between the eyes and encircles the esophagus—
tured nervous system than flatworms, with a well- in other words, a large and complex brain.
developed brain, ganglia in each body segment, An octopus has a brain that is much larger rel-
and one or more nerve cords that communicate in- ative to its body size than the brain of a fish or a
338
Brain Brain
Nerve net
Nerve ring Brain
Nerve
cords Ventral
nerve cord
Ganglion
Thoracic ganglion
(a) Cnidarian (b) Platyhelminth (c) Annelid (d) Arthropod

(jellyfish) (planarian) (earthworm) (crab)
Ganglion
Ganglia Radial
nerve Brain
Brain
Nerve
cord
Nerve Dorsal nerve cord
Ganglion ring (spinal cord)
Ganglion
(e) Mollusc (f) Cephalopod (g) Echinoderm (h) Chordate

(limpet) mollusc (squid) (sea star) (alligator)
Figure 4 Organization of the nervous system in representative animal

groups The cnidarians have a nerve net, while all other groups (with the exception of the
radially symmetrical echinoderms) display some degree of cephalization.
reptile, suggesting the possibility of substantial in- nerve rings. Echinoderms are descended from a bi-
telligence. An octopus can learn to navigate a laterally symmetrical ancestor that likely had some
maze and distinguish between objects with differ- cephalization. Presumably, present-day echino-
ent shapes, sizes, and degrees of brightness. Some derms lost this ancestral cephalization during the
studies indicate that an octopus can even learn by transition to a radially symmetrical body plan. In
simply watching another octopus perform a task. fact, many modern echinoderm groups have bilat-
Although an octopus has a very large brain, it has erally symmetrical larvae that develop radial sym-
another important integrating center; each arm metry during metamorphosis to the adult form.
has a large ganglion that controls arm movements In general, organisms with more complex ner-
and that can function essentially independently of vous systems have more neurons than organisms
the brain. When researchers severed the connec- with less complex nervous systems. However, the
tions between the brain and the arm of an octopus total number of neurons is not necessarily larger
and then stimulated the skin on the arm, the arm in species with more complex integrating centers.
behaved exactly as it would have in an intact octo- For example, some species of flatworms have sev-
pus. Thus, the integrating center of an octopus is eral thousand neurons, despite lacking an obvious
actually highly distributed and involves both the brain. In contrast, the entire nervous system of the
brain and the ganglia. nematode Caenorhabditis elegans contains only
The echinoderms (sea stars and their relatives) 302 neurons and about 6000 synapses, despite
are one of the few exceptions to the general trend having a clearly recognizable brain. Thus, the re-
of increasing cephalization in animals. These radi- lationship between the number of neurons and the
ally symmetrical animals lack an obvious brain, organization of the nervous system is not always
and instead have a series of ganglia and several clear-cut.
339
The vertebrate central nervous system is from a common ancestor with a nervous system
enclosed in a protective covering similar to that of flatworms. One of the unique
characteristics of the vertebrate nervous system is
Vertebrates are among the most highly cephalized
that a portion of the nervous system is encased
organisms, and are unique in possessing a hollow
within a cartilaginous or bony covering. This por-
dorsal nerve cord, rather than the solid ventral
tion of the nervous system is termed the central
nerve cord seen in invertebrates (Figure 5). How
nervous system, and is composed of the brain
the vertebrate nervous system evolved from an in-
(located within the skull) and the spinal cord (lo-
vertebrate ancestor is still a matter of consider-
cated within the spine). The remainder of the ner-
able debate, although it has been suggested that
vous system, which is found throughout the rest
protostome (e.g., worm, mollusc, and arthropod)
of the body, is termed the peripheral nervous
and deuterostome (e.g., vertebrate and echino-
system.
derm) nervous systems evolved independently
Cerebrum
Cerebellum
Brainstem
Cervical
nerves
Spinal
cord
Thoracic
nerves
Gray matter Dorsal root

Afferent neuron
Dorsal horn White matter (cell body)
Lumbar
nerves Dorsal root ganglion
Afferent axon
Spinal nerve
Sacral nerves
Ventral horn Efferent axon
Coccygeal Efferent neuron Ventral
nerve (cell body) root
(a) (b)
Figure 5 Structure of the vertebrate central regular intervals. These nerves are part of the peripheral
nervous system (a) The brain and spinal cord. The nervous system. (b) Cross-section of a mammalian spinal
central nervous system is composed of the brain and spinal cord. The spinal cord contains both gray and white matter.
cord, enclosed in a cartilaginous or bony covering (the skull Afferent sensory neurons enter the spinal cord on the dorsal
and spine). The cranial nerves emerge from the braincase, side, and efferent neurons exit the spinal cord on the ventral
whereas the spinal nerves emanate from the spinal cord at side.
340
The cranial and spinal nerves form in the region of the neck and innervate the head,
synapses in the central nervous system neck, arms, hands, and diaphragm. The thoracic
spinal nerves emerge from the spinal cord in the
In the vertebrates, a series of nerves, called the
chest region, and innervate the intercostal muscles
cranial nerves, exit directly from the braincase,
(involved in breathing) and the heart. The lumbar,
whereas the spinal nerves emerge from the
sacral, and coccygeal spinal nerves emerge in the
spinal cord at regular intervals. For historical rea-
lower back and pelvis and innervate the legs,
sons, we often refer to the 12 pairs of cranial
pelvis, bladder, and bowel. Although the spinal
nerves, which are labeled with roman numerals,
nerves emerge from the vertebral column along its
but in fact many vertebrates have 13 pairs of cra-
entire length, the spinal cord itself does not reach
nial nerves (Table 1). Some of the cranial nerves
all the way down into the lumbar region. Instead,
bring in afferent information from the sense or-
the lumbar, sacral, and coccygeal nerves branch
gans, whereas other nerves send efferent signals
out from the spinal cord and travel down the ver-
out to effector organs, such as muscles, glands,
tebral column to the point where they exit. Thus,
and organs. The spinal nerves are named based on
the bottom third of the vertebral column contains
the region of the spine where they originate. The
spinal nerves but no spinal cord.
cervical spinal nerves emerge from the spinal cord
Table 1 The cranial nerves.
Number Name Principal functions

0 Terminal Function unclear. Probably neuromodulatory, regulating olfactory sensitivity
and reproductive behavior. Absent in cyclostomes, birds, and humans.
I Olfactory Olfaction; chemosensory afferents.
II Optic Vision; integrates information from the retina. An extension of the central
nervous system rather than a true nerve.
III Oculomotor Controls eye movements, constriction of pupil, and focusing of lens.
Innervates most of the muscles of the eye and eyelid (where present).
IV Trochlear Eye movement. Innervates the superior oblique eye muscle.
V Trigeminal Motor nerve controlling muscles of chewing and mouth. Contains sensory
afferents from most of head and parts of lateral line in fishes.
VI Abducens Eye movement. Innervates the lateral rectus muscle of the eye and the
nictitating membrane (additional eyelid) of reptiles, birds, and some
mammals.
VII Facial Taste and somatosensory afferents. Motor nerve controlling muscles of face.
Controls lachrymal and some salivary glands. Serves parts of lateral line in
fishes.
VIII Vestibulocochlear Sensory afferents for hearing and equilibrium.
(also called auditory)
IX Glossopharyngeal Motor control of one of the muscles of swallowing. General and taste
sensation from pharynx and posterior part of tongue. Innervates parts of
lateral line in fishes.
X Vagus Motor control of larynx, pharynx, upper end of esophagus. Parasympathetic
neurons controlling internal organs, including heart, breathing, and much of
the alimentary canal. Also includes a sensory component. In fishes, contains
sensory afferents from lateral line system of body and tail.
XI Accessory Motor control of some muscles that move the head. Not a true cranial nerve:
results from fusion of parts of vagus and first two spinal nerves. Absent in
fishes except the Crossopterygii.
XII Hyopoglossal Motor control of the muscles of the tongue. Absent in fishes except the
Crossopterygii.
341
Both the brain and spinal cord contain two called the dura mater and a thin secondary
types of tissue, the so-called gray matter and meninx. Mammals have three meninges. Like the
white matter. White matter consists of bundles of other tetrapods they have the dura mater, but the
axons and their associated myelin sheaths, while secondary meninx is divided into a weblike middle
gray matter is composed of neuronal cell bodies layer called the arachnoid and a thin inner layer
and dendrites. In the spinal cords of all vertebrates, called the pia mater. Within the meninges, the
the white matter is located at the surface, and the brain and spinal cord float in a plasma-like fluid
gray matter is located inside. In cross-section, the called cerebrospinal fluid (CSF), which acts as a
gray matter of the spinal cord often has a butterfly- shock absorber and cushions the delicate tissues
shaped appearance, a pattern that is particularly of the central nervous system.
evident in humans (see Figure 5). The “wings” of The vertebrate central nervous system is also
this butterfly are termed the dorsal and ventral physiologically separated from the rest of the body.
horns. Afferent sensory neurons from the periph- The blood-brain barrier, which is formed by
ery terminate in the dorsal horn where they tight junctions between the endothelial cells lining
synapse on interneurons or efferent neurons. The the brain capillaries, prevents materials from leak-
cell bodies of these bipolar sensory neurons are lo- ing out of the bloodstream and into the central ner-
cated outside the spinal cord in the dorsal root gan- vous system via paracellular pathways (between
glia. Efferent neurons originate in the ventral horn the cells). In addition, these cells do not perform
of the spinal cord and exit through the ventral root. pinocytosis, so the only ways that substances can
move into the brain are by directly dissolving in the
membrane or by catalyzed transport via a protein
The central nervous system is separated exchanger, channel, or pump. Small, lipid-soluble
from the rest of the body molecules such as ethanol and some barbiturate
One or more protective layers of connective tissue drugs can cross directly into the central nervous
called the meninges (singular meninx) surround system, but most substances are excluded. How-
the brain and spinal cord (Figure 6). Fish have ever, a number of specialized carrier transport
only a single thin meninx, whereas amphibians, systems allow the brain to take up circulating nu-
reptiles, and birds have two: a thick outer layer trients such as glucose and amino acids. Thus, the
blood-brain barrier protects the brain
from harmful substances while allow-
ing useful molecules to enter. There
are several areas of the brain where
Skull (cranium) the blood-brain barrier is more per-
meable. In particular, the regions
Dura mater around the pineal gland, the pituitary
Arachnoid mater Cranial gland, and parts of the hypothalamus
Pia mater meninges are quite permeable, allowing se-
creted molecules such as hormones to
leave the brain and enter the circula-
tory system.
Dura mater
The vertebrate brain has three
Arachnoid mater Spinal main regions
meninges
Pia mater
During embryonic development, both
the brain and the spinal cord of verte-
Vertebra brates are formed from a simple hollow
Spinal cord tube of ectoderm-derived cells called
the neural tube. The posterior portion
of the neural tube forms the spinal
Figure 6 The meninges The meninges are protective membranes that cord, while the anterior end of the neu-
surround the brain. Mammals have three meninges, whereas other species have fewer. ral tube develops three swellings that
342
ultimately form the brain (Figure 7). Anterior (rostral) Posterior (caudal)
These three regions, which are found
in all vertebrate brains, are called the
rhombencephalon (hindbrain), the
Primary Forebrain Midbrain Hindbrain Spinal cord
mesencephalon (midbrain), and the brain vesicles
prosencephalon (forebrain). Be-
cause the vertebrate brain is simply
an extension of the spinal cord, it is
also hollow on the inside. These cen-
tral cavities are called the ventricles, Secondary
and they are filled with cerebrospinal brain vesicles
fluid. Ciliated ependymal cells circu-
late the cerebrospinal fluid through
the ventricles and the spinal cord.
The hindbrain controls most re-
Myelencephalon
flex responses and regulates invol-
Mesencephalon
Metencephalon
Telencephalon
Diencephalon
untary behaviors such as breathing
Spinal cord
and the maintenance of body posi-
tion. The midbrain is predominantly
involved in coordinating visual, au-
ditory, and sensory information
Adult brain
from touch and pressure receptors (generalized
(although in mammals, as we shall vertebrate)
see later in the chapter, it acts
largely as a routing center rather Cerebral Cerebellum Medulla Spinal cord
than an integrating center per se). cortex
Thalamus
The forebrain is involved in process-
ing olfactory information, integrating
Pons
it with other sensory information,
and regulating functions such as
Olfactory bulb Hypothalamus Pituitary
body temperature, reproduction, eat-
ing, sleeping, and emotion. The fore-
Figure 7 Fundamental divisions of the vertebrate central nervous
brain is also involved in learning and system During embryonic development, the neural tube quickly subdivides into the
memory, and performs other com- primary brain vesicles, which subsequently form the secondary brain vesicles and
plex processing tasks, particularly in then the structures of the adult brain.
mammals.
Variation in brain size among taxa is largely a

Brain size and structure vary among result of changes in the relative sizes of different
vertebrates parts of the brain, rather than in the development
Brain size varies greatly among vertebrates (Fig- of entirely new structures (Figure 9). For example,
ure 8), but much of this variation can be accounted bony fishes and birds have a relatively large mid-
for by differences in body size, because, within brain and cerebellum—the parts of the brain in-
each group, larger animals tend to have larger volved in the interpretation of sensory signals and
brains. But at any given body size, brain size can coordinating motion. Fishes and birds live in a com-
differ substantially among taxa. In particular, plex world that they move through in three dimen-
birds and mammals have unusually large brains sions, in contrast to terrestrial organisms that can
for their body size—six to ten times larger than move only along the ground. It has been suggested
those of similarly sized reptiles. Presumably, or- that fishes and birds use their enlarged midbrain
ganisms with large brains compared to their body and cerebellum in order to interpret complex sen-
size have more complex integrating centers and sory information and coordinate their body move-
an expanded repertoire of behaviors. ments in this three-dimensional environment.
343
brain, as is typical for reptiles. The

10,000
isocortex of mammals and the DVR of
Mammals birds perform similar functions, and
1,000 are thought to have evolved inde-
pendently from similar structures in
100 the reptilian brain. This subject is of
Brain weight (g)
Birds Cartilaginous fishes more than just academic interest, be-

10
cause both birds and mammals are
1 capable of performing complex,
Reptiles
Amphibians
learned behaviors, and thus the evo-
.1 lution of brain structures may shed
Agnathans
light on the evolution of intelligence,
.01
a process governed by the isocortex
.001 Bony fishes in mammals.
In addition to this variation
0
.001 .01 .1 1 10 100 1,000 among major groups of vertebrates,
Body weight (kg) there is also substantial variation in
brain size within groups. For exam-
Figure 8 Brain size and body weight The relationship between brain size
and body weight for representative animal groups is plotted on a double logarithmic
ple, the mormyrid fishes have unusu-
scale. Each polygon encloses data from a major vertebrate group. For each group, ally large midbrains relative to other
the polygon rises toward the right, showing that brain size tends to increase with fishes. Mormyrids are weakly electric
body size. fish that use electric fields for naviga-
tion and communication. The mid-
However, the midbrain and cerebellum are not par- brain is involved in sensory processing, and
ticularly large in sharks, which presumably face processing electrosensory information likely re-
similar challenges. In mammals, the midbrain is quires sophisticated neural circuitry. Probably the
greatly reduced in size. In most vertebrates, the most familiar example of variation in brain size
midbrain contains the regions that are involved in within a group of organisms is the relatively large
interpreting visual information, but in mammals size of the human brain compared to that of other
this function has been taken over by the forebrain. mammals—the result of a vast increase in the size
The forebrain is enlarged in both birds and of the forebrain in humans.
mammals relative to the other major groups of
vertebrates. In mammals, the outer layer of the
forebrain is enlarged and reorganized, forming
the isocortex (also called the neocortex). The iso-
cortex is made up of gray matter, whereas the ma-
jority of the internal parts of the mammalian brain 1. Do cnidarians have clearly defined afferent
are made up of white matter, with the exception of neurons, interneurons, and efferent neurons?
structures called the basal nuclei—clusters of 2. What is cephalization?
gray matter deep within the brain. Thus, the 3. What is the difference between a brain and a
mammalian brain is fundamentally reorganized ganglion?
compared to the brains of other vertebrates, 4. Compare and contrast gray matter and white
which have an outer layer of white matter sur- matter.
rounding an inner core of gray matter. Like mam- 5. What is the purpose of the blood-brain barrier?
mals, birds have large forebrains; however, in
birds the cortex is relatively thin and undeveloped.
In contrast, other parts of the forebrain are en-
larged, particularly in a structure called the
dorsoventricular ridge (DVR). The enlarged fore-
Structure and Function
brains of birds and mammals presumably evolved
of the Mammalian Brain
independently, since the last common ancestor of Table 2 lists the names and structures of the prin-
birds and mammals would have had a small fore- cipal parts of the vertebrate brain.
344
Midbrain Cerebellum Midbrain Cerebellum

Forebrain
Forebrain
Mammal
Pituitary
Bird
Midbrain Cerebellum
Pituitary
Forebrain
Midbrain Cerebellum
Forebrain Bony fish

Pituitary
Forebrain
Reptile Midbrain
Pituitary
Cerebellum
Midbrain Cerebellum
Shark
Forebrain Pituitary
Midbrain Cerebellum
Amphibian Forebrain
Pituitary Lamprey
Pituitary
Figure 9 Brain structure in representative vertebrate groups Most groups of

vertebrates have the same major brain structures, although these structures vary greatly in
relative size.
The hindbrain supports basic functions The pons (which means “bridge” in Latin) is
The hindbrain is located between the spinal cord located immediately above the medulla, and is an
and the remainder of the brain, and contains three important pathway that communicates informa-
structurally and functionally distinct regions, the tion between the medulla, the cerebellum, and the
pons, the cerebellum, and the medulla oblongata, forebrain. The pons also contains centers that
which function collectively to support vital bodily control alertness and initiate states such as sleep
processes such as breathing, circulation, and and dreaming, and it regulates reflex activities
movement. such as breathing by influencing the activity of the
The medulla oblongata (often referred to sim- medulla oblongata.
ply as the medulla) is located at the top of the spinal The cerebellum is located at the back of the
cord, and contains reflex centers regulating breath- brain, and consists of two highly folded hemi-
ing, heart rate, and the diameter of blood vessels, spheres. The cerebellum integrates sensory input
thus regulating blood pressure. The medulla oblon- from the eyes, ears, and muscle with motor com-
gata also contains neural pathways that communi- mands from the forebrain, and thus is responsible
cate between the spinal cord and the brain. Many of for motor coordination. In humans, damage to this
these pathways cross over each other in the medulla area during birth can cause cerebral palsy, a dis-
such that the left side of the brain controls the right order characterized by uncontrollable tremors.
side of the body and the right side of the brain con- The cerebellum may also play a role in speech,
trols the left side of the body. Because it regulates learning, emotions, and attention. Although the
such important survival systems, damage to the
medulla is almost always fatal.
345
Table 2 The parts of the brain.
Structure Function
Forebrain: telencephalon
Cerebrum Information processing
Basal ganglia Movements
Amygdala Emotions
Hippocampus Memory
Olfactory bulb Sense of smell
Accessory olfactory bulb Detection of pheromones
Forebrain: diencephalon
Thalamus Integrates sensory information
Hypothalamus, pituitary Regulate body temperature, feeding, reproduction, and circadian rhythms
Epithalamus Melatonin secretion, regulation of hunger and thirst
Midbrain
Tectum (optic lobes) Processes visual, auditory, and touch information
Tegmentum Reflex responses to visual, auditory, and touch information
Hindbrain
Medulla oblongata Generates rhythmic breathing
Regulates heart rate and blood pressure
Pons Regulates breath-holding
Integrates among areas
Cerebellum Maintains body posture
Coordinates locomotion
Integrates information from proprioceptors
cerebellum makes up only 10% of the weight of the flex optical responses such as orienting the eyes
human brain, it contains as many neurons as the toward visual stimuli or adjusting focus, while the
rest of the brain combined. forebrain takes over the majority of visual pro-
cessing. The tectum also contains the paired
inferior colliculi, nuclei that are involved in hear-
The midbrain is greatly reduced ing. Neurons conducting signals from the inner
in mammals
ear form synapses in this region. The posterior
In fish and amphibians, the midbrain coordinates part of the midbrain is called the tegmentum, and
reflex responses to auditory and visual stimuli and contains regions that help with fine control of
is the primary center for coordinating and initiat- muscles. Lesions in this area of the brain can lead
ing behavioral responses. In contrast, in mammals to Parkinson’s disease, a condition associated with
it is much smaller relative to the rest of the brain muscle tremors. In mammals the midbrain is
and primarily serves as a relay center. In non- sometimes grouped together with the pons and
mammalian vertebrates, the roof of the midbrain, medulla oblongata and termed the brainstem.
called the tectum, contains a pair of brain centers
called optic lobes that coordinate sensory input
from the eyes. In mammals these regions are
The forebrain controls complex processes
called the superior colliculi, and are much smaller In mammals, the forebrain is involved in process-
than in other vertebrates, functioning only in re- ing and integrating sensory information, and in
346
coordinating behavior. The forebrain consists of and can lead to a variety of unusual symptoms (see
the cerebrum, the thalamus, the epithalamus, and Box 1, Applications: Split-Brain Syndrome).
the hypothalamus. The cerebrum, whose outer
layer is the cortex, is divided into two cerebral
hemispheres (Figure 10). The left hemisphere The hypothalamus maintains homeostasis
controls the right half of the body, and the right The hypothalamus is located at the base of the
hemisphere controls the left half of the body. Al- forebrain and, as the name suggests, just below the
though the right and left hemispheres seem to be thalamus. The hypothalamus controls the internal
mirror images, they are not functionally identical. organs and interacts with the autonomic nervous
For example, in most humans the areas that con- system, which we discuss later in this chapter. In
trol speech are located in the left hemisphere, and addition, it regulates the secretion of pituitary hor-
areas that govern perception of spatial relation- mones and thus plays a role in regulating the en-
ships are found in the right hemisphere. Even docrine system, serving as a crucial link between
though the two hemispheres have somewhat dif- the nervous and endocrine systems. Indeed, the pri-
ferent functions, they do not work entirely inde- mary function of the hypothalamus is to maintain
pendently. They are connected by a mass of white the body’s homeostatic balance. The hypothalamus
matter known as the corpus callosum, which al- regulates body temperature, fluid balance, blood
lows the two hemispheres to communicate with pressure, body weight, and many bodily sensations
each other. Damage to the corpus callosum pre- such as hunger, thirst, pleasure, and sex drive.
vents communication between the hemispheres
Left hemisphere
Right hemisphere Cerebral cortex
Corpus callosum
Epithalamus
Ventricles
Thalamus
Basal nuclei
Gray matter
White matter
Hypothalamus Amygdala
Figure 10 A coronal section through the human cerebrum The cerebrum is

divided into two hemispheres connected via the corpus callosum. A thin layer of gray matter
(the cerebral cortex) surrounds a large mass of white matter. Embedded within this white
matter are more areas of gray matter (the epithalamus, thalamus, hypothalamus, basal nuclei,
and amygdala).
347
BOX 1 APPLICATIONS
Split-Brain Syndrome
Mammalian brains are divided into two ered reported seeing the word ring that had been pro-
hemispheres, with the right hemisphere receiv- jected to the right visual field and processed by the left
ing sensory input from, and controlling, the left half of hemisphere. They were entirely unaware that the word
the body, and the left hemisphere receiving sensory in- key had been presented to the left visual field and
put from, and controlling, the right half of the body. Ordi- processed by the right hemisphere, although some sub-
narily, the left and right sides of the brain coordinate jects occasionally reported that they saw a flash of light
their actions by communicating information via the cor- on the left side of the screen.
pus callosum, a region of white matter connecting the In most humans, the ability to communicate using
two hemispheres. But what would happen if the corpus language is localized in the left hemisphere of the brain,
callosum ceased to function? Roger Sperry was the first while the right hemisphere lacks language ability. Thus,
to investigate this question, when he performed experi- the right hemisphere was unable to communicate that
ments in which he cut the corpus callosum and optic chi- the light observed in the left visual field represented a
asm in cats, and tested the effects of the surgery on the word. Control subjects could verbalize both the words
animals’ behavior. Each cat was apparently normal fol- key and ring because the intact corpus callosum could
lowing the surgery, but when Sperry covered its left eye transfer the information between the two hemispheres.
and then taught it a simple conditioned behavior, the cat This difference between normal subjects and “split-
could not perform this task when its right eye was cov- brain” patients is not obvious in everyday life because we
ered instead of the left. It was as if only one side of the seldom look at objects using only one eye. We can easily
brain learned to perform the task, and could not commu- move our eyes or turn our heads so that both halves of
nicate this learning to the other side of the brain. Sperry the brain receive complete sensory information.
termed this phenomenon the split-brain syndrome. Although the right hemisphere does not have the
Similar observations have been made in human pa- ability to speak, it can still reason and communicate in
tients following brain surgery designed to reduce the other ways. For example, Sperry asked the split-brain
severity of epileptic seizures. In this surgery, a patient’s subjects to reach behind a curtain and choose the object
corpus callosum is cut so that an epileptic seizure in one whose name had just been projected on the screen.
part of the brain cannot spread to the other hemisphere. They could not see the objects, but had to distinguish
Although it seems like rather radical surgery, cutting the them by touch. When split-brain patients were asked to
corpus callosum is actually quite effective, and greatly use their left hand (which is under the control of the
reduces the severity of seizures with few apparent side right hemisphere), they chose the key, even though they
effects. However, Sperry was able to demonstrate that had denied seeing the word. Thus, the right hemisphere
these patients had a subtle form of split-brain syn- had seen the word key and recognized its meaning, but
drome. Sperry presented images or words to either the was simply unable to communicate this information
right or left visual field of these patients, and then asked verbally. Interestingly, when asked to name the object
the subjects a series of simple questions or had them they had just touched with their left hand, split-brain
perform basic tasks. For example, in one experiment, subjects responded by saying “ring”—the word ob-
the word key was presented to the left visual field (which served by the left hemisphere.
is processed by the right hemisphere of the brain), while Together, these and many subsequent studies have
the word ring was simultaneously presented to the right demonstrated that mammalian brains, and particularly
visual field (which is processed by the left hemisphere of the brains of humans, are highly lateralized with differ-
the brain). Normal subjects report seeing the word ing functions performed in each hemisphere.
keyring. Patients whose corpus callosum had been sev-
The limbic system influences emotions tivation, and memory. Thus, the limbic system is
The hypothalamus is part of the limbic system, a sometimes called the “emotional brain” because it
network of connected structures that lie along the controls emotions, decisions, and motivation. The
border between the cortex and the rest of the limbic system includes several structures in addi-
brain (Figure 11). These regions work together to tion to the hypothalamus, including the amygdala,
influence many processes including emotions, mo- hippocampus, and olfactory bulbs.
348
Cingulate Fornix or she can remember new facts for a short time,
gyrus but will forget them within a few minutes. In con-
trast, memories from before the time of damage
are unaffected. We discuss how the hippocampus
helps to form lasting memories at the end of this
chapter.
The olfactory bulb, which also forms part of
Thalamus
the limbic system, is important for the sense of
smell. Sensory neurons from the olfactory epithe-
lium connect directly to the olfactory bulb, rather
Hippocampus than being routed through the midbrain, as is the
case for most other incoming sensory information.
Olfactory The olfactory bulb then integrates the signals from
bulb Hypothalamus Amygdala
the olfactory neurons and transmits them to the
cortex for processing. As we discuss later in the
Figure 11 Anatomy of the limbic system The chapter, all other sensory information is first
limbic system consists of structures including the thalamus, processed by the thalamus before being sent to the
hypothalamus, hippocampus, amygdala, and olfactory bulb. cortex. In contrast, olfactory information bypasses
the thalamus and instead takes a more direct route.
The olfactory bulb is also connected to the amyg-
The amygdala is involved in emotional re- dala and hippocampus, and thus odors tend to pro-
sponses, particularly those of aggression and fear. voke strong emotions and memories in humans.
Electrical stimulation of the amygdala causes ag-
gressive behavior, while removal of the amygdala
results in decreased aggression and fear. For ex-
The thalamus acts as a relay station
ample, rats with damage to the amygdala will The thalamus is a large grouping of gray matter
readily approach cats. Monkeys with damage to located deep within the forebrain, immediately
the amygdala are more eager to approach and in- above the hypothalamus. The thalamic nuclei re-
teract with novel objects or unknown monkeys, ceive input from the limbic system and from every
suggesting that the amygdala controls fear reac- sensory modality except olfaction. In fact, some re-
tions in primates. However, a different response is searchers consider it to be part of the limbic system
observed if the amygdala is damaged in infant itself. The thalamus integrates and relays this in-
monkeys. These monkeys are unable to develop formation to the cortex. The thalamus is part of a
normal social interactions, suggesting that the structure called the reticular formation. The retic-
amygdala performs other roles in addition to sim- ular formation is a net of neurons extending from
ply regulating fear and aggression, at least in pri- the thalamus down through the brainstem, includ-
mates. For example, humans with damage to the ing parts of the midbrain, pons, and medulla ob-
amygdala are unable to accurately interpret facial longata. The reticular formation acts as a filter for
expressions, particularly those associated with incoming sensory information. In fact, we do not
negative emotions such as fear or anger. The consciously attend to the vast majority of incoming
amygdala is also involved in maintaining memo- sensory information. Instead, it is filtered by the
ries of the emotional effects of an event. thalamus. We have all experienced this phenome-
The hippocampus converts short-term mem- non. Imagine that you are at a party, surrounded
ories to long-term memories. For example, if you by the buzz of many conversations. Suddenly, you
look up a telephone number, you can keep the hear your name spoken behind you and you be-
number in your short-term memory by repeating come aware that someone is talking about you, de-
it a few times, but the memory of this number usu- spite not having noticed the conversation before.
ally fades quickly once you have placed the call. If Although you were receiving sensory information
you want to remember the number for a long time, about this conversation all along, your thalamus
the hippocampus must convert this short-term filtered out the unimportant information, and only
memory to a lasting one. A person with a damaged triggered conscious attention by sending relays to
hippocampus cannot build lasting memories. He the cortex when your name was mentioned.
349
The epithalamus is located above the thalamus, pears to be correlated with the functional complex-
and contains the habenular nuclei and the pineal ity of the brain and the intelligence of the organism.
complex. The habenular nuclei communicate with The cortex of mammals is rather distinct in
the tegmentum of the midbrain, while the pineal is structure compared to the cortex of other verte-
involved in establishing circadian rhythms and se- brates. Because of its unusual organization, the
cretes the hormone melatonin. mammalian cortex is often referred to as the neo-
cortex or isocortex. The isocortex is organized into
six functionally distinct layers with neuronal
The cortex integrates and interprets processes and cell bodies distributed within the
information layers in a specific fashion (Figure 13). The main
The outer layer of the mammalian cerebrum inte- visible difference between the layers is the shape
grates and interprets sensory information and ini- and density of the neurons located in each layer.
tiates voluntary movements, and thus has taken The outermost layer (I) contains few cell bodies
over many of the functions that are performed by and few connections among cells. Layers II and III
the midbrain in other vertebrates. This region, are involved in integrating signals within the cor-
called the cortex, is necessary for cognition and all tex, while the remaining layers contain neurons
other so-called higher functions, including the abil- that communicate with other parts of the brain in-
ity to concentrate, reason, and think in abstract cluding the thalamus, brainstem, and spinal cord.
form. In some mammals, the cortex is smooth, The cortex is thought to be organized into func-
whereas in other species it is folded so that the sur- tional units called columns that are oriented verti-
face of the brain has a walnut-like appearance (Fig- cally within the cortex and extend through all six
ure 12b). The outer, visible regions of these folds of the cortical layers, although the functional sig-
are called gyri (singular: gyrus), and the grooves nificance of this vertical organization is still a mat-
are called sulci (singular: sulcus). These folds ter of debate. Indeed, the degree of columnar
greatly increase the surface area of the cortex, in- organization appears to vary among parts of the
creasing the number of neurons and their intercon- cortex and among species. Columns may be fur-
nections, and thus increasing the functional ther broken down into minicolumns of less than a
complexity of the forebrain. The cortex varies in millimeter in diameter, containing only about 100
surface area by a factor of 125 between the least neurons. There are numerous interconnections
cortical mammals, such as hedgehogs, and the between neurons within a column, and although
most cortical mammals, such as primates and there are fewer connections among columns,
cetaceans. The degree of folding of the cortex ap- these connections can extend far across the cor-
1 cm 1 cm
Gyrus Sulcus
Cortex Cortex
(a) Hedgehog brain (b) Sea lion brain
Figure 12 Structural variation in mammalian brains In some species the cortex

is folded into a series of elaborate gyri and sulci, whereas in other species it is relatively
smooth.
350
II
III
Gyrus
Layers
Sulcus of cortex
(gray IV
matter)
Cerebral
cortex
(gray matter)
V
White
matter
VI
White
matter
Axons
Figure 13 Layers of the human cortex The cerebral cortex is arranged in six
distinct layers, although the cellular composition of these layers varies depending on the
particular area of the cortex.
tex, or into subcortical areas such as the thalamus. beled lines, which we encountered when discussing
Thus, the cortex may act as a massively parallel sensory systems, and applies to the visual cortex,
processor with each column acting as a semiau- the auditory cortex, the somatosensory cortex, and
tonomous unit. the motor cortex. The somatosensory cortex and
Each of the cerebral hemispheres is divided primary motor cortex are particularly good exam-
into four regions, or lobes, that are defined based ples of this topographic arrangement: each part of
on the names of the overlying bones (Figure 14). the cortex corresponds to the specific part of the
The frontal lobe is involved in reasoning, plan- body that it governs (Figure 15). Notice that the ar-
ning, and some aspects of speech in humans. The eas of the somatosensory cortex devoted to various
parietal lobe is associated with movement, orien- parts of the body are disproportionate. For exam-
tation, recognition, and perception of stimuli. The ple, the face and hands take up more than half the
occipital lobe is involved with visual processing, map of both the sensory cortex and motor cortex
and the temporal lobe is involved with perception in humans. The size of the cortical region typically
and recognition of auditory stimuli, memory, and reflects the number of sensory or motor neurons
speech. Alternatively, the brain can be divided into present in a particular body part, rather than the
areas that are specialized for different functions size of the body part itself. Thus, the amount of
that roughly fall within the divisions defined by the cortex devoted to inputs from a particular part of
lobes of the brain (Figure 14b). the body differs among species, reflecting the rel-
Many of the functional regions of the cortex ative importance of various parts of the body for
are organized topographically, such that specific sensation and movement. For example, the nose
areas of the cortex correspond to particular func- takes up a disproportionate amount of the so-
tions. This arrangement echoes the concept of la- matosensory cortex in the star-nosed mole. These
351
Frontal lobe Parietal lobe frontal association cortex, which is responsible for
various skills such as language, logical thinking,
planning, and judgment. The human prefrontal
association cortex is six times the size of that in a
Occipital chimpanzee, and this brain region is even less de-
lobe
veloped in other mammals, so experiments on
nonhuman animals are likely to be of limited use
in understanding the mechanisms underlying the
Temporal lobe
complex behavior of humans.
(a) Lobes of the brain
Primary motor cortex

Somatosensory
6. What type of symptoms would you expect in an
Premotor cortex cortex
Sensory individual who had a stroke that damaged part
association of the cerebellum?
Prefrontal areas
cortex 7. Compare and contrast the function of the
(thought) Visual midbrain in mammals with its function in other
association
Broca’s areas vertebrates.
area
Visual cortex 8. What is the function of the corpus callosum?
(speech)
9. What do somatosensory maps tell us about the
Olfactory organization of the cortex?
cortex
Limbic
association Auditory
areas cortex
(b) Cortical areas

The Peripheral Nervous System
Figure 14 Lobes, cortices, and association
areas of the human brain (a) The cerebrum can be Afferent neurons carry sensory information to inte-
divided into several lobes, each named after the overlying grating centers (such as the vertebrate central ner-
bones. (b) The cerebrum can also be divided into functional
regions called cortical areas, each involved in coordinating a vous system) where it is processed. The integrating
different function. centers then send out signals via efferent pathways
that govern physiological responses and behavior.
Together, the afferent sensory neurons and the ef-
animals live in burrows and use their sensitive ferent neurons that send signals to effector organs
noses to probe their environments. This topo- make up the peripheral nervous system. We have
graphical organization of the cortex is maintained already discussed the afferent branch of the periph-
at even finer levels. For example, the neurons in eral nervous system. The efferent branch of the pe-
the region of the somatosensory cortex of the star- ripheral nervous system is separated into two main
nosed mole that is devoted to the nose are organ- divisions: the autonomic division and the somatic
ized in a star shape, reflecting the shape of the motor division (Figure 16). In the remainder of this
nose. section we discuss each of these divisions in turn.
In addition to the various sensory cortices, the
brain also contains several association areas in-
volved in higher-level cortical processing. Associ-
ation areas receive input from adjacent cortical
Autonomic Pathways
areas and further process and integrate this infor- The autonomic nervous system is involved in the
mation. The functions of these association areas homeostatic regulation of most physiological func-
are not very well understood, because of the tions, including heart rate, blood pressure, breath-
complex nature of their processing tasks and the ing, and many other processes that are critical for
difficulty of studying them experimentally. This life. These functions are not usually under con-
difficulty is particularly acute for the human pre-
352
scious control, and thus this nervous

system is sometimes referred to as
the involuntary nervous system. The
autonomic division can be differenti-
ated into three branches. The sym-
pathetic nervous system is most
active during periods of stress or
physical activity, whereas the para-
sympathetic nervous system is
most active during periods of rest.
Thus, the parasympathetic branch is
sometimes referred to as the “resting
Human body proportions Star-nosed mole body proportions
and digesting” system, because it is
(a)
mainly concerned with redirecting
energy toward quiet activities such
as digestion. In contrast, the sympa-
thetic branch is sometimes called the
“fight-or-flight” system. Stimulating
the sympathetic nervous system
causes increases in heart rate,
deeper breathing, and diversion of
blood from the digestive system to
the working muscles. Although the
action of the sympathetic branch is
most obvious during the fight-or- Human sensory homunculus Star-nosed mole sensory homunculus
flight response, it also plays an im- (b)
portant role in daily activities, in Figure 15 Somatosensory maps The area of the cortex devoted to a given
particular in regulating blood pres- body part depends on the importance of that body part to the organism. (a) Body
sure and blood flow to tissues. The proportions of a human and a star-nosed mole. (b) Proportion of the somatosensory
enteric branch of the autonomic cortex devoted to particular body parts. In humans, a disproportionate area of the
cortex is devoted to sensory input from the hands and mouth. In star-nosed moles,
nervous system operates independ-
a disproportionate amount of the cortex is devoted to the front paws and nose.
ently of the other two branches, al-
though the parasympathetic and
sympathetic branches can regulate its activity. The creas, and gallbladder. Now, we concentrate on the
enteric branch is entirely concerned with diges- sympathetic and parasympathetic branches of the
tion, and innervates the gastrointestinal tract, pan- autonomic nervous system.
Peripheral nervous system
Efferent Afferent
branch (sensory) Figure 16 Major divisions of the vertebrate
branch peripheral nervous system The vertebrate nervous
system can be divided into the peripheral nervous system
(consisting of afferent and efferent pathways), and the central
Autonomic division Motor division
nervous system (consisting of the brain and spinal cord). The
efferent pathways of the peripheral nervous system can be
further separated into two pathways: the motor division that
Sympathetic Enteric
initiates movement by stimulating skeletal muscles, and the
autonomic division that regulates physiological functions.
Parasympathetic The autonomic division is divided into the sympathetic,
parasympathetic, and enteric nervous systems.
353
The sympathetic and parasympathetic from both the sympathetic and parasympathetic
branches act together to maintain nervous systems. Through this process of dual in-
homeostasis nervation, the two branches can work together to
regulate effector organs. The effects of the sympa-
The autonomic nervous system maintains homeo-
thetic branch and the parasympathetic branch are
stasis by balancing the activity of the sympathetic
generally antagonistic—one stimulatory and the
and parasympathetic nervous systems and their
other inhibitory (Table 3). For example, stimula-
effects on their target organs. Three important fea-
tion of the parasympathetic nervous system causes
tures of the autonomic nervous system underlie its
the bronchioles of the lung to constrict by causing
ability to maintain homeostasis: dual innervation,
the associated smooth muscle to contract. In
antagonistic action, and basal tone. As you can see
contrast, stimulation of the sympathetic
from Figure 17, most internal organs receive input
nervous system causes bronchioles to dilate
Sympathetic Parasympathetic
Eye
Lacrimal
and salivary
glands
Lungs Cranial nerve III

Pons Sympathetic Cranial nerve VII
Parasympathetic Cranial nerve IX
ganglion ganglion
Medulla
Cranial nerve X
Cervical
Heart
Vagus nerve
Liver (cranial nerve X)
Stomach
Spleen
Pancreas
Thoracic
Kidney
Large
intestine
Small
intestine
Lumbar
Collateral
ganglion Rectum
Sacral
Bladder
Coccygeal
Genitalia
Figure 17 Dual innervation in the autonomic nervous system Most organs

receive input from both the parasympathetic and sympathetic nervous systems.
354
Table 3 Actions of the sympathetic and parasympathetic nervous systems in humans.
Parasympathetic Sympathetic Adrenergic

Effector organ stimulation stimulation receptor
Pupil of eye Constricts Dilates ␣
Lacrimal glands of eyes Stimulates secretion None None
Salivary gland Watery secretion Thick secretion ␣, ␤2
Heart Slows heart rate Increases rate and force ␤1
of contraction
Arterioles None Constricts ␣
Nasal glands Stimulates secretion None None
Bronchioles of lungs Constricts Dilates ␤2
Digestive tract Increased motility and Decreased motility and secretion ␣, ␤2
secretion
Exocrine pancreas Increases enzyme secretion Decreases enzyme secretion ␣
Endocrine pancreas Stimulates insulin secretion Inhibits insulin secretion ␣
Adrenal medulla None Secretes epinephrine None
Kidney None Increases renin secretion ␤1
Bladder Release of urine Retention of urine ␣, ␤2
Adipose tissue None Fat breakdown ␤1
Sweat glands General sweating Localized sweating ␣
Arrector pili muscles of skin None Contract, causing hair to stand ␣
on end
Male sex organs Erection Ejaculation ␣
Uterus Depends on stage of cycle Depends on stage of cycle ␣, ␤2
through relaxation of the associated smooth mus-

cle. Finally, both the parasympathetic and sympa- CNS PNS
thetic nervous systems have basal tone (or basal
tonic activity), such that even under resting condi-
tions autonomic neurons produce action poten- Peripheral
autonomic
tials. Thus, both increases and decreases in action ganglion
Preganglionic
potential frequency can alter the response of the neuron
target organ, similar to a volume control on a ra- Postganglionic
dio. Together these three organizing principles al- neuron
low the autonomic nervous system to exert precise

control and to maintain homeostasis by balancing
the input of the parasympathetic and sympathetic Effector
organ
branches of the autonomic nervous system.
Figure 18 Structure of an autonomic pathway

Autonomic pathways share some Autonomic pathways consist of a two-neuron chain. The
structural features preganglionic neuron originates in the central nervous
system, and forms a synapse at the peripheral ganglion. The
All autonomic pathways contain two neurons in postganglionic neuron originates at the peripheral ganglion
series (Figure 18). The cell body of the first, or and forms a synapse at the effector organ.
355
preganglionic, neuron is located within the cen- The anatomy of the sympathetic and
tral nervous system. This neuron synapses with a parasympathetic branches differ
second, or postganglionic, efferent neuron in pe-
There are three main anatomical differences be-
ripheral structures called autonomic ganglia
tween the sympathetic and parasympathetic
that contain many such synapses. A single pregan-
branches of the autonomic nervous system. First,
glionic neuron generally synapses with several
the cell bodies of preganglionic sympathetic and
postganglionic neurons, and may also make con-
parasympathetic neurons are located in different
tact with intrinsic neurons that are located en-
regions of the central nervous system. Most sym-
tirely within the ganglion, allowing for relatively
pathetic pathways originate in the thoracic and
complex integration of function within the gan-
lumbar regions of the spinal cord, while most of
glion itself. At the effector organ, the postgan-
the parasympathetic pathways originate either in
glionic neuron releases neurotransmitter from
the hindbrain or in the sacral region of the spinal
specialized structures called varicosities. The ax-
cord (see Figure 17). Second, the locations of the
ons of postganglionic autonomic neurons have a
ganglia differ between the sympathetic and
series of swellings at their distal end arranged in
parasympathetic branches of the autonomic ner-
series along the surface of the effector organ, like
vous system. Sympathetic ganglia are found in a
beads on a string. Each varicosity acts as a
chain that runs close to the spinal cord, while
synapse with the effector organ, releasing neuro-
parasympathetic ganglia are located close to the
transmitter in response to action potentials. The
effector organ. Thus, most sympathetic pathways
underlying membrane of the effector organ is not
have short preganglionic neurons and long post-
specialized and does not contain high concentra-
ganglionic neurons, while parasympathetic path-
tions of receptors. Instead, the neuron simply re-
ways have long preganglionic neurons and short
leases neurotransmitter into the extracellular
postganglionic neurons (Figure 19). The final
fluid. The neurotransmitter then diffuses to recep-
anatomical difference between the sympathetic
tors distributed across the membrane of the effec-
and parasympathetic pathways lies in the rela-
tor organ.
tionship between the preganglionic and postgan-
CNS PNS CNS PNS
ACh
Nicotinic
cholinergic
receptor
Preganglionic
neuron Preganglionic
ACh neuron
Nicotinic
cholinergic Postganglionic
receptor neuron
Postganglionic
neuron
ACh NE
Muscarinic Adrenergic
cholinergic receptor
Effector receptor Effector
organ organ
(a) Parasympathetic nervous system (b) Sympathetic nervous system
Figure 19 Structure and neurotransmitters of the sympathetic and

parasympathetic nervous systems The parasympathetic nervous system has a long
preganglionic neuron and a short postganglionic neuron, while the sympathetic nervous system
has a short preganglionic neuron and a long postganglionic neuron.
356
glionic neurons. In the sympathetic nervous sys- In the parasympathetic nervous system, the
tem, on average, a preganglionic sympathetic neu- postganglionic cell releases ACh, but the target or-
ron forms synapses with 10 or more postganglionic gan has muscarinic rather than nicotinic ACh re-
neurons. In contrast, in the parasympathetic sys- ceptors. Muscarinic ACh receptors are coupled to
tem, an average preganglionic neuron forms G proteins, and thus typically cause somewhat
synapses with three or fewer postganglionic neu- slower responses than do nicotinic receptors.
rons. Stimulation of a single sympathetic pregan- There are several types of muscarinic receptors,
glionic neuron will thus have rather widespread and binding of ACh can be either stimulatory or in-
effects, while stimulation of a preganglionic hibitory, depending on the type of receptor present
parasympathetic neuron typically causes a much on the target cell.
more localized response. In contrast, in the sympathetic nervous sys-
The sympathetic and parasympathetic nervous tem, postganglionic cells typically release the neu-
systems can also be distinguished based on the rotransmitter norepinephrine, which binds to ␣ or
neurotransmitters they release at the synapse with ␤ adrenergic receptors on the effector organ. The
the effector organ. In both the sympathetic and various types of adrenergic receptors work
parasympathetic divisions, the preganglionic neu- through different second messenger pathways
ron releases the neurotransmitter acetylcholine and cause a variety of responses in the target cell.
(ACh), and the postganglionic neuron has nicotinic Differences in receptor subtypes among effector
receptors that bind the ACh. Nicotinic acetylcholine organs explain the diverse effects of sympathetic
receptors are ligand-gated ion channels, and bind- and parasympathetic stimulation of various tis-
ing of ACh allows Na⫹ to enter and rapidly depolar- sues. As we discuss in Box 2, Applications:
ize the postganglionic cell. The effects of nicotinic Receptor Subtype and Drug Design, these
receptors are always stimulatory. differences are important clinically in predicting
BOX 2 APPLICATIONS
Receptor Subtype and Drug Design
Asthma is a respiratory condition that af- heart rate and the force of cardiac contraction, redis-
fects up to 15 million people in the United States, tributing blood flow to the active muscles, increasing
many of them children. The symptoms of asthma in- alertness, and readying the body for action. Thus,
clude wheezing, coughing, and difficulty breathing. Dur- ephedrine and epinephrine can have substantial side ef-
ing an asthma attack, the smooth muscles surrounding fects when used as drugs. For example, ephedrine can
the bronchioles contract, narrowing the passages that induce anxiety, tremors, irritability, sleeplessness, and
normally lead air into the lungs. The causes of asthma a rapid or irregular heartbeat. Indeed, several countries
are not known, but a variety of fairly effective treatments have recently banned ephedrine as an ingredient in diet
are available to reduce the severity of an asthma attack. pills and food supplements because of these dangerous
Up until the mid-1980s, administering the drugs side effects.
epinephrine or ephedrine was the main treatment for Recently, antiasthma drugs have been developed
asthma. Both epinephrine and ephedrine bind to ␤ that specifically target the ␤2 adrenergic receptors that
adrenergic receptors, stimulating these receptors on are expressed on the smooth muscle of the bronchioles.
the smooth muscles of the bronchioles, and causing For example, albuterol (which is marketed under such
them to relax. When the smooth muscle relaxes, the trade names as Ventolin) binds to ␤2 adrenergic recep-
bronchioles dilate, opening the passages to the lungs, tors with approximately 500 times greater affinity than it
counteracting the effects of an asthma attack. Unfortu- does to ␤1 adrenergic receptors, and binds poorly if at
nately, both ephedrine and epinephrine bind to many all to ␣ adrenergic receptors. Use of drugs like albuterol
kinds of adrenergic receptors, including the ␣1, ␣2, ␤1, reduces the risks of serious cardiac side effects relative
and ␤2 subtypes of the adrenergic receptors that are to epinephrine, because the heart expresses mostly ␤1
found on many tissues throughout the body. Recall that adrenergic receptors. But these drugs still provide good
epinephrine is released as part of the fight-or-flight re- relief from asthma attacks because of their effects on
sponse of the sympathetic nervous system, increasing the ␤2 receptors of the bronchiolar smooth muscle.
357
the effects of many drugs. In general, binding of minate in the adrenal medulla, but the postgan-
norepinephrine to ␣ receptors is stimulatory, while glionic neurons do not go on to innervate a target
binding to ␤ receptors is inhibitory. A few classes organ (Figure 20). Instead, they are modified into
of postganglionic sympathetic neurons, including neurosecretory cells called chromaffin cells that
those innervating the sweat glands of the skin, re- release epinephrine and norepinephrine directly
lease ACh rather than norepinephrine, but these into the circulation, producing widespread excita-
neurons are much less numerous than the adren- tory effects. we can easily see the origins of the ad-
ergic neurons. renal glands as sympathetic ganglia by looking at
Table 4 summarizes some of the similarities fish, which lack a discrete adrenal gland. In the
and differences between the sympathetic and elasmobranchs (sharks and rays), these neurose-
parasympathetic nervous systems. cretory cells are directly associated with the auto-
nomic ganglia. In bony fishes, these cells are
dispersed throughout the anterior part of the kid-
Some effectors receive only sympathetic ney, similar to the location in mammals, although
innervation they are not grouped into a discrete gland. This
Although the principle of dual innervation ap- progression from a clear ganglionic structure to
plies to most of the target organs of the auto- dispersed cells to a non-ganglionic tissue (the ad-
nomic nervous system, some organs— including renal medulla) suggests the likely evolutionary ori-
the sweat glands, the arrector pili muscles of the gin of this unusual structure.
skin, the adrenal medulla, the kidneys, and most
blood vessels—are only innervated by sympa-
thetic neurons (see Table 3). The effects of sym- The central nervous system regulates the
pathetic stimulation on the sweat glands and
autonomic nervous system
arrector pili muscles are obvious. Humans com- The central nervous system exerts control over the
monly sweat during stressful situations, and in autonomic nervous system at several levels, in-
many mammals fear causes the hair (or fur) to cluding the spinal cord, brainstem, hypothalamus,
stand on end, because of the actions of the arrec- and cortex. The relationship between these brain
tor pili muscles. regions and the autonomic nervous system is out-
The adrenal medulla, the core of the adrenal lined in Figure 21. Many of the inputs from the
gland, is also involved in the response to stressful central nervous system reach the autonomic ner-
situations. The adrenal glands are paired glands lo- vous system via the reticular formation, a set of
cated immediately above the kidneys. The adrenal neurons located throughout the brainstem, which
medulla is actually a highly modified sympathetic we mention in relation to the thalamus. Although
ganglion. Preganglionic sympathetic neurons ter-
Table 4 Similarities and differences between the sympathetic and parasympathetic nervous systems.
Characteristic Sympathetic Parasympathetic

Number of neurons in chain Two Two
Location of cell bodies Thoracic and lumbar Hindbrain
regions of spinal cord Sacral region of spinal cord
Location of ganglia Close to spinal cord Close to effector organ
Preganglionic neuron Short Long
Postganglionic neuron Long Short
Synapses per preganglionic neuron Many Few
Neurotransmitter released by ACh ACh
preganglionic neuron
Neurotransmitter released by NE ACh
postganglionic neuron
358
CNS PNS
the reticular formation can itself act as an integrat-
ing center, its main role is to communicate signals
Chromaffin cell
coming from the cortex, the medulla oblongata,
Adrenal and the hypothalamus. The hypothalamus plays a
medulla
Preganglionic dominant role in regulating the autonomic ner-
sympathetic
neuron
vous system, and can communicate with the auto-
nomic nervous system directly or via the reticular
Nicotinic
cholinergic formation. The hypothalamus initiates the fight-or-
receptor flight response, which involves widespread activa-
Epinephrine tion of sympathetic neurons. The hypothalamus
also contains regulatory centers for body tempera-
Circulatory ture, food intake, and water balance, all of which
system
are homeostatically regulated via the autonomic
nervous system. The medulla oblongata contains
Adrenergic
receptor centers that control heart rate, blood pressure,
Effector organ
and breathing by influencing the activity of the au-
tonomic nervous system.
Most of these changes in the activity of the au-
Figure 20 Sympathetic innervation of the
adrenal medulla The adrenal medulla receives tonomic nervous system occur at the unconscious
innervation from a preganglionic sympathetic neuron, and is level via reflex arcs, simple neural circuits that do
thus equivalent to a sympathetic ganglion. not involve the conscious centers of the brain. Fig-
ure 22 shows an example of such a reflex arc, one
involved in regulating blood pressure. When blood
pressure falls, receptors located in various parts of
the body detect the decrease. These receptors send
Cortex
Blood pressure
Limbic system
–
Receptors detect
Negative decrease in blood
feedback pressure
Hypothalamus Medulla oblongata
Afferent pathway
Reticular formation Medulla oblongata

(cardiovascular
control center)
Spinal cord
Great Vagus
cardiac nerve
nerve
Autonomic nervous system
Sympathetic Parasympathetic
activity activity
Figure 21 Regulation of the autonomic nervous
system by the brain Many brain regions can modulate
the activity of the autonomic nervous system. The reticular
formation in the brainstem processes and communicates
most of the descending information from higher brain
centers to the autonomic nervous system. The hypothalamus Blood pressure
is the most important of these brain regions and can
communicate with the autonomic nervous system either Figure 22 An example of an autonomic reflex
directly or via the reticular formation. arc: the reflex control of blood pressure
359
a signal to the cardiovascular control center in the autonomic neurons, which have several
medulla oblongata via afferent sensory neurons. synaptic varicosities arranged in series like a
The cardiovascular control center then influences string of beads.
the activity of the autonomic nervous system, in- 5. The synaptic cleft between the motor neuron
creasing sympathetic activity and decreasing and the muscle cell membrane is much nar-
parasympathetic activity. These resulting changes rower than that between autonomic neurons
in autonomic output cause adjustments in heart and their effector cells. Thus, neurotransmit-
rate, stroke volume, and vasoconstriction, return- ters typically diffuse across the neuromuscular
ing blood pressure back to normal in a negative junction more rapidly than across the synaptic
feedback loop. cleft of autonomic neurons, and motor neu-
The limbic system, which governs emotions, rons tend to communicate more rapidly with
also has a profound effect on the activity of the au- their effectors.
tonomic nervous system. Blushing, fainting at the
6. All vertebrate motor neurons release acetyl-
sight of blood, and “butterflies” in the stomach are
choline at the neuromuscular junction,
all examples of the response of the autonomic ner-
whereas sympathetic neurons release epi-
vous system to emotions.
nephrine and parasympathetic neurons re-
lease acetylcholine. In many invertebrates,
motor neurons release glutamate.
Somatic Motor Pathways 7. The effect of acetylcholine on skeletal muscle is
Somatic motor pathways control skeletal muscles, always excitatory, whereas autonomic neurons
which are usually under conscious control. Thus, may be excitatory or inhibitory. Stimulation of
the motor pathways are sometimes called the “vol- an efferent motor neuron leads to the contrac-
untary nervous system.” However, some efferent tion of skeletal muscle, and muscles relax only
when the associated motor neurons are at rest.
motor pathways are not under conscious control,
and instead represent reflex responses—rapid in-
voluntary movements in response to a stimulus.
For example, if you sit with your legs crossed and
tap sharply just under your kneecap, your leg will
kick out, in the patellar (knee-jerk) reflex. Efferent 10. Compare and contrast the sympathetic and
motor pathways can be distinguished from auto- parasympathetic nervous systems.
nomic pathways in seven ways. 11. What is the significance of having dual
innervation of many organs by both the
1. Efferent motor neurons control only one type sympathetic and parasympathetic nervous
of effector organ—skeletal muscle. systems?
2. The cell bodies of motor neurons are located in 12. What sort of receptors would you expect the
the central nervous system in the vertebrates, neurosecretory chromaffin cells of the adrenal
medulla to express?
and never within ganglia outside of the central
nervous system. 13. What is a reflex arc?
3. Efferent motor pathways are monosynaptic—

there is only a single synapse between the cen-
tral nervous system and the effector organ. As
a result, efferent motor neurons can be among Integrative Functions
the longest neurons in the vertebrate body.
Their axons can reach from the spinal cord out
of Nervous Systems
to the periphery of the body, a distance that Neurobiologists are only beginning to understand
can span several meters in large mammals. how integrating centers such as the brain take in-
4. The morphology of the synapse differs be- formation from sensory systems and integrate this
tween the autonomic and motor pathways. At information to allow animals to respond to their
the neuromuscular junction, a motor neuron environments in a dynamic way. In this section we
splits into a cluster of axon terminals that discuss some of the important topics relating to
branch out over the motor end plate, unlike how nervous systems function, beginning with
360
simple behaviors, and then examining some of the deed, most monosynaptic reflex arcs contain
more complex functions of the nervous system. many neurons.
Neurons in a reflex arc can be arranged in two
fundamentally different ways. Figure 24a illus-
trates the principle of convergence, in which
Coordination of Behavior multiple afferent neurons synapse with a single ef-
Multicellular animals are capable of diverse forms ferent neuron. A convergent arrangement of neu-
of behavior, which are made possible by the com- rons allows spatial summation. For example, the
plexity of nervous system organization and func- activity of a single afferent neuron may be insuffi-
tion. Animal behaviors can be loosely grouped into cient to excite the efferent neuron, but the simul-
three categories: reflex behaviors, rhythmic be- taneous activity of many afferent neurons may be
haviors, and voluntary behaviors. Reflex behav- sufficient to cause a response. This effect occurs as
iors are involuntary responses to stimuli, and are a result of spatial summation. Convergence can
among the simplest types of animal behaviors. also allow the comparison and integration of sen-
Many animals also have a series of rhythmic be- sory signals from multiple parts of the body, in-
haviors, and these rhythms underlie such impor- creasing the complexity of information processing.
tant processes as locomotion, breathing, and the For example, we have already discussed the sig-
function of the heart. Voluntary behaviors range nificance of a convergent arrangement of neurons
greatly in complexity, from apparently simple acts in the mammalian retina.
such as mating or fighting, to complex behaviors Figure 24b illustrates an alternative organiza-
such as reading and writing. In this section we dis- tion, called divergence. In this arrangement, a sin-
cuss each of these kinds of behaviors in turn, gle afferent neuron forms synapses with more than
working from the simplest to the most complex. one efferent neuron. Divergence allows a single sig-
nal to control multiple independent processes, and
is a way to amplify the effect of a signal. Divergent
Reflex arcs control many involuntary
functional arrangements allow the nervous system
behaviors
to engage in parallel processing, which allows
The least complex integrated response of the ner- very rapid integration of inputs and responses.
vous system is the reflex arc, which controls the The autonomic nervous system shows high levels
simplest type of animal behavior—reflexes, or
rapid involuntary responses to stimuli. In princi-
ple, a reflex arc could involve as few as two neu- R1
rons (Figure 23): a sensory afferent neuron that
detects the stimulus and an efferent neuron that R2 E
carries the output to an effector cell (such as a
R3
muscle). This reflex arc is called a monosynaptic
reflex arc, because it contains only a single neuron- (a) Convergence
to-neuron synapse in the chain from sensory neu-
ron to effector neuron. A monosynaptic reflex arc
E1
may contain more than two neurons, as long as
there is only one neuron-to-neuron synapse along E2
any path from the stimulus to the response. In- R
E3
E4
Input Output
(b) Divergence
Figure 24 Convergence and divergence in a

Receptor R E Effector monosynaptic reflex arc (a) In a convergent
arrangement, many presynaptic neurons interact with a
Afferent Efferent single postsynaptic neuron. (b) In a divergent arrangement, a
sensory neuron
neuron single presynaptic neuron forms synapses with many
postsynaptic neurons. R ⫽ sensory receptor; E ⫽ effector
Figure 23 A two-neuron reflex arc organ.
361
of divergence. A single neural pathway from the also be made up of neurons that do not, as individ-
autonomic nervous system may make connections uals, generate rhythmic depolarizations. Instead,
with many target organs, allowing a coordinated the rhythm is an emergent property of the network
and amplified response. that manifests itself because of the organization of
Note that all of the reflex arcs illustrated in the neurons in the network, rather than being an
Figure 24 are monosynaptic reflex arcs, because intrinsic property of the neurons themselves.
they contain only a single synapse in the chain be- To get a sense of how pattern generators op-
tween stimulus and response. Most reflex arcs erate, consider a two-neuron pair. In this neuron
have a more complex structure, and are called pair, neither neuron generates a rhythm by itself,
polysynaptic reflex arcs, because they contain but when the first neuron (A) fires, it inhibits the
synapses between more than two types of neu- other neuron (B) from firing until a defined period
rons. A simple polysynaptic reflex arc is shown in elapses, at which point neuron B fires. Neuron B
Figure 25, and includes a sensory cell, an afferent then inhibits neuron A for a defined period of
sensory neuron, an interneuron, an efferent neu- time, after which point it fires, and the loop con-
ron, and an effector cell. This type of reflex arc is tinues. Imagine two robots programmed to hit if
illustrated by the reflex response to touch in C. they are hit first. If robot A hits robot B, then ro-
elegans, which is governed by six touch receptors, bot B will respond by hitting back, which will
five pairs of interneurons, and 69 motor neurons. cause robot A to hit back, and so on. The trick in
Adding interneurons to a reflex arc greatly in- this kind of network is getting it started in the first
creases the potential responses of the arc and the place. Once the chain of events is established, it
complexity of the processing. will continue indefinitely, and it is no longer pos-
sible to determine where the behavior was initi-
ated. Various mechanisms can start the rhythmic
Pattern generators initiate rhythmic
oscillations. Often, input from a sensory receptor
behaviors
is needed in order to start the rhythm. Thus, the
Pattern generators govern many important phys- distinction between reflex arcs and pattern gener-
iological processes and simple rhythmic behaviors ators is not precise. Instead, these two types of
such as chewing, walking, swimming, and breath- control pathways interact to produce the complex
ing. Pattern generators are groups of neurons that behavior and physiological responses of animals.
produce self-sustaining patterns of depolarization,
independent of sensory input. Pattern generators
can be organized in two different ways. The sim- Pattern generators govern swimming
plest form of organization involves a pacemaker
behavior in the leech
cell. A pacemaker cell generates a spontaneous One approach to understanding the neurobiology
rhythmic depolarization, and thus controls the fir- underlying complex behaviors is to study simple
ing of all the cells in the network. Pacemaker cells behaviors in organisms with less complex nervous
are common in biological systems. For example, systems than those found in mammals. One such
spontaneous pacemaker cells initiate the heartbeat organism is the medicinal leech, Hirudo medici-
in many kinds of animals. Pattern generators can nalis. Like other members of the phylum Annelida,
leeches are segmented worms with a brain, a ven-
tral nerve cord, and a series of ganglia located in
Afferent neuron
each body segment. Each segmental ganglion
R E2 contains approximately 400 neurons, and this
simple nervous organization makes the leech an
excellent experimental model system. Leeches
Interneuron
E2 are ectoparasitic—they attach themselves to ver-
tebrate hosts and feed on their blood. When a
Efferent
neuron leech bites into the skin it injects a local anesthetic
and anticoagulant to keep the blood running freely
Figure 25 A polysynaptic reflex arc A
polysynaptic reflex arc includes a sensory receptor (R), an
and to avoid detection by the host. A leech can con-
afferent neuron, an interneuron, one or more efferent
neurons, and one or more effector organs (E).
362
sume up to 15 ml of blood during a single blood absence of a touch stimulus. An additional neuron
meal, or 10 times its unfed body size. Up to the mid- in the circuit, sometimes called the swim excitor in-
dle of the 19th century, leeches were commonly used terneuron, can modulate the activity of the swim
in a medical treatment called “bloodletting” in which gating neuron or the central pattern generator itself
physicians would apply leeches to the skin and allow in response to signals from the leech brain, but the
them to suck the patient’s blood. This therapy was pathways involved in this higher level of control are
thought to be helpful for a wide range of illnesses, in- not yet understood.
cluding fever, headaches, and even obesity. Bloodlet-
ting is no longer a common therapy, but leeches are
still occasionally used during surgical procedures, Pattern generators and reflexes are
such as skin or tissue grafting. For example, leech involved in tetrapod locomotion
therapy is particularly useful during finger or ear Four-limbed (tetrapod) vertebrates move by
reattachment surgery to prevent pooling of blood, swinging their legs in stereotyped patterns that we
which can damage the newly grafted tissue. call gaits (such as running, walking, or trotting).
In its natural habitat, a leech detects its prey by Gaits such as walking involve rhythmic back-and-
sensing the waves made by a prey animal as it forth movements of the legs. Even the seemingly
moves about in the water. The leech then swims to- simple movements involved in walking or running
ward the potential prey, using a rhythmic undula- require the coordinated contraction of many mus-
tory motion. Over the last 30 years, neurobiologists cles so that each joint moves just the right distance
have unraveled many components of the neural net- at just the right time. In some ways, the mecha-
work that regulates this behavior (Figure 26). Swim- nisms underlying locomotion in four-limbed verte-
ming begins when mechanoreceptors in the skin brates bear a striking resemblance to the control
sense a stimulus such as the waves made by a prey of swimming behavior in leeches. The brainstem
animal. These mechanoreceptors send an afferent (particularly the pons and medulla) usually initiates
sensory signal to the swim trigger interneuron, the command to begin locomotion (Figure 27). The
which makes a synaptic connection with the swim brainstem then sends a signal to a network of neu-
gating interneuron. When stimulated, the swim gat- rons in the spinal cord that acts as a central pat-
ing interneuron activates a network of neurons that tern generator, similar to the pattern generator in
form a central pattern generator called the swim os- the leech ganglia. The pattern generator then
cillator. This central pattern generator sends out sends coordinated motor output signals to the
rhythmic signals to motor neurons that stimulate muscles that control the movement of the limbs,
muscles in the body wall to initiate rhythmic swim- initiating rhythmic movements. Unlike the pattern
ming. The circuit diagram of the swim oscillator is generator that controls swimming in leeches, the
not yet fully worked out, but it involves at least seven structure and neural connections of this pattern
oscillator interneurons and four motor neurons. generator are not yet known, and even their loca-
Leeches can also initiate swimming behavior in the tion within the spinal cord remains somewhat
Brain Motor
Skin Swim excitor neuron
mechano- interneuron
receptor
Swim oscillator E
(central pattern
generator) E
Swim trigger
interneuron Swim gating
interneuron Effector
(swimming
musculature)
Figure 26 The neural circuit governing swimming behavior in the leech A

sensory signal from skin mechanoreceptors stimulates a swim trigger interneuron that stimulates a
swim gating interneuron and a swim excitor interneuron. These interneurons activate the group of
neurons that make up the swim oscillator central pattern generator. The central pattern generator
then sends out a rhythmic signal to the swimming musculature. The swim excitor interneurons also
process descending information from the leech brain, allowing the leech to initiate swimming even in
the absence of a touch stimulus.
363
Thalamus Cerebral cortex comotory patterns, but simply modifies the output
of the pattern generator.
The brain regulates and coordinates the activity
of the spinal cord pattern generators, controlling
Cerebellum Brainstem
(pons and
the speed and smoothness of locomotion and ad-
medulla) justing locomotion in response to visual stimuli.
Three parts of the brain (the brainstem, the cortex,
and the cerebellum) have important roles to play in
Spinal cord (central
pattern generator) regulating locomotion. Centers in the brainstem
regulate speed. By placing electrodes into the brains
of experimental animals, neuroscientists have been
Sensory Motor
feedback output able to demonstrate that weakly stimulating this
part of the brain initiates walking. Increasing the
stimulus intensity increases walking speed and
Figure 27 The neural circuit governing eventually causes trotting and then galloping. The
locomotion in mammals The brainstem sends a cortex plays an important role in guiding locomo-
signal to the spinal cord central pattern generator. The
tion in complex environments, and in coordinating
central pattern generator then sends a rhythmic motor
output signal to skeletal muscles. Sensory feedback from visual signals with locomotion. For example, a cat
proprioceptors and vision travels to the pattern generator, with damage to the premotor cortex can still walk
the cerebellum, and the cerebral cortex (via the thalamus), on a smooth surface, or even on an inclined plane,
modifying the output of the central pattern generator.
but cannot step over objects. Sensory feedback from
the working muscles and from other senses, such as
elusive. However, a variety of experiments have vision, enters the cerebral cortex via the thalamus.
demonstrated that a pattern generator must exist The cerebral cortex then sends signals to the brain-
within the spinal cord. stem and spinal cord to modify locomotion.
In addition to generating rhythmic limb move- The cerebellum fine-tunes locomotion by regu-
ments, animals must be able to respond to obsta- lating the timing and intensity of signals to the spinal
cles as they walk or run by dynamically changing cord pattern generator. Humans or experimental
their movements in response to changes in the animals with damage to the cerebellum walk in an
contours of the ground. Stretch receptors and pro- uncoordinated way that resembles a drunken gait;
prioceptors in the limbs sense information about their movements are jerky and uncoordinated, and
the position of the limbs and the impact of the feet they may stumble. In normal animals the cerebel-
on the ground during walking or running. These lum receives inputs from the stretch receptors and
receptors send sensory feedback to the pattern proprioceptors in the limbs, compares these signals
generator, allowing the pattern generator to mod- to the intended movement, and then sends signals
ify its output in response to changing environ- to the brainstem to correct the movement if neces-
mental demands. Thus, reflex arcs play an sary, thus coordinating locomotion.
important role in regulating locomotory move-
ments. However, these afferent inputs are not
necessary to initiate rhythmic locomotion. For ex-
The brain coordinates voluntary
ample, if you apply a drug such as curare, which
movements
paralyzes the muscles without interfering with Although reflex responses and central pattern
nervous system function, and then record electri- generators play an important role in animal be-
cal activity in the motor neurons leading to the havior, most vertebrates (and many invertebrates)
limb musculature, you will observe a phenome- can perform much more complex behavioral
non called fictive locomotion. If you stimulate the tasks. These voluntary behaviors are consciously
central pattern generator, the motor neurons will planned and coordinated by the brain, and can be
produce rhythmic firing patterns much as they finely regulated in response to environmental cir-
would during normal locomotion, even in the cumstances. Figure 28 shows a schematic dia-
complete absence of any movement-related feed- gram of the parts of the vertebrate nervous system
back from the paralyzed muscles. Thus, sensory that are involved in regulating voluntary move-
feedback is not necessary to generate rhythmic lo- ments. First, an animal must decide to make a
364
Vestibular
apparatus
Visual Association Supplementary

Motor cortex Cerebellum
cortex cortex motor cortex
Cerebral cortex
Thalamus
Extrapyramidal tract
Limbic system Basal nuclei
Reticular formation
Pyramidal tract
Brainstem
Spinal cord Spinal cord
Motor neurons Motor neurons
Muscles of Muscles of posture

limbs and balance
Proprioceptors Sensory input
Figure 28 Control of voluntary movement in cord without forming any intermediate synapses, sending a
mammals The cerebral cortex initiates voluntary signal via motor neurons to the muscles of the limbs to
movements. The motor cortex then initiates a motor program control movement. The extrapyramidal tract is a multineuron
by sending efferent signals via the direct pyramidal tract and chain that forms synapses in many brain areas before
the indirect extrapyramidal tract. The neurons of the reaching the spinal cord and sending signals via motor
pyramidal tract proceed directly from the cortex to the spinal neurons to the muscles of posture and balance.
motion. This decision is made in the cerebral cor- pathways are involved in voluntary movements.
tex of the brain, and includes inputs from the sup- The pyramidal tracts are direct pathways from the
plementary motor cortex, the association cortex, primary motor cortex to the spinal cord and are so
the visual cortex, and the limbic system. The deci- named because they pass through a portion of the
sion to move is then developed into a program for medulla called the medullary pyramids. The py-
movement in the primary motor cortex. This mo- ramidal tracts play the major role in directing vol-
tor program is independent of the actual muscles untary movements. These tracts cross over each
that execute the program. For example, a person other in the medulla, and thus the left side of the
who knows how to write his or her name can eas- brain controls the right side of the body and vice
ily (although a little clumsily) write it by holding a versa. The extrapyramidal tracts are indirect
pencil between the toes. Similar regions of the pathways to motor neurons that, unlike the py-
brain are activated in each case, demonstrating ramidal tracts, make numerous synaptic connec-
that the “program” for writing your name is inde- tions within the brain prior to entering the spinal
pendent of the specific controls of the muscles of cord. They control the muscle groups that regulate
your hands (or feet). posture and balance. For example, when you sign
The primary motor cortex executes the motor your name, the pyramidal tracts control the fine
program by sending signals along a series of tracts movements of your hands and arms, while the ex-
(groups of axons) to the spinal cord. Two main trapyramidal tracts maintain your body position
365
and orientation, although there is some overlap in simple nervous system consisting of about 20,000
function between the two systems. neurons organized into a series of ganglia. Aplysia
The axons in the pyramidal and extrapyrami- demonstrates a simple kind of learning called
dal tracts synapse with motor neurons within the habituation—a decline in the tendency to re-
spinal cord, and these motor neurons cause the spond to a stimulus due to repeated exposure. Hu-
appropriate muscles to contract in order to initiate mans also show habituation. For example, if you
movements. Just as with rhythmic locomotion, live near a construction site, at first the noise of the
sensory afferent neurons return feedback from construction may be very disturbing, and you may
stretch receptors and proprioceptors in the mus- have difficulty concentrating or studying, but after a
cles to the cerebellum. The cerebellum also re- while you “get used to” the noise and easily ignore
ceives sensory information from other sensory it—you have become habituated to the stimulus.
receptors such as the vestibular apparatus of the Habituation is an important property of nervous
ear, which is involved in the sense of balance. The systems, because it allows animals to ignore unim-
cerebellum integrates these inputs and sends a portant routine stimuli and pay more attention to
signal to the cortex (via the thalamus) to refine and novel, potentially dangerous ones. If you gently
adjust the descending motor output in order to touch Aplysia on its siphon (a fleshy spout above
complete the planned movement successfully. the gill used to expel seawater), the animal will
withdraw its gills and siphon into the mantle cavity
(Figure 29). However, after repeated gentle touches,
Aplysia will reduce gill withdrawal by about one-
2 CO N CEP T C HE C K third. If you repeatedly touch the siphon 10 or 15
14. What is the difference between a monosynaptic
reflex arc and a polysynaptic reflex arc?
15. What kinds of behaviors involve pattern Mantle
generators?
16. What is the location of the pattern generator Tail
governing walking in the vertebrates?
Head
Siphon
Gill
Learning and Memory (a) Aplysia californica, dorsal view

In addition to performing complex behaviors,
most animals can remember experiences, and Sensory neuron
modify their behavior accordingly. Although Interneurons
Skin of
learning and memory are related concepts, these siphon
words describe two distinct tasks. Learning refers
to the process of acquiring new information, while
Motor neuron
memory refers to the retention and retrieval of
that learned information. The vast majority of an-
imals have the ability to form memories and to
learn. Learning and memory are possible because Gill
of the plasticity of the nervous system—the abil-
(b) The neural circuit governing the gill-withdrawal reflex
ity to change both synaptic connections and func-
tional properties of neurons in response to stimuli. Figure 29 The gill-withdrawal reflex in Aplysia
californica (a) Dorsal view of Aplysia californica. (b) The
neural circuit governing the gill-withdrawal reflex. Sensory
neurons in the skin of the siphon detect a mechanical
Invertebrates show simple learning stimulus. These sensory neurons form synapses with
and memory interneurons and motor neurons. These motor neurons send
an efferent signal that causes the gill to withdraw.
The physiology of learning and memory is under-
Habituation of the reflex occurs because of functional
stood in the greatest detail in the sea slug Aplysia changes at the synapse between the sensory and motor
californica. Like other molluscs, Aplysia has a fairly neuron as a result of repeated stimulation.
366
times over the course of a few min- Sensory neuron

utes, the habituation response lasts Facilitating
for about a day, a phenomenon called interneuron Skin of tail
short-term habituation. If you repeat
this stimulation protocol on several
Sensory neuron
consecutive days, the habituation
Interneuron
lasts for three or four weeks, a phe- Skin of
nomenon called long-term habitua- siphon
tion.
Habituation occurs because of Motor neuron
functional changes at the synapse
between the sensory neuron and the
motor neuron. In short-term habitu-
Gill
ation, a Ca2⫹ channel in the mem-
brane of the presynaptic axon Figure 30 The neural network involved in sensitization in Aplysia
terminal of the sensory neuron is in- Sensitization of the gill-withdrawal reflex involves a second neural circuit from the
activated. Touching the siphon still skin of the tail. An electrical shock to the tail sends an afferent signal along a sensory
generates an action potential in the neuron that makes a synaptic connection with a facilitating interneuron. This
facilitating interneuron makes synaptic connections with the neurons involved in the
sensory neuron, but when the action gill-withdrawal reflex, modifying their response to touch stimuli.
potential reaches the axon termi-
nal, less Ca2⫹ flows into the axon
terminal, because of the partial inactivation of larger and last longer than in an unsensitized ani-
the voltage-gated Ca2⫹ channels. Neurotransmit- mal. The effects of a single shock die out after about
ter release depends on the influx of Ca2⫹ into the an hour, but multiple strong shocks will affect the
axon terminals, and therefore habituated animals gill-withdrawal response for a week or more.
release less neurotransmitter. In addition, there As with habituation, during sensitization
are some morphological changes in the presynap- physiological changes occur in the presynaptic
tic axon terminal, including changes in the num- axon terminal of the sensory neuron from the
ber and location of neurotransmitter-containing siphon. However, in the case of sensitization there
vesicles. Long-term habituation results in similar is an increase in Ca2⫹ entry, and increased neuro-
changes in the presynaptic axon terminal, but to a transmitter release, rather than a reduction. The
greater degree. Although the molecular mecha- mechanism underlying this increase in neuro-
nisms involved in the inactivation of the voltage- transmitter release involves a second neural cir-
gated Ca2⫹ channels and the changes in vesicle cuit: a sensory neuron from the tail that makes a
distribution are not yet known, it is clear that synaptic connection with several interneurons
changes in the presynaptic axon terminal of sen- (only one interneuron is shown in Figure 30 for
sory neurons that contact motor neurons cause clarity). In turn, these interneurons make synaptic
habituation in Aplysia. connections on the axon terminal of the sensory
Aplysia also demonstrates a kind of learning neuron involved in the gill-withdrawal response.
called sensitization (Figure 30). In contrast to ha- An electrical shock to the tail sends an afferent
bituation, sensitization is an increase in the re- signal to the interneurons, which then release the
sponse to a gentle stimulus after exposure to a neurotransmitter serotonin onto the axon termi-
strong stimulus. For example, imagine being alone nal of the sensory neuron involved in the gill-
in your house in the middle of the night. You sud- withdrawal response (Figure 31). Serotonin binds
denly hear a loud noise coming from the basement. to a G-protein-coupled receptor that activates
For the next little while you will probably be acutely adenylate cyclase, which catalyzes the formation of
aware of all the sounds around you—you will be the second messenger cAMP. The increase in cAMP
sensitized to your environment. You can demon- activates protein kinase A (PKA), which phospho-
strate the phenomenon of sensitization in Aplysia rylates voltage-gated K⫹ channels in the mem-
by delivering an electrical shock to the tail. If you brane of the axon terminal, inactivating them.
gently touch Aplysia on its siphon after this electri- Voltage-gated K⫹ channels are responsible for
cal shock, the gill-withdrawal reflex will be much repolarizing the cell after the depolarization
367
Axon terminal of phosphorylates a transcription fac-

facilitating interneuron tor called CREB-1 (cAMP response
element binding protein 1), which
binds to cAMP-responsive sequences
in the promoters of many genes, in-
creasing their transcription. These
activated genes code for protein
Serotonin
Axon terminal of products that fall into two classes:
sensory neuron
proteins involved in forming new
G protein Voltage-gated synapses and proteins that increase
PKA Ca2+ channels
PKA activity. Together these proteins
Voltage-gated
K+ channels
increase the number of synaptic con-
cAMP
nections and their responsiveness,
Adenylate Synaptic
cyclase vesicles leading to long-term sensitization of
ATP
the gill-withdrawal reflex.
Neurotransmitter The hippocampus is important

for memory formation in
Cell body
of motor mammals
neuron
Memory formation has also been ex-
Figure 31 The molecular mechanism of sensitization in Aplysia tensively studied in mammals. For
The facilitating interneuron releases serotonin onto the axon terminal of the sensory example, rats and mice can be
neurons involved in the gill-withdrawal reflex. Serotonin binds to a G-protein-coupled
receptor that increases intracellular cAMP, activating protein kinase A (PKA), which
trained to perform simple tasks such
inactivates voltage-gated K⫹ channels. When these K⫹ channels are inactivated, action as locating a hidden object. If you
potentials last longer, leading to more Ca2⫹ influx through voltage-gated Ca2⫹ place a mouse in an enclosure filled
channels, and greater neurotransmitter release from the sensory neuron onto the with murky water, but with a plat-
cell body of the motor neuron.
form hidden below the surface, the
mouse will swim around randomly
phase of an action potential. When these K⫹ chan- until it encounters the platform, at which point it
nels are inactivated, action potentials last longer, will climb onto the platform and remain there.
leading to more Ca2⫹ influx through voltage-gated With repetition, the mouse will learn to find the
Ca2⫹ channels, and greater neurotransmitter re- platform very quickly, by remembering its location
lease. The second messenger pathways activated relative to the walls of the enclosure. A mouse with
when serotonin binds to its receptor also increase a damaged hippocampus cannot learn to perform
the number and location of neurotransmitter vesi- this task; however, if it learned the task prior to its
cles and activate another Ca2⫹ channel, allowing brain damage, it performs as well as an undam-
more Ca2⫹ to enter the cell, further increasing neu- aged mouse. Experiments such as these demon-
rotransmitter release. These direct effects of strate that the hippocampus is involved in the
serotonin are relatively short-lived and account formation of long-term memories, but the memo-
for the short-term sensitization of the gill-with- ries themselves appear to be stored elsewhere.
drawal reflex. The cellular and molecular mechanisms un-
Longer-term sensitization, such as occurs fol- derlying memory formation in the hippocampus
lowing repeated electrical shocks, involves more have been examined in vitro using recording elec-
lasting changes to the neurons and neural cir- trodes placed into thin slices of hippocampal tis-
cuitry. With repeated electrical shocks (and thus sue. In these preparations, repetitive stimulation
repeated release of serotonin onto the axon termi- of a particular presynaptic neuron eventually
nal of the sensory neuron in the withdrawal reflex), leads to an increase in the response of the postsy-
the levels of cAMP in the axon terminal become still naptic neuron, a phenomenon called long-term
higher, increasing the levels of activated PKA. potentiation. Over time, a particular level of
Some of the activated PKA enters the nucleus and presynaptic stimulation is converted to a larger
368
postsynaptic output. Long-term potentiation is AMPA receptors and NMDA receptors (which are
thought to be important in memory formation be- named because they selectively bind the drugs
cause it provides a mechanism in which repetitive AMPA and NMDA). NMDA receptors are ligand-
activity of a particular neural pathway can leave a gated Ca2⫹ channels, so when glutamate binds to
record of itself even after the activity has stopped. NMDA receptors, Ca2⫹ enters the cell. AMPA re-
Although long-term potentiation can occur in sev- ceptors are ligand-gated Na⫹ channels, so when
eral parts of the brain, it is easiest to demonstrate glutamate binds to AMPA receptors, Na⫹ enters
in the hippocampus, further suggesting that the the cell. Low-frequency stimulation of the presy-
hippocampus is important in memory formation. naptic neuron causes moderate release of gluta-
Long-term potentiation likely occurs via sev- mate into the synapse, and only the AMPA
eral mechanisms, but the best-studied mechanism receptors open, because Mg2⫹ blocks the NMDA
involves changes in certain specific postsynaptic ion channels (Figure 32a).
neurons in the hippocampus, the so-called CA1 High-frequency stimulation of the presynaptic
cells (Figure 32). Note that this is in contrast to ha- neuron causes greater release of glutamate, and the
bituation and sensitization in Aplysia, which in- resulting greater depolarization of the postsynaptic
volve changes in presynaptic neurons. These membrane displaces the magnesium ions from the
postsynaptic CA1 cells express two different types channel of the NMDA receptor (Figure 32b). With
of receptors for the neurotransmitter glutamate: the Mg2⫹ gone and the ion channel open,
Presynaptic cell
Glutamate
Paracrine
signals
AMPA receptor Ca2+ NMDA receptor AMPA receptor
Mg2+
NMDA
Mg2+ P receptor
Na+ Na+ Ca2+
Depolarization Greater
depolarization
CaMKII PKC
Postsynaptic cell Postsynaptic cell
(a) Low-frequency stimulation (b) High-frequency stimulation
Figure 32 Long-term potentiation in receptor types on the postsynaptic cell. Increased glutamate
hippocampal neurons (a) Low-frequency stimulation causes increased Na⫹ entry through AMPA receptors,
of the presynaptic cell results in moderate release of causing a greater depolarization. This greater depolarization
glutamate. Glutamate released from the presynaptic cell displaces Mg2⫹ from the NMDA receptor, allowing Ca2⫹ to
binds to the AMPA and NMDA receptors on the postsynaptic enter the cell. The influx of Ca2⫹ activates protein kinases
cell. Na⫹ enters through the AMPA receptor, causing (CaMKII and PKC), phosphorylating the AMPA receptor,
depolarization, but the presence of Mg2⫹ in the NMDA increasing its sensitivity to glutamate, and triggering the
receptor prevents Ca2⫹ from entering the cell. (b) High- release of paracrine factors that cause the presynaptic cell to
frequency stimulation of the presynaptic cell results in release more glutamate.
greater release of glutamate. Glutamate binds to both
369
Ca2⫹ enters the postsynaptic cell via the NMDA reproduce too much CaMKII show greater long-term
ceptor. The increase in intracellular calcium levels potentiation and perform better on hidden-platform
activates calcium-calmodulin-dependent protein tests and other tests of learning and memory. Sim-
kinase II (CaMKII) and protein kinase C (PKC), ilarly, transgenic mice that lack NMDA receptor
which phosphorylate a variety of proteins. For ex- expression in hippocampal neurons have more
ample, in CA1 cells CaMKII phosphorylates the difficulty learning to find their way through a
AMPA receptor, making it more sensitive to gluta- maze, or to find a hidden platform underwater.
mate, and also increases the number of AMPA re- These results strongly indicate that long-term po-
ceptors on the postsynaptic membrane by tentiation is involved in at least some kinds of
relocating receptors from intracellular stores. PKC memory formation in vertebrates.
activates a paracrine signaling pathway that
causes the presynaptic cell to produce more gluta-
mate. The net effect of these changes is more glu-
tamate acting on more sensitive postsynaptic
neurons, increasing the response to subsequent
stimuli, and improving memory formation. 17. What is the difference between habituation and
Transgenic mice have been used to test this sensitization. Compare and contrast the
mechanisms underlying these processes in the
mechanism of long-term potentiation and its rela-
Aplysia tail withdrawal reflex.
tionship to memory formation. For example,
18. What is long-term potentiation?
transgenic mice that lack the CaMKII gene do not
19. What kinds of evidence suggest that long-term
show long-term potentiation and have more trou-
potentiation is involved in learning and memory
ble finding a hidden platform under murky water in mammals?
than do normal mice, while transgenic mice that
Integrating Systems Stress and the Brain

The nervous system and the endocrine system work to- to the sensory cortex where it is integrated. The brain
gether to control and regulate the activity of essentially concludes that this sensory information represents a
every physiological system. The stress response provides hyena, and that hyenas are dangerous, and sends a sig-
an ideal example of this integration among multiple phys- nal to the limbic system, and more particularly to the
iological systems. amygdala—the seat of the fear response. At the same
Imagine that you are a baboon sitting beneath an time, using a second pathway, the thalamus can send
acacia tree, calmly grooming one of the members of signals directly to the limbic system without any sophis-
your troop. Suddenly, a hyena emerges from the long ticated processing, bypassing the sensory cortex. Thus,
grass. Your nervous and endocrine systems leap into ac- the baboon may initiate a fear response even before it
tion, engaging the fight-or-flight response that activates concludes that the stimulus represents a hyena. For ex-
the cardiovascular, respiratory, and musculoskeletal ample, you may be startled and frightened by a sudden
systems and causes you to flee. But how do these myr- noise in the night, and a moment later realize that it was
iad physiological systems work together to perform this only the wind, but your heart will already be pounding,
complex response? First, a baboon must perceive the and you may have some trouble going back to sleep.
stimulus, using its sense organs to see, hear, or smell When activated, the amygdala sends a signal to the
the hyena. The stimulated sensory receptors then com- spinal cord, activating the autonomic nervous system.
municate this incoming sensory information to the brain Within seconds, the postganglionic neurons of the sym-
in the form of action potentials conducted along primary pathetic nervous system begin to release norepineph-
afferent neurons. The brain integrates this information rine from their varicosities onto target tissues.
using two different pathways. In one pathway, the in- Preganglionic sympathetic neurons that form synapses
coming sensory information travels from the thalamus with the adrenal medulla release acetylcholine, causing
370
the adrenal medulla to release the catecholamines be important in preparing an animal to respond to a sub-
(epinephrine and norepinephrine) into the circulatory sequent stressor, or to recover from the previous one.
system. The catecholamines from the adrenal medulla The fight-or-flight response is a vital survival tool
and the sympathetic nervous system bind to their re- that allows vertebrates to respond to stressful situations
ceptors on many target tissues, increasing heart rate quickly and efficiently. But what happens if a stressful sit-
and the force of contraction, diverting blood flow from uation is prolonged? In the Serengeti, baboons encounter
nonessential organs to the muscles, brain, heart, and a wide variety of stressful situations, but one of their most
lungs, and increasing blood pressure. Catecholamines important stressors may be social—as a result of inter-
dilate the bronchioles of the lungs and increase the rate actions with other baboons. Baboons live in troops of be-
and depth of breathing, readying the baboon for action. tween 20 and 200 individuals, with a complex social
The sensory cortex also sends a signal to the motor cor- hierarchy. Female baboons inherit their position in this
tex of the brain, making the decision that the best hierarchy—if a mother baboon is high-ranking, then her
course of action when confronted with a hyena is to run offspring will be of high rank as well. In contrast, male
away. The motor cortex then sends out a signal via mo- baboons fight for their position in the dominance hier-
tor neurons to the muscles, and the baboon runs up the archy. Life can be rough for a low-ranking male baboon.
tree, escaping from the hyena. Once the danger has High-ranking males pester low-ranking baboons and
passed, the sympathetic nervous system decreases its steal food from them, and the males can improve their
firing and the baboon begins to calm down. rank only by fighting their way to the top. Thus, low-
At the same time that the amygdala is activating the ranking baboons are chronically exposed to social stres-
sympathetic nervous system, another part of the limbic sors. In fact, low-ranking baboons have elevated levels of
system—the hypothalamus—activates the endocrine sys- glucocorticoid hormones in their blood even under “rest-
tem. The hypothalamus releases corticotropin-releasing ing” conditions, and their physiological response to a
hormone (CRH) into the hypothalamic-pituitary portal stressor differs from that of high-ranking baboons.
blood system, causing (perhaps five or ten seconds later) Chronic stress of this kind can have many deleteri-
the pituitary to release adrenocorticotropic hormone ous effects, including a weakened immune system, ele-
(ACTH) into the circulation. The ACTH binds to receptors vated blood cholesterol levels, high blood pressure, and
on the adrenal cortex (a part of the adrenal gland, sur- even impaired growth. In addition, chronic stress can af-
rounding the adrenal medulla). The adrenal cortex then fect the brain. In particular, chronic elevation of stress
releases glucocorticoid hormones, such as cortisol, into hormones interferes with long-term potentiation in the
the blood. Cortisol plays a critical role in regulating car- hippocampus—a process that is critically important in
bohydrate and protein metabolism, causing the muscles learning and memory. Indeed, long-term exposure to
to release amino acids and the liver to convert these high levels of glucocorticoids can cause the hippocam-
amino acids to glucose and glycogen. Cortisol is a steroid pus to atrophy, decreasing the total number of neurons
hormone, and it mediates many of its actions by altering in this area of the brain, eventually causing irreversible
gene transcription in its target cells. Thus, cortisol typi- memory loss. So what is a low-ranking baboon to do?
cally acts fairly slowly, over the course of an hour or so— Researchers have shown that low-ranking baboons
long after the baboon has escaped up the tree and with strong social networks have reduced glucocorti-
returned to its normal activities. Because of the generally coid levels compared with baboons with poor social net-
slow time-course of the cortisol response, the role of the works. Perhaps making friends and having good
glucocorticoid hormones in the immediate response to relationships with siblings is an effective strategy to
stress is not entirely understood. Cortisol may, however, deal with the effects of chronic stress.2
371
Summary
Organization of Nervous Systems k The cortex is the thin outer layer of the cerebral
k Nervous systems consist of sensory pathways, hemispheres, and is involved in integrating and
integrating centers, and efferent pathways. interpreting sensory information.
k Cnidarians have relatively simple nerve nets k The cerebral hemispheres are divided into lobes
with few obvious integrating centers, but over that are named based on the overlying bones.
the course of evolution there has been a general
k The cerebral hemispheres can also be divided
trend toward cephalization, or the grouping of
into a number of cortices and association areas
sensory organs and integrating centers at the
that roughly correspond to functional regions of
anterior end of the body.
the brain.
k Integrating centers vary among the inverte-
k Many of the cerebral cortices are organized
brates but generally include one or more gan-
topographically, with particular areas dealing
glia and a brain.
with specific parts of the body.
k Vertebrate nervous systems have a clearly de-
marcated central nervous system, consisting of The Peripheral Nervous System
the brain and spinal cord, encased in either a k The brain integrates and interprets sensory in-
cartilaginous or bony covering. formation and sends out signals via efferent
pathways to effector organs.
k Additional integrating centers may be located in
the peripheral nervous system in the form of k Efferent pathways can be divided into the so-
ganglia. matic motor division and the autonomic division.
k The size of the brain varies greatly among major k Autonomic pathways are involved in maintaining
vertebrate groups, although the overall organiza- homeostasis, and can be divided into the sympa-
tion of the brain is similar among all vertebrates. thetic, the parasympathetic, and the enteric ner-
vous systems.
k The three primary regions of the vertebrate
brain are the forebrain, the midbrain, and the k The sympathetic and parasympathetic systems
hindbrain. work together, while the enteric nervous system
is more autonomous.
k The spinal cord acts as a reflex integrating cen-
ter in the vertebrates. k The sympathetic nervous system is most active
during periods of stress or physical activity,
k The hindbrain controls essential functions, in-
whereas the parasympathetic nervous system is
cluding breathing and heart rate.
most active during periods of rest.
k The midbrain is greatly reduced in mammals
k Both the sympathetic and parasympathetic ner-
relative to other vertebrates and acts largely as
vous systems exhibit basal tone, and are at least
a relay station.
somewhat active under all conditions.
k In mammals, the forebrain has taken over
k Sympathetic and parasympathetic pathways
many of the sensory integration functions of the
contain two neurons in series (a preganglionic
midbrain, and also controls more complex
and a postganglionic neuron).
processes such as reasoning and the control of
voluntary behavior. k In both the sympathetic and parasympathetic
divisions, the preganglionic neuron releases
k The hypothalamus is a part of the forebrain that
acetylcholine.
maintains homeostasis and helps to coordinate
many aspects of the endocrine system. k Sympathetic postganglionic neurons release
norepinephrine, whereas parasympathetic
k The hypothalamus is part of the limbic system,
postganglionic neurons release acetylcholine.
a group of related structures that are involved
in emotions and memory.
372
k Somatic (motor) pathways have only a single such as swimming in animals like leeches and
neuron between the spinal cord and the effector, locomotion in mammals.
and these neurons release only acetylcholine.
k Voluntary movements require coordination by
k In addition, skeletal muscle is the only effector more complex integrating centers such as the
for motor pathways, whereas autonomic path- higher centers of the brain.
ways innervate almost every organ in the body.
k Animals are also able to modify their behavior
Integrative Functions of Nervous Systems based on experience.
k The afferent pathways, integrating centers, and
k The molecular basis of learning and memory
efferent pathways of the nervous system work
has been worked out for a variety of model sys-
together to coordinate behavior and maintain
tems, and appears to involve changes in either
physiological homeostasis.
presynaptic or postsynaptic neurons that are
k Reflex arcs control many involuntary behaviors, involved in reflex arcs, or in regions of the brain
and pattern generators initiate rhythmic behav- such as the hippocampus, which is important
iors, including apparently complex behaviors for memory formation in mammals.
Review Questions
1. What is a central pattern generator? Ex- when you are (a) sitting quietly, (b) studying for
plain how a neural circuit can form a pat- an exam, (c) writing an exam?
tern generator. 6. Why is the autonomic nervous system some-
2. What is the limbic system? How is it important times termed the involuntary nervous system?
in behavior? 7. What is the importance of the phenomenon of
3. Outline some of the ways in which the verte- basal tone in the autonomic nervous system?
brate brain can be subdivided. 8. Compare and contrast a neuron with a nerve.
4. Compare and contrast the somatic and auto- What is the difference between a nerve and a
nomic nervous systems. tract?
5. Would you expect the sympathetic or parasym-
pathetic nervous system to be more active
Synthesis Questions
1. You can surgically remove large parts of the plain why chewing nicotine-containing gum can
forebrain from a mammal, and the animal will cause a rapid heart rate and tremors in the
survive. However, destruction of even rela- hands of nonsmokers.
tively small parts of the hindbrain usually 4. Would the autonomic nervous system function
causes death. Why might that be so? if the preganglionic neurotransmitters were
2. What is the functional significance of the different between the sympathetic and
highly folded and grooved appearance of the parasympathetic nervous systems, and the
surface of the brain in some mammals? postganglionic neurotransmitters were the
3. Nicotinic acetylcholine receptors are found on same?
muscle cells, and on postganglionic neurons in 5. Compare the role of presynaptic and post-
the sympathetic nervous system (among other synaptic mechanisms in habituation and
places in the body). Use this information to ex- sensitization.
373
For Further Reading

See the Additional References section at the end Mackie, G. O. 2004. Central neural circuitry in
of the chapter for more readings related to the the jellyfish Aglantha: A model “simple
topics in this chapter. nervous system.” Neurosignals 13: 5–19.
Organization of Nervous Systems Structure of the Mammalian Brain

The following is an engaging look at the scien- This fascinating book discusses many important
tists and the discoveries that shaped modern topics relating to the brain, including brain
neuroscience and outlines the changing view of evolution, brain structure, and the nature of
the brain from the time of the ancient Egyptians consciousness.
to the present. Bownds, M. D. 1999. The biology of mind:
Finger, S. 2000. Minds behind the brain: A Origins and structures of mind, brain, and
history of the pioneers and their discoveries. consciousness. Toronto: Wiley.
New York: Oxford University Press.
This article provides a clear and readable
This excellent and detailed book by Kandel introduction to the structure of mammalian
covers a wide range of material in neuroscience, brains.
from the functions of single neurons to the Nauta, W. J. H., and M. Feirtag. 1979. The
functions of the nervous system as a whole. organization of the brain. Scientific American
Kandel, E. R. 2000. Principles of neural science. 241: 88–111.
New York: McGraw-Hill.
This comprehensive review discusses the
This book provides an excellent review of how evolution and development of the brain and
neurons work, and how these signals are tackles the complex issue of the nomenclature for
integrated into the higher functions of the brain. the parts of the central nervous system.
Nicholls, J. G., A. R. Martin, B. G. Wallace, and Swanson, L. 2000. What is the brain? Trends in
P. A. Fuchs. 2001. From neuron to brain. Neuroscience 23: 519–527.
Sunderland, MA: Sinauer Associates.
The Peripheral Nervous System
Evolution of Nervous Systems This comprehensive review article and short
The following interesting book, although highly book provide an excellent overview of the
speculative, reviews the evolution of the brain autonomic nervous system.
and particularly addresses the question of the Donald, J. A. 1998. Autonomic nervous system. In
costs and benefits of having a large brain. The physiology of fishes, 2nd ed., D. H. Evans,
Allman, J. M. 1999. Evolving brains. New York: ed., 407–493. Boca Raton, FL: CRC Press.
Scientific American Library/W. H. Freeman. Robertson, D., P. A. Low, and R. J. Polinsky.
1996. Primer on the autonomic nervous
These reviews discuss the structure and system. San Diego: Academic Press.
evolution of the brain in vertebrates and
invertebrates. Integrative Functions of Nervous Systems
Ghysen, A. 2003. The origin and evolution of the This review provides an in-depth discussion of
nervous system. International Journal of the neural circuitry involved in leech swimming
Developmental Biology 47: 555–562. behavior.
Northcutt, R. G. 2002. Understanding vertebrate Brodfuehrer, P. D., and M. S. Thorogood. 2001.
brain evolution. Integrative and Comparative Identified neurons and leech swimming
Biology 42: 743–756. behavior. Progress in Neurobiology 63:
371–381.
These comprehensive reviews outline some of
the complexities of the seemingly simple nervous This review by Dietz discusses the control of
systems of cnidarians. locomotion in the vertebrates.
Grimmelikhuijzen, C. J., and J. A. Westfall. Dietz, V. 2003. Spinal cord pattern generators for
1995. The nervous systems of cnidarians. EXS locomotion. Clinical Neurophysiology 114:
72: 7–24. 1379–1389.
374
Dr. Eric Kandel was awarded the Nobel Prize in Stress and the Brain
Physiology or Medicine in 2000 for “discoveries These engaging and highly entertaining books
concerning signal transduction in the nervous outline the effects of stress hormones on the
system.” This paper is the published version of brain of mammals.
his lecture at the Nobel Prize ceremonies.
Sapolsky, R. M. 1992. Stress, the aging brain,
Kandel, E. R. 2001. The molecular biology of and the mechanisms of neuron death.
memory storage: A dialog between genes and Cambridge, MA: MIT Press.
synapses. Bioscience Reports 21: 565–611.
Sapolsky, R. M. 2004. Why zebras don’t get
ulcers, 3rd ed. New York: Owl Books.
Biegler, R., A. McGregor, J. R. Krebs, and S. D. Healy. 2001. A Consortium). 2005. Avian brains and a new understanding
larger hippocampus is associated with longer-lasting of vertebrate brain evolution. Nature Reviews in
spatial memory. Proceedings of the National Academy of Neuroscience 6: 151–159.
Sciences, USA 98: 6941–6944. Koch, C., and G. Laurent. 1999. Complexity and the nervous
Bullock, T. H. 1993. How are more complex brains different? system. Science 284: 96–98.
One view and an agenda for comparative neurobiology. Lin, Y. C., W. J. Gallin, and A. N. Spencer. 2001. The anatomy
Brain, Behavior and Evolution 41: 88–96. of the nervous system of the hydrozoan jellyfish,
Bullock, T. H. 2002. Grades in neural complexity: How large Polyorchis penicillatus, as revealed by a monoclonal
is the span? Integrative and Comparative Biology 42: antibody. Invertebrate Neuroscience 4: 65–75.
757–761. Lotze, M., G. Scheler, H. R. Tan, C. Braun, and N. Birbaumer.
Catania, K. G. 1995. Magnified cortex in star-nosed moles. 2003. The musician’s brain: Functional imaging of
Nature 375: 453–454. amateurs and professionals during performance and
Greenspan, R. J. 2004. Systems neurobiology without imagery. NeuroImage 20: 1817–1829.
backbones. Current Biology 14: R177–R179. Maguire, E. A., R. S. Frackowiak, and
Holland, L. Z., and N. D. Holland. 1999. Chordate origins of C. D. Frith. 1997. Recalling routes around London:
the vertebrate central nervous system. Current Opinion in Activation of the right hippocampus in taxi drivers.
Neurobiology 9: 596–602. Journal of Neuroscience 17: 7103–7110.
Iwaniuk, A. N., K. M. Dean, and J. E. Nelson. 2005. Nishikawa, K. C. 2002. Evolutionary convergence in nervous
Interspecific allometry of the brain and brain regions in systems: Insights from comparative phylogenetic studies.
parrots (Psittaciformes): Comparisons with other birds Brain, Behavior and Evolution 59: 240–249.
and primates. Brain, Behavior and Evolution 65: 40–59. Pittenger, C., and E. R. Kandel. 2003. In search of general
Jarvis, E. D., O. Gunturkun, L. Bruce, mechanisms for long-lasting plasticity: Aplysia and the
A. Csillag, H. Karten, W. Kuenzel, hippocampus. Philosophical Transactions of the Royal
L. Medina, G. Paxinos, D. J. Perkel, Society of London, Series B: Biological Sciences 358:
T. Shimizu, G. Striedter, J. M. Wild, G. F. Ball, J. Dugas- 757–763.
Ford, S. E. Durand, G. E. Hough, S. Husband, Roth, G., and M. F. Wullimann. 2001. Brain evolution and
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V. Smulders, K. Wada, S. A. White, K. Yamamoto, J. Yu, A.
Reiner, and A. B. Butler. (The Avian Brain Nomenclature
Credits
306 Dr. Martin Wiesmann.
307 National Library of Medicine.
307 CORBIS, Peter Turnley/CORBIS.
322 University of Wisconsin Media Solutions, Waller
Welder/University of Wisconsin Media Solutions.
375
Circulatory Systems
Animal circulatory systems are structurally diverse, rang- Although we now take this transport function for
ing in complexity from the relatively simple circulatory sys- granted, the structure and function of circulatory systems
tems of insects to the highly branched circulatory systems remained obscure for many centuries. The correct path-
of animals such as decapod crustaceans and vertebrates. way for the circulation of blood in mammals was first de-
Despite this structural diversity, animal circulatory sys- scribed by the 11th-century Muslim physician and
tems share many features in common. Circulatory systems theologian Ibn al Nafis. However, this insight was lost to
transport oxygen and nutrients to actively metabolizing tis- the Western world, and it was not rediscovered until the
sues, and remove carbon dioxide and other waste prod- early 17th century when the careful experimental work of
ucts. They help to coordinate physiological processes by William Harvey demonstrated that the heart circulates
transporting signaling molecules from place to place blood through the blood vessels to various parts of the
within the body, and they assist in the defense of the body body. In Harvey’s words: “It is absolutely necessary to con-
by transporting immune cells to the site of invasion by for- clude that the blood in the animal body is impelled in a cir-
eign organisms. cle, and is in a state of ceaseless motion.” We know now
376
Circulatory Systems
William Harvey’s experiments on the circulation of blood.
that the heart pumps blood through the arterial system

and into the capillaries where exchange of materials with
the tissues takes place. The blood then returns to the heart
via the venous system. Because good compound micro-
scopes were not available in the early 17th century, Harvey
was unable to directly observe the capillaries that connect
arteries and veins; however, he hypothesized their exis-
Resin cast of the coronary arteries of a human heart.
tence based on the results of his experiments. Three
decades later, and four years after Harvey’s death, the Ital-
ian physician and anatomist Marcello Malpighi used the vided a partial answer to this puzzle. They have shown that
newly available compound microscopes to identify tiny the beating of the heart is critical for the appropriate devel-
blood vessels in the lungs and kidneys, which he named opment of the circulatory system.
capillaries. This discovery completed and confirmed the pi- By implanting a tiny bead at either the entrance or exit
oneering work of Harvey, and set the stage for our modern of the developing heart, researchers were able to reduce
understanding of circulatory systems. the flow of blood in the circulatory system. Blocking the
Consistent with the importance of the circulatory sys- flow of blood through the heart interfered with its develop-
tem, the heart is one of the first organs to form in a devel- ment; the chambers of the heart were out of alignment or
oping vertebrate embryo. For example, in zebrafish (Danio did not form properly, and the heart valves did not develop
rerio, a common model system used by developmental bi- at all. Similarly, other researchers have shown that the
ologists), the heart forms and begins to beat rhythmically force imposed by blood pulsating at the ends of developing
during the first day following the fertilization of the egg. blood vessels causes the vessels to grow and sprout, help-
However, day-old zebrafish embryos are tiny, suggesting ing to form the circulatory system. Some of these
that diffusion should be more than adequate to deliver oxy- processes continue to occur in adult animals, demonstrat-
gen and nutrients to the tissues. Indeed, a variety of exper- ing that a circulatory system is not simply a passive plumb-
iments have shown that zebrafish do not require a ing system that transports substances around the body.
functioning circulatory system for oxygen transport during Instead, circulatory systems are dynamic physiological sys-
early development. But if the circulatory system is not tems whose structure and function are regulated in re-
needed for oxygen transport, why does the heart begin sponse to the ever-changing demands of the body’s
beating so early? Developmental physiologists have pro- tissues.2
377
Circulatory Systems
Overview Because of this limitation on the rate of diffu-

sion, larger animals move fluids through their bod-
Unicellular organisms and some small metazoans ies by a process called bulk flow, or convective
lack circulatory systems and instead rely on diffu- transport. The bulk flow of fluids can transport sub-
sion to transport molecules from place to place. Al- stances across long distances far faster than would
though diffusion can be rapid over short distances be possible by diffusion alone. For example, the hu-
(such as across a cell membrane or within a single man circulatory system can move a milliliter of
cell), it is slow across long distances (Figure 1a). In blood from the heart to the feet and back again in
fact, the time (t) needed for a molecule to diffuse about 60 seconds, rather than the 60 years needed
between two points is proportional to the square of for diffusion! The phenomenon of bulk flow is fun-
the distance (x) over which diffusion occurs (t ∝ x2). damental to many physiological processes, includ-
This relationship is a simplified form of Einstein’s ing respiration, digestion, and excretion.
diffusion equation (which is also called the second As stated in Newton’s second law of motion
law of diffusion). Using this equation, we can cal- (force mass × acceleration), if we exert sufficient
culate that at 37°C a small molecule such as glucose force on an object, it will start moving (or acceler-
in aqueous solution takes about 5 seconds to dif- ate, if it is already in motion). Thus, bulk flow of a
fuse across 100 µm (the size of an average cell) but fluid occurs when an external force is applied to
would take more than 60 years to diffuse across the fluid, setting it in motion. In circulatory sys-
several meters (the distance from the heart to the tems, the fluid is confined within a series of cham-
feet and back again in an average-size human). bers and tubes (Figure 1b). By pressing down on
this confined fluid, you increase the pressure in
the immediate area. The fluid then flows from this
area of high pressure to any adjacent areas of
lower pressure. In many circulatory systems, one-
Time needed for diffusion (t )
way valves help to ensure that the fluid flows in

one direction around the system. In this chapter,
we examine the structure, function, and regula-
tion of animal circulatory systems, in all their di-
versity, to see how they use bulk flow to perform
their critical transport function.
Distance (x ) Characteristics of Circulatory

(a) Diffusion Systems
All animal circulatory systems play similar roles,
Increased pressure
carrying oxygen, carbon dioxide, nutrients, waste
products, immune cells, and signaling molecules
One-way valve One-way valve
from one part of an animal to another. In some an-
Flow
(closed) (open) imals, the circulatory system even plays a role in
temperature regulation, by conveying heat from
the working muscles out to the surface of the body
Increased pressure where it can be lost to the environment. Because
(b) Bulk flow of its important transport role, the circulatory sys-
tem affects almost every physiological process that
Figure 1 Diffusion and bulk flow (a) Diffusion is
rapid over short distances, but the time needed for diffusion an animal performs.
increases exponentially with distance. To transport
substances rapidly across long distances, animals use the
bulk flow of fluids. (b) Increased local pressure in one area of
the circulatory system drives flow from the area of high Components of Circulatory Systems
pressure to any adjacent areas of lower pressure, a
phenomenon known as bulk flow. One-way valves ensure that Like all pumping systems, animal circulatory sys-
this flow is unidirectional. tems have three important components:
378
Circulatory Systems
1. One or more pumps or other propulsive struc- Muscular wall

tures that apply a force to drive fluid flow, of- One-way valve One-way valve
ten in combination with one-way valves to
ensure unidirectional flow Flow
2. A system of tubes, channels, or other spaces
Vein Artery
through which the fluid can flow
Pressure from
3. A fluid that circulates through the system contraction
There is, however, substantial diversity among an- (a) Contractile chamber
imals in the structure and organization of each of
these components. Skeletal muscle Blood vessel
Flow
Circulatory systems use diverse pumping
structures
One-way valve One-way valve
All circulatory systems have some type of pumping
structure that propels fluids around the system. (b) External pump
We are most familiar with the pumping action of

Contractile blood
contractile chambers such as the vertebrate heart vessel or peristaltic
(Figure 2). Chambered hearts are found in both Wave of contraction heart
vertebrates and invertebrates. Muscular contrac-
tion of the heart increases the pressure within the Flow
heart chambers. When the pressure in the heart
exceeds that in the rest of the circulatory system,
blood flows down this pressure gradient out into (c) Peristaltic contraction
the circulatory system. One-way valves help to en-
Figure 2 Types of pumping structures in animal
sure unidirectional flow. circulatory systems (a) Contractile chambers such as
Chambered hearts often have more than one the vertebrate heart increase blood pressure in a closed
chamber. The chambers that the circulatory fluid chamber through contractions of their muscular walls. As
first enters are typically called atria. Animal pressure increases, valves open allowing fluid to flow down the
resulting pressure gradient. One-way valves are required to
hearts may have one or more atria, and these ensure unidirectional flow. (b) Structures such as skeletal
chambers function both as reservoirs and as muscles can act as pumps. Contraction and relaxation of
pumps. Fluid flows from the atria into an even skeletal muscles alternatively compress and expand a blood
more muscular chamber, called the ventricle, vessel, forcing the fluid along the vessel. One-way valves
ensure unidirectional flow. (c) Contractile blood vessels and
which acts as the primary pump. peristaltic hearts push blood using waves of rhythmic
Chambered hearts are not the only type of contraction. These vessels may contain valves to ensure
pumping structures found in animal circulatory unidirectional flow, but the direction of contraction is often
systems. Organs that are not strictly associated sufficient to cause flow to be largely unidirectional.
with the circulatory system, such as skeletal mus-
cles, can be used to develop pressure gradients tion that proceed in a coordinated fashion from
(Figure 2b). For example, in terrestrial vertebrates one end of a tube to the other. Similar to squeez-
the actions of the leg muscles help to push blood ing toothpaste from its tube, peristaltic contrac-
back to the heart. Similarly, in many arthropods, tions squeeze blood through the pumping
normal body movements propel blood around the structure and into the circulatory system. Because
body. In these systems, the blood vessels generally peristaltic contractions usually occur in a specific
contain one-way valves to maintain the unidirec- direction, these pumps can cause unidirectional
tional flow of the circulatory fluid. flow even when no valves are present.
Pulsating or contractile blood vessels and
tubelike hearts, which are found in some inverte-
brates and the early embryos of vertebrates, move
Circulatory systems can be open or closed
blood by peristalsis (Figure 2c). Peristaltic con- Circulatory fluids flow either through enclosed
tractions are rhythmic waves of muscle contrac- blood vessels that have walls with a specialized
379
Circulatory Systems
lining that separates the circulatory fluid from the that circulates a fluid called lymph around the
tissues, or through open spaces called sinuses body. Lymph is formed from blood by a process
that allow the circulatory fluid to make direct con- called ultrafiltration in the small blood vessels.
tact with the tissues. In a closed circulatory sys- The pressure difference across the walls of the
tem, the circulatory fluid remains within blood small blood vessels forces fluid out of the blood
vessels at all points in the circulatory system. and into the interstitial space where it mixes with
Thus, substances must diffuse across the walls of the interstitial fluid. Blood cells and large mole-
the blood vessels to enter the tissues in animals cules such as dissolved proteins cannot pass
with closed circulatory systems. In an open cir- across the walls of most of the small blood vessels,
culatory system, the circulating fluid enters a si- but these walls are quite permeable to small mol-
nus at least at one point in the circulatory system ecules and water. The walls of the small blood ves-
and thus comes into direct contact with the tis- sels thus act as a filter, forming a lymphatic fluid
sues, allowing the circulating fluid to mix with ex- that is similar in composition to plasma, but con-
tracellular fluids. tains few proteins or cells. The lymphatic system
Open circulatory systems usually contain both pumps this ultrafiltrate through the body and re-
blood vessels and sinuses, and sinuses can have turns it to the circulatory system.
complex, highly branched structures. As a result, Many fishes have an additional secondary cir-
the difference between open and closed circula- culation that is distinct from both the primary cir-
tory systems is not absolute. For example, the circulatory system and the lymphatic system. This
culatory systems of decapod crustaceans such as secondary circulation is found in the gills and the
crabs and lobsters are usually described as open, skin of the fish, and may serve an osmoregulatory
because they contain sinuses. However, these ani- function. Like lymph, the fluid in the secondary
mals have some very small blood vessels across circulatory system of fish is derived from blood,
which diffusion to the tissue occurs, as is the case but it is not formed by ultrafiltration across the
in a closed circulatory system, and in the sinuses walls of the small blood vessels. Instead, fluid en-
blood flows through well-defined channels within ters the secondary circulatory system through
the tissues as it returns to the heart. So on a func- openings between the two circulatory systems.
tional basis, we might classify decapod circulatory These openings allow plasma, proteins, and some
systems as closed, although based on their struc- cells to enter the secondary circulation. Thus, the
ture, they are open systems. fluid in this secondary circulation is very similar to
blood, except that it has a lower concentration of
blood cells.
Circulatory systems pump several types Hemolymph is the circulating fluid of open
of fluids circulatory systems. In an open circulatory sys-
There is some disagreement among comparative tem, hemolymph flows through blood vessels, but
physiologists about the terminology that should be when it enters the sinuses it directly contacts the
used for circulatory fluids, but for the purposes of tissues, and thus is continuous with the interstitial
this text we distinguish several major types of flu- fluid. As a result, it is difficult to distinguish be-
ids. We use the term interstitial fluid for the ex- tween blood, lymph, and interstitial fluid in these
tracellular fluid that directly bathes the tissues of organisms. Indeed, the word hemolymph was
either vertebrates or invertebrates. Even animals coined to imply this combination of blood and
that lack a specialized circulatory system are usu- lymph (hema is the Greek root for blood). The si-
ally able to propel interstitial fluid around their nuses of open circulatory systems are sometimes
bodies by bulk flow. We define blood as the fluid referred to collectively as the hemocoel.
that circulates within a closed circulatory system,
such as that of a vertebrate. Blood is a complex tis-
sue that has multiple components. It contains pro-
teins and a variety of cells suspended in a fluid
Diversity of Circulatory Systems
called plasma. We discuss the composition of There is substantial diversity in the structure of cir-
blood in more detail at the end of this chapter. culatory systems among animals. Animals such as
Most vertebrates have a secondary circulatory sponges, cnidarians, and flatworms lack a circula-
system, in addition to the cardiovascular system, tory system that transports an internal fluid, but all
380
Circulatory Systems
Osculum
Choanocyte Water
Water
Mouth
Gastrovascular
Gastrovascular cavity
Porocyte cavity Pharynx
Mouth
Spongocoel
(a) Sponges (Porifera) (b) Cnidaria (c) Platyhelminthes
Figure 3 Bulk flow in animals that lack circulatory systems (a) The body wall
of a sponge is full of pores that lead into an inner cavity called the spongocoel. The beating of
flagellated choanocytes propels water through the pores into the spongocoel and out the
osculum. (b) Cnidarians use muscular contractions to propel water into the mouth and through
the gastrovascular cavity. (c) Platyhelminths and nematodes use contractions of a muscular
pharynx to propel fluid through their gastrovascular cavity.
of these animals have mechanisms for propelling

Most annelids have closed circulatory
fluids around their bodies (Figure 3). For example,
systems
sponges propel water through their bodies using Phylum Annelida is divided into three main
choanocytes, specialized cells with rhythmically branches: class Polychaeta (e.g., tube worms),
beating flagellae. Cnidarians propel water from the class Oligochaeta (e.g., earthworms), and class
external medium through their mouths into a gas- Hirudinea (leeches). The circulatory systems of
trovascular cavity using muscular contractions, leeches are different from those of the other an-
and pump the water down to their tentacles, carry- nelids, and we do not discuss them further here.
ing oxygen and digested food along with it. Flat- All polychaetes and oligochaetes are able to circu-
worms also have a gastrovascular cavity, which in late interstitial fluid using either cilia or muscular
many species is lined with ciliated flame cells contractions of the body wall. Some polychaetes
whose beating propels water containing food parti- rely solely on this system, but most polychaetes
cles to all parts of the body. In all these species, the and oligochaetes have a system of blood vessels
bulk flow of fluids is part of a combined respiratory, that circulates a specialized fluid containing oxy-
digestive, and circulatory system. gen carrier proteins. This system may have an
Nematodes (phylum Nematoda) and horsehair open design, as in some polychaetes (Figure 4a),
worms (phylum Nematomorpha) also lack special- but the majority of annelids have closed circula-
ized circulatory systems, but they can move inter- tory systems that circulate blood through the body
stitial fluid through their body cavity (called a (Figure 4b).
pseudocoelom) by bulk flow powered by contrac- Oligochaetes such as earthworms have a se-
tions of the muscles in their body walls. Nema- ries of small blood vessels connecting the large
todes and horsehair worms are seldom more than dorsal and ventral blood vessels that run the
a millimeter thick (although some species can be length of the animal. The dorsal vessel is contrac-
up to 30 m long), and they obtain oxygen by diffu- tile, and moves blood toward the head using
sion across the entire body surface. As a result, rhythmic waves of peristaltic contraction. The
these animals probably have little need for a circu- blood then flows through five pairs of muscular
latory system to transport oxygen. Instead, bulk contractile tubes (or simple tubelike hearts) that
flow of interstitial fluid is most important for trans- pump blood from the dorsal to the ventral blood
porting signaling molecules and immune cells. vessel. The blood travels back along the body
381
Circulatory Systems
Sinus Heart
Heart Blood vessels
Blood vessels
(a) Open circulatory system of annelid (polychaete)
Sinus Hemocoel
(a) Open circulatory system of a bivalve mollusc (clam)
Dorsal blood vessel
Connecting vessels Systemic
Hearts heart
Gill
Branchial
hearts
Ventral blood vessel Systemic

Branchial heart
(b) Closed circulatory system of annelid (oligochaete) hearts
Figure 4 Circulatory systems of annelid
(a) Some polychaetes have open circulatory systems.
(b) Oligochaetes have closed circulatory systems.
Gills Body tissue
(b) Closed circulatory system of a cephalopod mollusc (squid)
through the ventral blood vessel. Small connecting
Figure 5 Circulatory systems of molluscs
blood vessels carry the blood from the tissues back (a) The circulatory system of a bivalve such as a clam. Most
to the dorsal vessel. molluscs have open circulatory systems. (b) The circulatory
system of a cephalopod mollusc (squid). Most cephalopods
have closed circulatory systems. The systemic heart pumps
Most molluscs have open circulatory oxygenated blood to the body. The branchial hearts pump
systems deoxygenated blood from the body through the gills.
The circulatory systems of molluscs are extremely

diverse, consistent with the enormous diversity in closed circulatory system and three muscular
body form within this phylum. All molluscs have chambered hearts (Figure 5b). The systemic heart
hearts or contractile organs of some sort, and pumps oxygenated blood to the body. After passing
most groups have at least some blood vessels, with through the body tissues, the deoxygenated blood
some species having extensive vascular networks. flows into the two branchial hearts that pump blood
However, almost all molluscs have open circula- through the gills. From the gills, the oxygenated
tory systems (Figure 5). Only the cephalopods blood flows back into the systemic heart.
(squid, octopus, and cuttlefish) have completely
closed circulatory systems.
The closed circulatory system of cephalopods All arthropods have open circulatory
evolved from an open circulatory system, likely one systems
similar to those in ancient cephalopods such as the Almost all arthropods have one or more hearts and
Nautilus. In nautiloids, blood returning from the at least some blood vessels, but no arthropod line-
gills enters the atria of the heart, and then is ages have evolved a completely closed circulatory
pumped by the ventricle through blood vessels that system. Here we consider two of the major arthro-
empty into a large sinus. Contractile blood vessels pod lineages: the crustaceans and the insects.
then pump blood across the gills and back to the The circulatory systems of crustaceans vary
heart. In contrast, squid and octopuses have a from quite simple in smaller and less active species
382
Circulatory Systems
Heart
Ostia
Accessory
pumping
organ
Aorta
Heart
(a) Brachiopod crustacean (fairy shrimp)
Ostia
Ostia
Heart
Blood Lateral
vessels arteries
Hemocoel
Figure 7 Circulatory system of insects Insects

Sinus have relatively simple open circulatory systems. The
contractile dorsal blood vessel is elaborated into a series of
hearts found along the body, often with one in each body
(b) Decapod crustacean (crayfish) segment. These hearts and the contractile dorsal blood
vessel push blood using peristaltic contractions from the
Figure 6 Circulatory systems in crustaceans (a) posterior end to the anterior end of the body. The circulatory
Circulation in a brachiopod crustacean. Brachiopods such as fluid then discharges into the open hemocoel and percolates
fairy shrimp have simple circulatory systems with few blood back through the sinuses of the body, assisted by normal
vessels and a long tubular heart. (b) Circulation in a decapod body movements.
crustacean. Decapod crustaceans have elaborate open
circulatory systems with arteries and capillary beds and a
muscular chamberlike heart. The heart pumps the circulatory Decapods have among the most sophisticated
fluid through the arteries into successively smaller blood open circulatory systems of any invertebrate, and
vessels that drain into small channels within the head and many of their blood vessels have muscular valves
body tissues. The fluid returns to the heart via a set of ostia.
that they can use to control the amount of blood
flowing to particular tissues. The sinuses are very
to extremely complex in large, active species small in some species, and act functionally as
(Figure 6). The brachiopod crustaceans such as the blood vessels. Thus, although crustacean circula-
fairy shrimp (also known as “sea monkeys” to gen- tory systems are structurally open, they may act as
erations of North American children) have a simple functionally closed systems.
tubular heart that may extend almost the entire In many insects the only obvious structure in
length of the body, and relatively few blood vessels. the circulatory system is a large dorsal vessel
In contrast, decapod crustaceans such as lobsters, that extends along most of the body (Figure 7).
crabs, and crayfish have a very muscular heart that The posterior part of the dorsal vessel is contrac-
acts as a contractile chamber, and an extensive net- tile and is often divided into several discrete
work of blood vessels (Figure 6b). These animals pumping organs that function as hearts, one per
have a single heart encased in a sac called the abdominal segment. The anterior part of the dor-
pericardial sinus. Several branching arteries lead sal vessel is less muscular and is termed the
out of the heart to many parts of the body, ulti- aorta. The contractions of the hearts pump he-
mately emptying out into sinuses deep within the molymph toward the head. The hemolymph
tissues. After passing through the tissues, the blood empties into a sinus in the region of the brain,
drains into a sinus located along the ventral side of and then percolates back to the abdomen, via an-
the body. This sinus leads to the gills, where the other sinus. Normal body movements help to
blood is reoxygenated prior to its return to the move the hemolymph through the sinuses, re-
heart. The blood passes into veins that empty into turning the blood to the heart via ostia, as in
the pericardial sinus, entering the heart via small other arthropods. Many insects also have acces-
holes called ostia that can be opened and closed to sory pulsatile organs (simple hearts) in their an-
regulate blood flow. tennae, wings, and limbs. In fact, some species
383
Circulatory Systems
have dozens of these small hearts, which help to Cephalochordates such as the lancelet (for-
propel hemolymph through their long, narrow merly called Amphioxus) lack an obvious cham-
appendages. bered heart and instead have a long tubular heart
or contractile blood vessel located at the base of
the digestive tract and additional pulsatile blood
Chordates have both open and closed vessels in other locations within the circulatory
circulatory systems system that assist in pumping blood through the
The vertebrates belong to the phylum Chordata, circulatory system. The circulatory system is
which also contains the invertebrate urochordates largely closed, with blood vessels emptying into si-
(the tunicates) and cephalochordates (the nuses in only a few locations in the body.
lancelets). Urochordates have a simple tubular Vertebrates have closed circulatory systems in
heart that propels fluid through a series of well- which the blood remains within blood vessels at
defined channels in the tissues. These channels all points in its passage through the body.
lack walls, so the urochordate circulatory system
is classified as open. The heart is located at the
base of the digestive tract in the posterior part of Closed circulatory systems evolved
the body and pumps fluid through the body using
multiple times in animals
peristaltic contractions. In some tunicates such as From the examples outlined above, it is clear that
Ciona, the direction of these contractions reverses there is substantial diversity in the structure and
periodically, causing the direction of blood flow to organization of animal circulatory systems, and
reverse. The physiological significance of this that there are many alternate evolutionary solu-
flow pattern is not yet understood, although some tions to the problem of moving fluids around the
authors have suggested that it serves to disperse body by bulk flow. Figure 8 summarizes the prop-
nutrient-gathering cells around the body. erties of the circulatory systems of the major
No circulatory system Open circulatory

Echinodermata Mollusca
(water vascular system systems (except
used to move O2 and cephalopods)
nutrients)
Closed circulatory Vertebrata Open circulatory

systems Arthropoda systems
No circulatory system
Open circulatory Nematoda
Cephalochordata (muscle contraction
systems moves interstitial fluids)
Open circulatory Urochordata
systems Open and closed
Annelida circulatory systems
Platyhelminthes
(ciliated cells move
interstitial fluid
by bulk flow)
Cnidaria (water pumped through
gastrovascular cavity
No circulatory system by muscle contractions)
Porifera
(water pumped through
body cavity by beating
of flagellated cells)
Protist
Figure 8 Evolution of animal circulatory systems
384
Circulatory Systems
animal groups. Most systematists agree that ani- The Circulatory Plan of Vertebrates
mals evolved from flagellated protists resembling
modern choanoflagellates. These small unicellular Jawed vertebrates share a common circulatory
organisms lack circulatory systems, and rely on plan (Figure 9), with a primary systemic heart that
diffusion to transport substances through their pumps blood to a large blood vessel termed an
bodies. Circulatory systems are thought to have artery. The word artery is the general term for
first evolved to transport nutrients and other small blood vessels that carry blood away from the
molecules around the body, but very early in the heart. The large artery leading from the heart to
evolution of animals the circulatory system began the body is termed the aorta. The aorta branches
to serve a respiratory function, helping to trans- into succeedingly smaller arteries, culminating in
port oxygen to the actively metabolizing tissues. In the feed arteries that lead to the tissues. Within
most animal groups, this respiratory function has the tissues, the arteries branch into arterioles
been a major force shaping the evolution of circu- that direct flow into the capillary beds. Capillary
latory systems. beds are made up of dense networks of thin-
Although the earliest animal groups lack cir- walled vessels called capillaries, which are the
culatory systems, most animals have them. Open primary site of diffusion of materials into the tis-
systems are present in at least some representa- sues. At the end of the capillary beds, capillaries
tives of most animal groups. Closed circulatory coalesce into small vessels called venules, which
systems evolved independently from these ances- in turn coalesce into larger vessels called veins
tral open circulatory systems in several lineages of that return blood to the heart.
animals, including the vertebrates, cephalopod Although this general circulatory plan provides
molluscs, and annelid worms. These closed circu- a good overview of the route of blood through the
latory systems differ in structure but are function- vertebrate circulatory system, actual circulatory
ally similar, and are thus examples of convergent systems are rather more complex. For example,
evolution. Closed circulatory systems provide sev- arteries do not always simply branch to form pro-
eral advantages over open circulatory systems, in- gressively smaller vessels. Arteries can also form
cluding the ability to generate high pressure and anastomoses (singular, anastomosis), which are
flow and the ability to better control and direct connections from one blood vessel to another.
blood flow to specific tissues. These features are Anastomoses provide an alternate pathway for
particularly important for oxygen delivery to ac- blood to flow if one route is blocked. For example,
tively metabolizing tissues. Consistent with this the arteries in the joints contain numerous anasto-
expectation, closed circulatory systems are usually moses, allowing blood to flow even if the bending
found in highly active organisms with high de- of the joint closes off one of the arteries. Anasto-
mands for oxygen, or those living in oxygen-limited moses become more frequent the farther you get
environments where oxygen supply is low.
Although insects can have extremely high Arteries Arterioles Capillaries Venules Veins
metabolic rates, they have relatively simple open
circulatory systems (see Figure 7). This pattern is
in direct contrast to that observed in other groups
in which closed or nearly closed circulatory sys-
tems are associated with highly active lifestyles.
However, insects do not use the circulatory system
Heart
as their primary means of gas transport. Instead,
insects have a tracheal system that consists of a
series of blind-ended air-filled tubes that conduct
oxygen directly to the tissues in gaseous form, by-
passing the circulatory system. Thus, in insects the Figure 9 The vertebrate circulatory plan
circulatory system serves primarily to deliver nu- Vertebrates share a common circulatory plan in which the
trients, immune cells, and signaling molecules, heart pumps blood to a large artery, then through
succeedingly smaller arteries to the arterioles that lead to
rather than being critical for oxygen delivery, and the capillary beds, where substances diffuse to the tissues
high flow rates and pressure may not be required. across the walls of the capillaries. Capillaries coalesce into
venules and then veins, which return blood to the heart.
385
Circulatory Systems
from the heart so that arterioles and capillaries sel is the tunica intima or tunica interna. It con-
tend to form dense interconnected networks. In sists of an inner lining called the vascular en-
addition, venous shunts and arterio-venous anas- dothelium, made up of a smooth sheet of
tomoses allow blood to be redirected to avoid a epithelial cells, and a basement membrane called
particular capillary bed if necessary. the subendothelial layer, which supports the vas-
cular endothelium. The tunica media, or middle
layer, of a blood vessel is largely composed of
smooth muscle and sheets of the extracellular ma-
Vertebrate blood vessels trix protein elastin that wrap around the tunica in-
have complex walls tima. Contraction and relaxation of the smooth
Vertebrate blood vessels are hollow tubular struc- muscle of the tunica media causes vasoconstric-
tures consisting of a complex wall surrounding a tion and vasodilation. The outermost layer of the
central lumen. In the vertebrates, the walls of blood vessel wall is called the tunica externa, or
blood vessels are composed of up to three layers tunica adventitia, and is composed largely of col-
(Figure 10). The innermost layer of the blood ves- lagen fibers that support and reinforce the blood
vessel.
Tunica externa Tunica externa
Tunica media Tunica media
Tunica intima Tunica intima
Endothelium Endothelium
Large vein Elastic artery
Tunica externa Tunica externa
Tunica media Tunica media
Tunica intima Tunica intima
Endothelium Endothelium
Vein Muscular artery
Tunica externa Tunica media
Endothelium
Endothelium
Venule Arteriole
Endothelium
Capillary
Figure 10 Variation in the structure of vertebrate blood vessels

Representative portions of blood vessels from the systemic circuit of a mammalian circulatory
system are shown in cross-section. Arteries and veins are composed of three layers (the tunica
externa, tunica media, and tunica intima) of varying thickness, lined with an endothelium.
Smaller vessels such as arterioles, capillaries, and venules lack one or more of these layers.
386
Circulatory Systems
Wall thickness varies among blood vessels

The thickness of the layers of the vessel walls Tight junction
varies greatly among types of blood vessels. Arter-
ies are large-diameter, thick-walled blood vessels Endothelial cell
with a thick tunica externa and tunica media. The
arteries closest to the heart have a particularly Intercellular cleft
thick tunica externa, which makes them highly
elastic. Arteries farther from the heart tend to (a) Continuous capillary
have a thicker tunica media, and are sometimes
called muscular arteries. Arterioles have thinner
walls and lack an extensive tunica externa. Larger
arterioles have a relatively extensive tunica media, Tight junction
composed of thick layers of smooth muscle, but in
Endothelial cell
the smallest arterioles, the tunica media consists
of a single layer of smooth muscle arranged in a
Intercellular cleft
spiral pattern around the endothelium. The
smooth muscle cells allow the arterioles to vaso- Fenestrations (pores)
constrict and vasodilate. (b) Fenestrated capillary
Capillaries lack the tunica media and tunica
externa and have extremely thin walls composed
of a single sheet of endothelial cells, wrapped in an
occasional contractile pericyte cell. These thin Tight junction
walls allow substances to pass between the blood
and the tissues. Substances can move across the Endothelial cell
capillary walls in several ways. Lipid-soluble sub-
stances can move across the cell membrane by Intercellular cleft
simple diffusion. Vesicles transport large water-
soluble substances such as proteins across the cell (c) Sinusoidal capillary
in a process called transcytosis. Small molecules Figure 11 Variation in capillary structure
such as water and ions can move across the capil- (a) In a continuous capillary, the endothelial cells are connected
lary wall via a paracellular pathway, through via tight junctions. (b) In a fenestrated capillary, the endothelial
cells have many oval pores (fenestrations) that allow the
pores between the cells of the capillary wall. Capil-
regulated movement of solutes. (c) In a sinusoidal capillary, the
laries have very small diameters, and are often just endothelial cells are loosely linked and large molecules can
large enough for blood cells to squeeze through. move between the cells.
The structure of the tunica intima varies
among capillaries (Figure 11). The cells of the vas-
cular endothelium of capillaries are held together found in areas of the body that are specialized for
with tight junctions. The capillaries of the central the exchange of substances, such as parts of the
nervous system are particularly tightly joined, al- kidney, the endocrine organs, and the intestine.
lowing few molecules to pass; this forms the Sinusoidal capillaries are the most porous of all
blood-brain barrier. Continuous capillaries are capillaries, and are found only in very specialized
found in the skin and muscle. The seal between organs such as the liver and bone marrow. They
the cells of a continuous capillary is not usually have fewer tight junctions and more spaces be-
complete, leaving areas of unjoined membrane tween the cells. This structure allows large pro-
that allow fluids and small molecules to pass from teins to move across the capillary wall.
the blood to the interstitial fluid. Fenestrated cap- Capillaries empty into venules, which lead
illaries are similar to continuous capillaries except into the veins that return blood to the heart. A
that the cells of the vascular endothelium contain vein usually has a thinner wall and larger lumen
numerous pores covered with a thin diaphragm. than a similarly sized artery. As a result, veins can
Small molecules and fluids can pass easily through
these pores, and thus fenestrated capillaries are
387
Circulatory Systems
be easily stretched. In particular, the tunica media occurs every month. Similarly, new vessels must
of the veins is much thinner than in the arteries. form as wounds heal. We now know a great deal
However, the tunica externa is often more promi- about the mechanisms involved in angiogenesis, and
nent than in the arteries. Veins differ from arter- these findings are aiding in the search for a treat-
ies in that some veins (particularly those in the ment for diseases including cancer and heart disease
limbs) contain one-way valves to prevent backflow (see Box 1, Genetics and Genomics: Angiogenesis).
of blood. The valves are part of the tunica intima.
For many years, physiologists assumed that the
tunica intima was structurally similar in arteries
Vertebrate circulatory systems contain one
and veins, differing only in thickness. But recent
or more pumps in series
studies using zebrafish have shown that the vas- Water-breathing fish have a single-circuit circu-
cular endothelium of the arteries and that of the latory system in which blood flows from the heart
veins express a different subset of genes, suggest- through the gills to the body tissues and then
ing that they are functionally differentiated. back to the heart (Figure 12a). Because the heart
Note that we distinguish arteries and veins by must pump blood through the gills and tissues in
whether they carry blood that is flowing toward or series, some fish have a small accessory or cau-
away from the heart, not whether they carry oxy- dal heart in the tail that assists blood flow back
genated or deoxygenated blood. For example, the to the heart. In other species, normal movements
pulmonary artery of mammals, which leads from of the body help venous return to the heart. In
the heart to the lungs, carries
deoxygenated blood, while the
pulmonary vein, which leads Tissues
from the lungs to the heart,
carries oxygenated blood. In Gills
contrast, the aorta carries oxy-
genated blood, while the venae
Gills Body
cavae (the large veins leading
from the body to the heart) Heart
carry deoxygenated blood.
Heart
(a) Single-circuit circulatory system

Blood vessels undergo
angiogenesis
During the embryonic develop- Pulmonary Systemic Pulmonary Systemic
ment of vertebrates, the major circuit circuit circuit circuit
Lungs Heart Tissues
vessels of the circulatory sys-
Left
tem grow into a network of ar- heart
teries, arterioles, capillaries,
venules, and veins, which re- Lungs Body
mains fairly stable throughout Right
adult life. Despite this overall heart
stability, however, the minor

vessels undergo constant re-
modeling throughout life, a (b) Double-circuit circulatory system
process called angiogenesis. Figure 12 Vertebrate circulatory systems The structure of vertebrate
For example, in female mam- circulatory systems varies depending on the respiratory strategy of the animal. (a) In
mals new blood vessels form water-breathing fish, blood travels from the heart through the aorta to the gills and
each time the uterus develops then to the body tissues, and returns to the heart. (b) Air-breathing tetrapods have a
double circulatory system with two pumps arranged in series. Blood travels through
during the estrous or menstrual the left heart to the aorta which leads to the systemic circuit through the body,
cycle. In humans, this returning to the right heart that pumps the blood via the pulmonary artery through
the pulmonary circuit through the lungs.
388
Circulatory Systems

Angiogenesis
Small blood vessels such as arterioles, gen to the tissues, reducing tissue hypoxia. Thus, the
capillaries, and venules undergo constant remod- angiogenic response to tissue hypoxia acts as a negative
eling. This process, called angiogenesis, is controlled by feedback loop, maintaining tissue oxygen homeostasis.
both activator and inhibitor molecules that influence the Angiogenic activators and inhibitors are currently
rate of growth and division of vascular endothelial cells. being studied as possible treatments for diseases such
Under normal circumstances, inhibitory factors are dom- as cancer and coronary artery disease. Cancerous tu-
inant, and vascular endothelial cells rarely divide, but mors secrete high levels of angiogenic activator mole-
when new blood vessels are needed (such as during cules, causing new blood vessels to grow to supply the
wound healing), the body secretes angiogenic activator tumor with oxygen and nutrients. Tumor growth de-
molecules that promote blood vessel growth. pends on this supply, so blocking angiogenesis can
Angiogenesis begins when cells in the region where halt or slow tumor growth. Several dozen angiogenic-
the blood vessel will develop (the target site) secrete inhibiting drugs are currently being tested as possible
one or more angiogenic growth factors. These proteins cancer therapies. Some of these drugs are simply natu-
are paracrine signaling molecules that bind to receptors rally occurring anti-angiogenic factors; others block the
on the endothelial cells of existing blood vessels. Bind- production of matrix metalloproteases, or aspects of
ing of the growth factor to its receptor activates a signal the angiogenic signal transduction cascade.
transduction cascade that helps to dissolve the base- Drugs that stimulate angiogenesis are also being
ment membrane of the endothelium, and causes the tested for treatment of diverse diseases, including coro-
endothelial cells to proliferate. The proliferating en- nary artery disease and diabetes. In coronary artery dis-
dothelial cells then migrate out through the holes disease, the arteries that supply oxygen to the working heart
solved in the wall of the existing vessel toward the target muscle become blocked by fatty deposits called plaques.
site. Specialized membrane proteins called integrins These plaques inhibit blood flow to the heart muscle, de-
help to pull the sprouting blood vessel forward. En- priving it of oxygen. Current treatments for coronary ar-
zymes called matrix metalloproteases help to dissolve tery disease involve the surgical replacement of the
the tissues ahead of the advancing endothelial cells, blocked section of the blood vessel, but researchers are
making space for the new blood vessel. Once in place, testing angiogenic growth factors as a way of making new
the endothelial cells join together, forming the tube of blood vessels grow to supply the heart.
the blood vessel, and the other cells of a blood vessel In late-stage diabetes, blood vessels begin to fail, and
(smooth muscle, pericytes) are laid down, completing circulation to the feet can be very poor. As a result, the
the development of the new vessel. tissues can become oxygen deprived and die. Thus, one
A number of factors, such as wounding and low oxy- of the complications of untreated diabetes can be gan-
gen levels (hypoxia) in tissue, can promote angiogene- grene of the toes or foot, requiring amputation. Angio-
sis. When cells are hypoxic, levels of the protein genic growth factors may help slow the progress of this
hypoxia-inducible factor-1 (Hif-1) increase. Hif-1 is disease by promoting new blood vessel growth and help-
part of a transcription factor complex. When the levels ing to improve oxygen delivery. This treatment is not a
of Hif-1 increase, the transcription factor complex cure, because it does not repair the underlying cause of
moves to the nucleus and binds to the promoters of a va- blood vessel degeneration, but it may reduce the sever-
riety of hypoxia-inducible genes. One of these genes en- ity of symptoms. In addition, the role of angiogenesis in
codes an angiogenic activator protein called vascular diabetic patients is complex, and varies from organ to or-
endothelial growth factor (Veg-f). Veg-f binds to recep- gan. In fact, one complication of diabetes—diabetic
tors on vascular endothelial cells and causes angiogen- retinopathy—is the result of excessive angiogenesis,
esis, increasing the density of the vasculature in the which damages the tissues of the retina of the eye, po-
area. The increased vasculature can supply more oxy- tentially causing blindness.
contrast, tetrapods (amphibians, reptiles, birds, pulmonary circuit of the circulatory system,
and mammals) have two circuits within their cir- whereas the left side of the heart pushes blood
culatory system. The right side of the heart through body tissues in the systemic circuit of
pushes blood through the lungs in the the circulatory system.
389
Circulatory Systems
Mammals and birds have completely to allow good gas exchange, but if blood flows
separated pulmonary and systemic circuits through these thin capillaries under high pres-
sure, fluid will leak through the capillary walls.
Although the right and left sides of the heart are
When this fluid accumulates it increases the diffu-
grouped together into a single organ, in mammals
sion distance and reduces the efficiency of gas ex-
and birds these two sides of the heart are completely
change. Therefore, a low-pressure circulatory
separated. As a result, a mammalian or bird circu-
system through the lungs may be advantageous. In
latory system is conceptually similar to a single-
contrast, high pressures are needed to force blood
circuit circulatory system with two pumps in series
through the long systemic circulatory system. Hav-
(Figure 12b). Oxygenated blood from the lungs flows
ing separate pulmonary and systemic circuits al-
to the left heart, which pumps the oxygenated blood
lows these two differing demands to be met.
to the body. The deoxygenated blood returning from
the body flows into the right heart, which then
pumps this deoxygenated blood to the lungs.
Many tetrapods have incompletely
The completely separated systemic and pul-
separated pulmonary and systemic circuits
monary circuits of circulatory systems of mammals Unlike mammals and birds, amphibians and
and birds are relatively inflexible, because blood can- most reptiles have an incompletely divided heart
not be diverted from one part of the system to the (Figure 13). Thus, it is possible for deoxygenated
other. For example, when a mammal holds its blood from the systemic circuit and oxygenated
breath, blood must still flow through the lungs, de- blood from the pulmonary circuit to mix. In many
spite the fact that this tissue is not being utilized. species the two streams of blood returning to the
However, because mammals and birds breathe more heart are kept fairly separate under most circum-
or less continuously, the ability to divert flow from the stances, although the mechanisms through which
pulmonary circuit has not been an important force this separation is maintained are not fully under-
shaping the evolution of their circulatory systems. stood. Because the ventricular chambers of the
Having completely separated pulmonary and heart are interconnected, blood can be diverted
systemic circuits has one important advantage: it from the systemic to the pulmonary circuit, or vice
allows pressures to be different in the pulmonary versa, if necessary. For example, these animals
and systemic circuits. But why would having dif- may divert blood from the pulmonary circuit to the
ferent pressures in the two circuits be an advan- systemic circuit during diving, allowing them to
tage? In the lungs, the capillaries must be very thin avoid perfusing the inactive lung.
Skin
Tissues
Tissues
Lung
Pulmocutaneous Lung
artery
Left atrium
Aorta
Heart
Ventricle Right atrium Heart
(a) Frog (b) Lizard
Figure 13 Circulatory patterns in amphibians the right atrium and is preferentially directed to the lungs.
and reptiles (a) Circulation in frogs. Deoxygenated blood Oxygenated blood from the lungs enters the left atrium and is
flows to the pulmocutaneous artery that leads to the skin and preferentially directed to the tissues. Oxygenated blood and
lungs, and oxygenated blood flows via the aorta to the deoxygenated blood are kept fairly separated under normal
tissues, although some mixing may occur in the heart. circumstances, although mixing is possible.
(b) In reptiles, deoxygenated blood from the tissues enters
390
Circulatory Systems
2 CO NC E P T C HE C K The radius of a tube affects its resistance

In circulatory systems, the circulating fluid is gen-
1. What is the difference between an open circulatory
erally confined within a system of tubes or spaces,
system and a closed circulatory system?
such as the blood vessels of vertebrates. We can
2. What is the major factor involved in the
evolution of closed circulatory systems? Do all begin to understand what sets the resistance of a
animals fit with this general rule? blood vessel in the circulatory system by thinking
3. What is the functional distinction between about factors that affect flow through a drinking
arteries and veins? straw. Is it easier to drink liquids through a very
4. Which blood vessels have thicker walls, arteries long straw or a shorter straw? What is the differ-
or veins? ence between drinking through a narrow straw
5. How can substances move across capillaries? and a wider straw? What is the difference between
drinking a milkshake and water (fluids with very
different viscosity) through a straw? We can quan-
tify these relationships mathematically as follows:
The Physics of Circulatory Systems R 8L/r4
From the preceding sections it is clear that there is where R the resistance of the tube, L the
substantial variation in the organization and length of the tube, η the viscosity of the fluid,
anatomy of animal circulatory systems. Despite and r the radius of the tube. Substituting this re-
this diversity, however, all circulatory systems use lationship into the law of bulk flow, we obtain
similar mechanisms to cause the bulk flow of flu- Poiseuille’s equation:
ids around the body. In order to understand these Q Pr4/8L
mechanisms, we must first review some of the fun-
damental physics of fluid flow. Recall from the be- Although real circulatory systems violate almost
ginning of the chapter that fluids flow down all of the assumptions of Poiseuille’s equation (see
pressure gradients. Resistance due to friction op- Box 2, Mathematical Underpinnings: Poiseuille’s
poses this movement. We can quantify the rela- Equation), it still provides a good conceptual sum-
tionship between flow, pressure, and resistance in mary of the factors that affect the flow of fluids
an equation called the law of bulk flow: through circulatory systems.
Because resistance is inversely proportional to
Q P/R radius to the fourth power, small changes in the ra-
where Q flow, P the pressure gradient, and dius of a tube result in large changes in its resis-
R resistance. Note that flow is defined as the vol- tance. Many animals (both vertebrates and
ume of fluid that moves past a given point per unit invertebrates) can control the flow through their
time, and has units such as liters per minute. You organs by changing the radius of the blood vessels
will see a variety of units of pressure used in the leading to those organs, a process called vasocon-
physiological literature. The SI unit for pressure is striction or vasodilation. During vasoconstric-
the pascal, or the force per unit area (in Newtons tion, the radius of the blood vessel decreases,
per meter squared). Physiologists and physicians increasing the resistance and reducing the flow
often also use non-SI units to express pressure, in- through the vessel. During vasodilation the radius
cluding millimeters of mercury (mm Hg) and torr of the blood vessel increases, reducing the resis-
(where 1 torr 1 mm Hg). These older units are tance and increasing the flow. Because small
the result of the use of mercury-filled manometers changes in radius cause large changes in resis-
for the clinical measurement of blood pressure. tance, even modest vasoconstriction and vasodila-
The units for resistance in a circulatory system are tion can result in large changes in flow.
complex, and depend upon the units chosen for
pressure and flow. For example, a unit for resis-
tance could be kPamin/L1. In medicine, the most
The total flow is constant across all parts
common unit of resistance is the so-called periph-
of a circulatory system
eral resistance unit (PRU) in mm Hgsec/ml1. The law of bulk flow is very similar to another ba-
sic physical principle—Ohm’s law—that quantifies
the behavior of charge in an electrical circuit.
391
Circulatory Systems

Poiseuille’s Equation
Although Poiseuille’s equation provides a moves in a linear way along the blood vessel. But the ve-
useful framework for thinking about the physics locity profile of the blood is not identical across the di-
of circulatory systems, real circulatory systems violate ameter of the vessel. Flow is slower near the walls
almost all of its assumptions. For example, Poiseuille’s because of the effects of friction. Poiseuille’s equation
equation assumes that the tubes in the system are un- ignores this effect. In larger vessels, flow is laminar but
branched and rigid, and that flow involves a simple fluid pulsatile, increasing when the heart contracts, and de-
moving steadily through the tubes. In real circulatory creasing between contractions. The end result of this
systems, the vessels are branched and are distensible, complex flow pattern is that the velocity profile is flatter,
changing their diameter as pressure changes; flow is and the direction of flow changes as the heart beats.
often pulsatile, increasing and decreasing with the The complex nature of blood has important effects on
heartbeat; and the fluid is a complex mixture of plasma its viscosity. The viscosity of the aqueous component of
and cells. the blood, called plasma, is low (about 1.8 times the vis-
The degree to which a blood vessel expands in re- cosity of pure water), but whole blood has a viscosity
sponse to increased pressure is called its compliance, about three to four times that of water because of the
C, and is equal to presence of blood cells. Because it is a mixture of com-
ponents with different viscosities, blood acts as a non-
C V/P
Newtonian fluid; its viscosity varies depending on the
where V volume and P pressure. Vessels with high size of the tube that it flows through, a phenomenon
compliance stretch easily when exposed to pressure, called the Fahraeus-Lindqvist effect. The Fahraeus-
whereas vessels with low compliance stretch less. If we Lindqvist effect occurs because blood tends to separate
plot the change in volume against the change in pres- in smaller blood vessels; in these smaller vessels, blood
sure of a representative blood vessel, the slope of the cells get swept into the higher-velocity flow at the cen-
line is the compliance of the vessel. The compliance of ter of the vessel, while the fluid close to the walls con-
a blood vessel is not constant; compliance decreases at sists largely of plasma. The “high-viscosity” component
higher pressures and volumes—vessels become at the center of the vessels has only minor interactions
“stiffer” at high pressures. The compliance of a vessel is with the walls of the vessels, while the “low-viscosity”
usually assessed under steady-state conditions, but plasma interacts with the vessel walls, reducing the ap-
blood vessels take some time to stretch, a phenomenon parent viscosity of the fluid. In contrast, in very small
known as the Windkessel effect. In essence, blood ves- vessels, blood cells fill almost the entire diameter of the
sels can store the potential energy imparted by pres- vessel, and have to change shape to squeeze through
sure, and release it at a later time. As we see later in the the small space. Also, in these small vessels the blood
chapter, this effect is important in the arteries. cells tend to stick to each other and to the blood vessel
Turbulent flow is relatively rare in the circulatory walls, and together these three factors greatly increase
system, occurring in the heart and at some vessel the apparent viscosity of the fluid.
branching points. In turbulent flow, the fluid moves in a Despite these (and other) violations of its assump-
complex pattern of eddies and whorls, oriented in vari- tions, Poiseuille’s equation still provides a good concep-
ous directions relative to the main axis of flow. In most tual model of flow through circulatory systems, and helps
blood vessels, flow is fairly laminar so that the fluid to explain the architecture of animal circulatory systems.
Ohm’s law is usually written as V IR (where V sels. Ohm’s law and the law of bulk flow both
voltage, I current, and R resistance). If we re- quantify a fundamental physical phenomenon that
arrange this equation, we can write I V/R. The is related to Newton’s second law. Substances
electrical current (I) is simply the flow of electrons, move because they are acted on by a force, and
and is thus equivalent to fluid flow (Q). The voltage this movement is impeded by resistance. Because
drop across the circuit is the driving force for cur- of this similarity, we can model circulatory sys-
rent movement, and is equivalent to the pressure tems as simple electrical circuits (Figure 14).
gradient (P). The electrical resistance is analo- Like electrical resistors, blood vessels can be
gous to the frictional resistance of the blood ves- arranged in series or in parallel. The total resis-
392
Circulatory Systems
tance of a circuit with resistors arranged in series Electrical circuit Blood vessels
is the sum of the individual resistances, or Resistor R1 R2
R R R ...
T 1 2 R1 R2 Pump
However, when resistors are arranged in parallel, Battery R3

the total resistance is determined as follows: R3
1/RT 1/R1 1/R2 1/R3 . . .

RT = R1 + R2 + R3
When you add resistors in series, the total resis-
tance of the circuit increases, but when you add (a) Resistors in series
resistors in parallel, the total resistance of the cir-
B
cuit decreases. In circulatory systems, resistors R1
R1
are arranged both in series and in parallel. R2
A
R2
Because of the law of conservation of mass, the
R3
flow through each segment of a circulatory system
must be equal. For example, in Figure 14b, the to- Battery R3 C
tal flow at point A and point B is the same. How- E
ever, the amount of flow in each of the parallel
blood vessels at point B need not be equal. The 1 = 1 + 1 + 1
D
RT R1 R2 R3
proportion of flow going through each of the par-
allel blood vessels depends upon the relative re- (b) Resistors in parallel
sistances of the blood vessels. As indicated by the Figure 14 Resistors in series and parallel Circulatory
law of bulk flow, blood tends to take the path of systems are analogous to electrical circuits with resistors arranged in
least resistance; more blood will flow through a both series and parallel. (a) The total resistance (RT) of a circuit with
low-resistance blood vessel than through one with resistors arranged in series is the sum of the individual resistances
(R1 R2 R3). (b) The total resistance of a group of resistors
high resistance. If we know the total flow and the
arranged in parallel decreases with increasing numbers of resistors.
resistance of each of the vessels in parallel, we can Total flow through each point of a circuit (A, B, C, D, E) is equal, but
calculate the amount of flow going through each flow divides among the resistors arranged in parallel, depending on
vessel, using the law of bulk flow. the resistance of each branch.
Velocity of flow is determined by pressure split up among the channels, so mass will be con-
and cross-sectional area served across the system as a whole, but all of the
flow does not have to pass through any one
Flow is, by definition, a rate—the volume of fluid smaller channel. The velocity of flow in the smaller
transferred per unit time. But when fluid flows it channels will be inversely proportional to the total
also moves across a certain distance per unit cross-sectional area of all the channels put to-
time—that is, it has a velocity. The velocity of blood gether. If there are enough small channels, flow
flow in a blood vessel is inversely related to the may be slower than in the wide part of the river.
cross-sectional area of the blood vessel. You can We can summarize these relationships as follows:
visualize this by thinking about what happens to a
volume of water as it flows through narrow and Blood velocity Q/A
wide parts of the river. Because of the principle of where A is equal to the summed cross-sectional
the conservation of mass, the same amount of flow area of the channels.
(volume per unit time) must pass through the nar- Exactly the same reasoning applies to circula-
row part of the river as the wide part of the river, tory systems. In areas where a single larger blood
but as a result its velocity (distance moved per unit vessel splits into many small blood vessels
time) must be greater in the narrow channel. arranged in parallel, the velocity of flow is likely to
So what happens if a wide river splits into decrease as the blood enters the many small ves-
many small channels, such as you might en- sels (assuming that the total cross-sectional area
counter in a river delta? In this case, the velocity of all the small vessels is greater than that of the
of flow in the small channels depends on the total single large vessel). This relationship between ve-
cross-sectional area of the channels. Flow will locity and cross-sectional area is significant for a
393
Circulatory Systems
circulatory system, because it takes time for sub- The law of LaPlace can be used to understand
stances to diffuse between the blood and the tis- the structure and function of blood vessels and the
sues. Regions of the circulatory system that are heart. As can be seen from this relationship, as
involved in the exchange of materials have a very the thickness of a vessel increases, the stress in the
high total cross-sectional area, and so have very wall of that vessel decreases. Thus, blood vessels
low flow velocities, which aids diffusion. such as the aorta, which are subjected to very high
pressures, must be thicker, or made of stronger
material, than vessels such as the arterioles, which
Pressure exerts a force on the walls
are subjected to lower pressures. In addition, this
of blood vessels
relationship explains why when a vessel dilates
The blood pressure within a walled chamber such (increases in radius), the stress or tension within
as a heart or blood vessel exerts a force on the the wall will increase, even if pressure remains the
walls of the chamber. This force can be quantified same. The law of LaPlace can also be used to un-
using the law of LaPlace (Figure 15), which states derstand the forces generated by the heart. A heart
that the tension on the walls of a blood vessel is with a large radius must develop more tension
proportional to the blood pressure and the vessel within the heart wall to develop the same pressure
radius according to the following equation: within the heart (i.e., must undergo a stronger con-
T aPr traction) as would a heart with a smaller radius.
Thus, we might expect a greater ratio of heart
where T is the tension on the walls (in N/cm), P is mass to heart volume in larger hearts.
the transmural pressure, or the difference be- In the next sections of the chapter, we use
tween the internal pressure and the external pres- these physical principles to understand the func-
sure (in Pa), r is the radius of the vessel, and a is a tioning of animal circulatory systems. We begin by
constant ( 12 for a cylindrical blood vessel or 1 for a examining the pumping function of hearts, and
spherical chamber). The law of LaPlace can also then turn to an examination of the regulation of
be rewritten to take into account the thickness of pressure and flow through the circulatory system.
the wall of the vessel, as follows:

Pr/w
where
is the wall stress (in N/cm2, or Pa), or the 2 C O N C EP T CH E CK
force per unit cross-sectional area of the wall, P is
transmural pressure, r is the radius of the vessel, 6. What physical force causes fluids to flow in
and w is the thickness of the wall. circulatory systems?
7. What are the major factors that determine the
resistance of a tube such as a blood vessel?
8. Imagine three identical blood vessels arranged
P = Transmural either in series or in parallel. In which case will
T pressure the total resistance be greatest?
P r = Radius
r T = Wall tension 9. What is transmural pressure?
(a) Thin-walled vessel
w
P = Transmural
Hearts
pressure
P σ r = Radius Because of the importance of hearts in animal cir-
r w = Wall thickness
σ = Wall stress
culatory systems, we devote a substantial part of
this chapter to a discussion of their structure and
(b) Thick-walled vessel
function. The pumping action of a heart, which is
Figure 15 The Law of LaPlace (a) For a thin-walled called the cardiac cycle, is divided into two phases:
vessel, the wall tension (T) is proportional to the transmural contraction (systole) and relaxation (diastole).
pressure (P) times the radius of the vessel.
(b) For a thick-walled vessel, the wall stress σ is proportional
During systole, the heart contracts, increasing the
to the transmural pressure (P) and the vessel radius (r), but pressure within the chambers of the heart and forc-
inversely proportional to the wall thickness (w). ing blood out into the circulation. During diastole,
394
Circulatory Systems
the heart relaxes, reducing the pressure within the hearts among animals. However, recent evidence
chambers of the heart and allowing blood to enter from developmental biology points to a surprising
the heart from the circulatory system. degree of similarity in the developmental program
Because chambered hearts evolved from sim- of hearts in very distantly related animal groups
ple pulsatile blood vessels or tubular peristaltic (see Box 3, Methods and Model Systems: Tran-
hearts independently many times in different ani- scription Factors and Heart Development), sug-
mal groups, it is not surprising that we find sub- gesting that there is a fundamental unity of these
stantial differences in the structure and function of diverse pumping structures.

Transcription Factors and Heart Development
All hearts perform similar functions, but of the mouse gene Nkx2.5 into a nematode with a defec-
they differ greatly in structure among taxa, rang- tive version of ceh-22, the pharynx develops normally.
ing from simple contractile blood vessels to peristaltic This experiment elegantly demonstrates that the genes
tubular hearts and muscular contractile chambers. For controlling development of the pharynx in C. elegans and
many years biologists assumed that these diverse hearts the heart of vertebrates are both structurally and func-
had little in common other than their pumping function. tionally similar.
However, recent work in model systems has revealed a Presumably, the ancestral function of ceh-22/Nkx/
surprising unity at the molecular level. Tinman was to specify the development of a rhythmi-
Using gene knockout technology, researchers are cally contracting structure. This developmental pro-
beginning to unravel the genetic program underlying gram was then co-opted during evolution to form the
the development of the heart in a range of organisms. In structurally diverse pumping organs of nematodes,
Drosophila, a gene called Tinman controls heart devel- fruitflies, and vertebrates. In fact, a gene related to Nkx
opment. Researchers named this gene after the Wizard has been detected in a cnidarian, the hydra (Hydra
of Oz character of the tin woodsman, who lacks a heart. magnipapillata). The expression of this gene is local-
Flies that lack the gene Tinman never develop a heart. In ized around the base of the gastrovascular cavity, in a
mice, a gene in a family called Nkx is needed for heart region that is involved in pumping fluids through the
development. Mice that have mutated versions of the body. These observations suggest that the genes in-
Nkx genes have defects in cardiac development. Nkx and volved in heart development predate the evolution of
Tinman make very similar proteins, and these genes circulatory systems, but have been involved in the de-
clearly share the same evolutionary origin. Similarly, an velopment of pumping structures since the time of the
Nkx/Tinman homologue has been discovered in the earliest metazoans.
lancelet (formerly called Amphioxus), an invertebrate
chordate. This gene is expressed in the developing tube- References
like heart of these animals. This high degree of conser- q Bodmer, R. 1993. The gene tinman is required for specification of
vation suggests a common evolutionary origin of these the heart and visceral muscles in Drosophila. Development 118:
very diverse hearts. 719–729.
Nematodes such as Caenorhabditis elegans lack a q Haun, C., J. Alexander, D. Y. Stanier, and P. G. Okkema. 1998.
heart and complex circulatory system, but they do have Rescue of Caenorhabditis elegans pharyngeal development by a
a digestive structure called the pharynx that contracts vertebrate heart specification gene. Proceedings of the National
rhythmically and aids in feeding. The nematode pharynx Academy of Sciences USA 95: 5072–5075.
shares a number of similarities with the hearts of other q Holland, N. D., T. V. Venkatesh, L. Z. Holland, D. K. Jacobs, and
organisms. Like the hearts of insects and vertebrates, R. Bodmer. 2003. AmphiNk2-tin, an amphioxus homeobox gene
expressed in myocardial progenitors: Insights into evolution of
the pharyngeal muscles are myogenic—they contract
the vertebrate heart. Developmental Biology 255: 128–137.
without input from the nervous system. In addition, the
q Lints, T. J., L. M. Parsons, L. Hartley, I. Lyons, and R. P. Harvey.
development of the pharynx is controlled by the gene
1993. Nkx-2.5: A novel murine homeobox gene expressed in
ceh-22, the molecular sequence of which is similar to early heart progenitor cells and their myogenic descendants.
Tinman and Nkx, suggesting that it is an evolutionary ho- Development 119: 419–431.
mologue of these genes. q Shimizu, H., and T. Fujisawa. 2003. Peduncle of Hydra and the
Nematodes with a defective ceh-22 gene do not de- heart of higher organisms share a common ancestral origin.
velop a proper pharynx. However, if you introduce a copy Genesis 36: 182–186.
395
Circulatory Systems
Arthropod Hearts tiate the heartbeat. As the cardiomyocytes con-

tract, they decrease the volume of the heart cham-
Although the shape and size of the heart varies ber, exerting pressure on the circulatory fluid. This
greatly among arthropods, their hearts share a increase in pressure causes blood to squirt out of
number of features in common. Arthropod hearts the heart and into the circulatory system via the
generally pump hemolymph out into the circula- arteries; the closed valves guarding the ostia pre-
tion via arteries, and blood returns to the heart via vent flow in the other direction.
a series of holes, or ostia. Valves within the ostia The contraction of the heart also pulls on the
open and close, actively regulating the flow of he- ligaments that connect the heart to the body wall,
molymph. The heart itself is suspended within the stretching them. During diastole, when the heart re-
body cavity via a series of ligaments. Figure 16 il- laxes, the ligaments spring back, pulling apart the
lustrates the cardiac cycle in decapod crustaceans, walls of the heart. This elastic recoil increases the
which have particularly strong and muscular volume of the heart, reducing the pressure in the in-
hearts. The hearts of most arthropods, including ternal chambers. At this point, the valves of the os-
crustaceans, are neurogenic—they contract in re- tia open, and the decrease in pressure sucks fluid
sponse to signals from the nervous system. The into the heart via the ostia. Thus, arthropod hearts
neurons of the cardiac ganglion, located on the act as both suction and pressure pumps. They fill by
surface of the heart and among the cardiomy- suction, and they empty as a result of increasing
ocytes, are the primary rhythm generator. These pressure.
neurons undergo spontaneous rhythmic depolar-
izations that initiate the rhythmic contraction of
the heart. The neurons of the cardiac ganglion
send a signal to close the ostia of the heart and ini- Vertebrate Hearts
Vertebrate hearts have complex walls with four main
parts (Figure 17). A sac called the pericardium sur-
rounds the heart. In some species, such as elasmo-
branchs, the pericardium is relatively rigid,
Ostium Suspensory whereas in other species the pericardium is com-
ligaments
pliant, and stretches easily as the heart beats. The
tough outer layer of the pericardium (the parietal
Arteries pericardium) is made of connective tissue that pro-
Arteries tects the heart and anchors it to surrounding
structures. The pericardium is filled with a small
(a) Systole amount of fluid that acts as a lubricant, reducing
friction as the heart beats.
The inner layer of the pericardium (the visceral
pericardium) is continuous with the outer con-
nective tissue of the heart, which is called the epi-
cardium. If present, the nerves that regulate the
heart and the coronary arteries that supply blood
to the heart are located in the epicardium. These
vessels extend into the next layer of the heart—the
heart muscle, or myocardium. The myocardium is
divided into several layers that can be distinguished
(b) Diastole based on the orientation of the cardiomyocytes (or
cardiac muscle cells) in each layer. The innermost
Figure 16 The cardiac cycle in decapod
crustaceans (a) Systole. When the heart contracts, lining of the heart is called the endocardium, and is
the ostia close, and blood flows out via the arteries. The composed of a layer of connective tissue covered by
contraction pulls on the elastic suspensory ligaments, which a layer of epithelial cells, called the endothelium,
store this potential energy. (b) Diastole. As the heart relaxes, that lines the chambers of the heart. This cardiac
the suspensory ligaments recoil, increasing the volume of
the heart. The ostia open, and the low pressure sucks blood
into the heart through the opened ostia.
396
Circulatory Systems
Myocardium Pericardium
Pericardial
fluid in
pericardial
cavity
Coronary
artery
Endothelium
connective Parietal
tissue pericardium
Endocardium Epicardium
(visceral pericardium)
(a)
Compact
myocardium
Spongy myocardium
Pericardium
Endocardium
Pericardial
cavity
Coronary
artery
Trabeculae
(b)
Figure 17 Structure of vertebrate hearts Vertebrate hearts have complex walls

consisting of a pericardium, epicardium, myocardium, and endocardium. (a) Mammalian
myocardium consists largely of compact myocardium. (b) In fishes and amphibians the myocardium
is composed largely of spongy myocardium surrounded by a thin layer of compact myocardium.
Spongy myocardium is poorly vascularized and receives oxygen from the blood flowing through the
heart, whereas compact myocardium is supplied with oxygen by the coronary arteries.
endothelium is contiguous with the vascular en- most entirely compact (Figure 17a), whereas in
dothelium that lines the blood vessels. most fish and amphibians it is almost entirely
spongy (Figure 17b). The compact myocardium on
the outside of the heart is vascularized (contains
The myocardium can be spongy blood vessels), but in many species the spongy my-
or compact ocardium does not contain blood vessels. In these
The ventricular muscle can be composed of two dif- species, the internal layer of the heart obtains its
ferent types of myocardium: an outer layer of oxygen from the blood in the heart chambers. The
compact myocardium, made of tightly packed cells spongy myocardium is often arranged into trab-
arranged in a regular pattern, and an inner layer of eculae that extend into the heart chambers. In
spongy myocardium consisting of a meshwork of fact, in some species the chambers of the heart are
loosely connected cells. However, the relative pro- so filled with trabeculae that they resemble a
portion of these two types of myocardium varies sponge rather than the open chambers of the
among species. In mammals the myocardium is al- mammalian heart.
397
Circulatory Systems
Fish heart chambers are arranged in series then into the muscular ventricle. The ventricle
pumps the blood into either an elastic structure
The heart of a water-breathing fish consists of four
called the bulbus arteriosus (in most bony fishes)
chambers arranged in series (Figure 18a). Blood
or a muscular conus arteriosus (in elasmo-
enters the heart via a thin-walled chamber called
branchs). All of these chambers are contractile,
the sinus venosus and flows into the atrium and
except the elastic bulbus arteriosus of bony fish.
Atrium
Sinus Amphibian hearts have three chambers
Bulbus venosus
arteriosus Amphibians have a three-chambered heart with two
atria and one ventricle (Figure 18b). The ventricle of
the heart pumps blood via the conus arteriosus into
both the pulmonary and systemic circuits of the cir-
culatory system. Oxygenated blood from the lungs
Spongy Compact returns to the left atrium via the pulmonary vein,
myocardium myocardium while the deoxygenated blood from the systemic cir-
Ventricle
cuit returns via several veins that empty into the si-
(a) Bony fish heart nus venosus and then into the right atrium. The two
atria then supply blood to the single ventricle. The
trabeculae within the ventricle help to keep the oxy-
Pulmocutaneous genated and deoxygenated blood separate, although
Systemic artery the mechanisms by which they work are not yet fully
arteries
understood. A spiral fold within the conus arterio-
Sinus
venosus sus directs deoxygenated blood to the pulmocuta-
neous artery leading to the lungs and skin and
Conus
arteriosus oxygenated blood to the systemic arteries.
Pulmonary
Spiral vein
fold Left atrium Most reptiles have five heart chambers
Right atrium The hearts of most non-crocodilian reptiles are
composed of five chambers (Figure 19a). As in am-
phibians, there are two atria, but the ventricle is
divided into three interconnected compartments
Ventricle
(the cavum venosum, the cavum pulmonale, and
the cavum arteriosum) by muscular ridges or
septa. The conus arteriosus is divided to form the
base of three large arteries: the pulmonary artery
that leads to the lungs, and the right and left aor-
(b) Amphibian heart
tas that lead to the rest of the body. The pulmonary
Figure 18 Cardiac anatomy of fish and frogs artery leads from the cavum pulmonale, whereas
(a) The heart of a fish is arranged in series. Blood enters the the aortas lead from the cavum venosum.
sinus venosus, which pumps blood into the atrium, and then
into the muscular ventricle. The ventricle pumps blood via Despite their incompletely separated ventri-
the bulbus arteriosus (in bony fish) or the conus arteriosus cles, reptiles generally maintain separation of oxy-
(in cartilaginous fish) to the body. (b) An amphibian heart has genated and deoxygenated blood. Deoxygenated
two atria and a single ventricle. Oxygenated blood from the blood enters the right atrium and flows into the
lungs enters the left atrium via the pulmonary vein.
Deoxygenated or partially oxygenated blood from the skin
cavum venosum and then across the muscular
and tissues enters the right atrium via the sinus venosus. The ridge into the cavum pulmonale and out the pul-
atria pump blood into the single ventricle, but the oxygenated monary artery. Oxygenated blood enters the left
and deoxygenated blood are kept largely separate, by atrium and flows into the cavum venosum and
mechanisms that are not well understood. Oxygenated blood
then out the right and left aortas.
flows preferentially to the systemic arteries, whereas
deoxygenated blood flows preferentially to the As mentioned earlier in this chapter, reptiles
pulmocutaneous artery, directed by the spiral fold. can also distribute blood selectively between the
398
Circulatory Systems
Right aorta Left aorta monary blood reenters the pulmonary circuit rather
than traveling to the body. Reptiles can regulate the
Pulmonary vein degree and timing of these shunts, although the
Pulmonary
artery mechanisms involved are not yet understood and
Right atrium
are likely to vary among species of reptile.
Left atrium Reptiles are intermittent breathers, often hold-
ing their breath for long periods of time. During
Cavum these periods, reptiles develop a pronounced R-L
venosum shunt, bypassing the pulmonary circulation and
Cavum directing most of the blood to the body. R-L shunts
Cavum arteriosum
pulmonale are also associated with diving, particularly when
a reptile dives to rest underwater. In contrast, L-R
shunts have been proposed to aid oxygen delivery
to the spongy myocardium of the right heart. The
adaptive significance of shunts in reptiles is a mat-
(a) Cardiac anatomy of non-crocodilian reptiles ter of debate among comparative physiologists,
and few of the proposed functions of shunting
Pulmonary Left Right have been carefully evaluated experimentally.
artery aorta aorta Crocodilian reptiles (crocodiles, alligators, and
caiman) have completely divided ventricles, and
thus have four fully separated heart chambers.
However, their pulmonary and systemic circuits
are still connected, and these animals can shunt
blood between them. (See Box 4, Evolution and Di-
L– Left versity: Shunting in Crocodiles.)
R
nt sh ventricle
s hu un
t
L
R–
Birds and mammals have four heart
chambers
The hearts of mammals and birds are composed of
Right atrium Left atrium four unobstructed chambers with relatively
(b) Blood flow through the heart of non-crocodilian reptiles smooth walls (Figure 20). The left side of the heart
(shown on the right in this ventral view) consists
Figure 19 Cardiac anatomy of non-crocodilian
reptiles (a) Non-crocodilian reptiles have two atria and of a thin-walled atrium and a thick-walled ventri-
three incompletely separated ventricular chambers. (b) Dia- cle. The right side of the heart also consists of an
grammatic view of blood flow through the heart of a non- atrium and ventricle, but the right ventricle has a
crocodilian reptile. (Note that the shape of the heart has been much thinner wall than the left ventricle. The left
“unfolded” so that the atria are shown at the bottom.) Under
nonshunting conditions, blood flows from the right atrium to ventricle, which pumps blood through the high-re-
the pulmonary artery, and from the left atrium to the right and sistance systemic circulation, must pump more
left aortas. During a right-to-left (R–L) shunt, some blood from forcefully than the right ventricle, which pumps
the right atrium enters the aortas, bypassing the lungs. During blood through the lower-resistance pulmonary cir-
a left-to-right (L–R) shunt, some blood from the left atrium
enters the pulmonary artery, bypassing the tissues.
culation. A thick ridge called the intraventricular
septum separates the two ventricles, while the in-
teratrial septum separates the two atria. These
pulmonary and systemic circulation. This capacity septa are composed of muscle reinforced by con-
to bypass either the pulmonary or systemic circuit nective tissue.
is called a shunt (Figure 19b). In a right-to-left shunt The atrioventricular (AV) valves are located be-
(R–L), some fraction of the deoxygenated venous tween the atria and ventricles and allow blood to
blood bypasses the pulmonary circulation and flow from the atrium to the ventricle, but not in the
reenters the systemic circulation, thus causing reverse direction. The right AV valve, also called
oxygen-poor blood to circulate through the body. In the tricuspid valve, and the left AV valve, also called
a left-to-right shunt (L–R), some fraction of the pul- the bicuspid valve, are attached on the ventricular
399
Shunting in Crocodiles
Crocodilian reptiles are unlike other rep- the right aorta and (via the foramen of Panizza and ar-
tiles in that they have a four-chambered heart terial anastomosis) into the left aorta because the pres-
with two atria and two ventricles that are completely di- sure in the right aorta is high compared to the pressure
vided by a muscular septum. However, like other reptiles, in the left aorta. This prevents deoxygenated blood in the
they have three major blood vessels leading away from right ventricle from moving into the systemic circula-
the heart. The right aorta emerges from the left ventricle, tion, and instead it flows almost entirely to the lungs.
whereas the pulmonary artery and the left aorta emerge The valve at the entrance of the pulmonary artery
from the right ventricle (see Figure A). The right aorta also helps to control the flow of blood between different
sends blood largely to the brain and anterior circulation, parts of the circulatory system. Unlike the passive flap-
whereas the left aorta sends blood largely to the viscera like valves of other vertebrates, this valve has cog teeth
and the posterior parts of the animal. The aortas are con- made up of nodules of connective tissue. The cog teeth
nected at two points in the circulatory system: the mesh together, forming a tight seal. The level of epi-
foramen of Panizza, a small opening located at the base nephrine in the bloodstream controls the position of the
of the aortas, near the heart, and an arterial anastomo- teeth in this valve, and thus the valve is controlled ac-
sis located in the abdomen. tively, rather than simply opening and closing passively
Because of the complete separation of the ventricles, in response to pressure changes in the heart. When the
crocodilians cannot shunt blood from the systemic to crocodile is at rest underwater, and levels of epineph-
the pulmonary circulation (a L-R shunt), but R-L shunts rine are low, the cog teeth close, diverting blood away
are possible (see Figure B). When blood pressure in the from the pulmonary artery. When the crocodile is active,
left and right ventricles is equal, such as might be ex- the cog teeth open, allowing blood to flow into the lungs.
pected in a resting crocodile breathing air, oxygenated Crocodiles use the cog valve to shut off the pul-
blood from the left ventricle is directed via the right monary system when they dive below the water to rest,
aorta to the brain, while deoxygenated blood flows via allowing them to remain submerged for several hours
the left aorta to the visceral organs, where it may aid in without perfusing their lungs.
digestion, because this acidic deoxygenated blood can
References
counteract the alkalinization of the blood caused by se-
q Franklin, C. E., and M. Axelsson. 2000. An actively controlled
cretion of digestive acids into the stomach. When the heart valve. Nature 406: 847.
animal is active and breathing air, blood pressure is
q Hicks, J. W. 2002. The physiological and evolutionary significance
high in the left ventricle compared to the right ventricle. of cardiovascular shunting patterns in reptiles. News in Physio-
Oxygenated blood flows from the left ventricle both into logical Sciences 17: 241–245.
q Syme, D. A., K. Gamperl, and D. R. Jones. 2002. Delayed depolar-
Vena Foramen of Pulmonary ization of the cog-wheel valve and pulmonary-to-systemic shunt-
cava Panizza vein ing in alligators. Journal of Experimental Biology 205: 1843–1851.
Pulmonary
artery Foramen of Panizza
Right Pulmonary Left Right
aorta Left artery aorta aorta
aorta
Right Left
atrium atrium Right Left
ventricle ventricle
Ventricular septum
t
Left
un
sh
ventricle
L
R–
Right
ventricle
Ventricular
septum
Anastomosis (complete)
Right atrium Left atrium
Figure A. Figure B.
400
Circulatory Systems
side to collagenous cords called the

chordae tendineae. These cords an-
chor the valves to the papillary mus-
cles, and prevent them from opening Superior vena cava Aorta
backward. The semilunar valves, lo-

cated at the exit from the ventricles,
prevent blood from flowing back- Pulmonary artery
ward into the ventricles. The
pulmonary semilunar valve is lo- Pulmonary veins
cated between the right ventricle and

Pulmonary
the pulmonary artery leading to the semilunar valve
lungs. The aortic semilunar valve is Left atrium
located between the left ventricle Right atrium Left AV valve
and the aorta, the artery leading to Aortic semilunar
the systemic circulation. valve
Blood returning to the heart Right AV valve Left ventricle
from the body first passes through
the superior and inferior venae Right ventricle Septum
cavae (superior vena cava and infe- Inferior vena cava
rior vena cava) into the right atrium.
The blood then passes via the right
AV, or tricuspid, valve into the right
ventricle. The right ventricle pumps Figure 20 Internal anatomy of the mammalian heart Blood flows
from the pulmonary veins into the left atrium and then the left ventricle. The left
the blood through the pulmonary ventricle pumps blood to the aorta and the systemic circuit of the circulatory system.
semilunar valve into the pulmonary Blood from the tissues flows via the venae cavae to the right atrium and the right
artery leading to the lungs. The ventricle, which pumps blood to the pulmonary artery and the pulmonary circulation.
blood travels through the pulmonary One-way flow through the heart is ensured by two sets of valves.
capillary bed where it is oxygenated.
It exits the lungs via the pulmonary veins that lead closing of one-way valves drive blood unidirec-
to the left atrium. The blood then travels from the tionally through the heart.
left atrium past the left AV, or bicuspid, valve into
the left ventricle. The left ventricle pumps the
blood through the aortic semilunar valve into the
Fish hearts contract in series
aorta. The aorta branches into smaller arteries During the cardiac cycle of a fish heart, each of
and then arterioles, finally leading to the capillary the cardiac chambers contracts in series, starting
beds of the systemic circulation. From these capil- with the sinus venosus. Contraction of the sinus
lary beds the blood travels through venules and venosus is unlikely to play an important role in
veins, finally draining into the venae cavae, and propelling blood through the system because this
returning to the right atrium. thin-walled chamber is unable to develop sub-
stantial pressure and it lacks a one-way valve to
prevent backflow into the circulation. Instead,
the primary role of the sinus venosus is to initiate
The Cardiac Cycle the heartbeat. Following the contraction of the si-
The vertebrate heart functions as an integrated nus venosus, the atrium contracts, causing pres-
organ, with each of the chambers contracting at sure to increase in this chamber. This increase in
appropriate points during the cardiac cycle. Only atrial pressure closes the valve to the sinus veno-
through this coordinated contraction can the sus, and opens the valve to the ventricle. It is im-
heart pump blood effectively through the circula- portant to note that the valves are passive
tory system. In this section we examine the car- structures that open and close in response to
diac cycle in fishes, birds, and mammals to changes in pressure in the heart chambers, not
explore how changes in pressure in the various as a result of active movements of the valves
heart chambers coupled with the opening and themselves.
401
Circulatory Systems
The pressure difference between the contract- trarily begin our examination of the events at any
ing atrium and the relaxed ventricle then causes point. Let’s begin at the point labeled step 1. At
blood to flow through the opened valve into the this point, the atria and ventricles are relaxed and
ventricle. Next the muscular ventricle contracts, the AV valves are open, but the semilunar valves
closing the valve to the atrium and opening the are closed. In mammals and birds, blood return-
valve to the bulbus arteriosus. In bony fishes, ing to the heart passes through the atria and en-
blood flows from the ventricle into the elastic bul- ters the ventricles passively, without any pumping
bus arteriosus, causing it to expand. The bulbus action of the heart. At step 2, the atria contract,
arteriosus acts as an elastic energy storage device but the ventricles are still relaxed. The pumping of
that, as we discuss in more detail later in the chap- the atria pushes some additional blood into the
ter, acts to dampen changes in blood pressure and ventricles until they reach the end-diastolic vol-
allow more continuous flow of blood. Contraction ume (EDV), the maximum volume of blood in the
of the muscular ventricle plays the main role in ventricle.
propelling blood through the circulatory system. Next, at step 3, the ventricles begin to contract.
In elasmobranchs, blood flows from the ventricle The increased pressure caused by this contraction
into the conus arteriosus. Contraction of the conus forces the AV valves shut. Since the semilunar
arteriosus further assists in propelling blood valves are shut at this time, the ventricle is a com-
through the body. The elasmobranch conus arte- pletely sealed compartment and blood cannot flow
riosus contains several valves that help to ensure out of it. Blood, like other liquids, is incompress-
unidirectional flow. ible, so the volume of the ventricle does not change.
Instead, the pressure inside the ventricle in-
creases. Thus, the ventricles are said to undergo
The mammalian cardiac cycle is similar isovolumetric contraction (also known as isovo-
to that of fishes lumic contraction) because the volume of the
Figure 21 illustrates the cardiac cycle of a mam- chamber does not change. Eventually, the pressure
malian heart. Because it is a cycle, we can arbi- in the ventricles is sufficiently high that it forces
1 Ventricular Diastole 2 Atrial Systole

Pressure in the atria Atrial contraction forces
exceeds ventricular additional blood into ventricles.
pressure. The AV valves
open and the ventricles
fill passively.
tole
d ias
r Atrial systo
l
ula
e
ric
Vent
5 Ventricular Diastole Cardiac 3 Ventricular Systole

As the ventricles Cycle (isovolumetric contraction)
relax, pressure in the Ventricular contraction
e
tol
le
arteries exceeds pushes the AV valves

sto
as
ventricular pressure, di closed and increases

sy
al
closing the semilunar A tri la
r pressure inside the
valves.
n t r icu ventricle.
Ve
4 Ventricular Systole
(ventricular ejection)
Increased ventricular
pressure forces the
semilunar valves open
and blood is ejected.
Figure 21 The cardiac cycle in mammals
402
Circulatory Systems
open the semilunar valves, and blood flows out of conditions, because it is difficult to measure the ex-
the ventricles into the arteries in step 4 of the car- act pressure within the pericardium of a swimming
diac cycle: the ventricular ejection phase, in which shark.
the volume of blood in the ventricle declines. The
chordae tendineae prevent the AV valves from be-
ing forced open, so blood cannot flow “backward” The right and left ventricles develop
into the atrium. At this point, the ventricle has different pressures
reached its minimum, or end-systolic volume During the cardiac cycle, the two ventricles of the
(ESV). The end-systolic volume is always greater mammalian heart contract simultaneously, but the
than zero, as the heart does not completely empty left ventricle contracts much more forcefully than
itself with each beat. In a healthy human at rest, the right ventricle, and develops much higher
ESV can be as much as 50% of EDV. pressure (Figure 22). Blood from the left ventricle
At the end of the ventricular ejection phase, travels via the aorta to the organs of the body,
the ventricles begin to relax, causing the pressure whereas blood from the right ventricle travels via
in the ventricles to drop (step 5). Once the ventric- the pulmonary artery to the lungs. The pulmonary
ular pressure drops below the pressure in the ar- circuit has relatively low total resistance because
teries, the backpressure forces the semilunar of the very large number of capillaries arranged in
valves shut. Throughout ventricular systole, the parallel and the relatively short distance traveled.
atria have been in diastole; they have been relaxed Because the resistance of the circuit is low, the
and filling with blood. The pressure in the filled right side of the heart does not need to pump as
atria eventually exceeds the pressure in the relax- forcefully to drive blood through the lungs, which
ing ventricles, and the AV valves pop open, return- protects the delicate blood vessels of the lungs.
ing the heart to the configuration shown in step 1.
Some vertebrate hearts fill actively 10. Which type of animal would you expect to have a
The ventricles of birds and mammals fill passively higher proportion of spongy myocardium, a fish
or a mammal?
during diastole, as a result of the relatively low
11. Compare and contrast the heart of an amphibian
pressure within the atria compared to the venous
and a mammal.
pressure, with only a small contribution from atrial
12. What is isovolumetric (or isovolumic)
contraction. But this is not the case for all verte-
contraction?
brates. For example, in fish and some amphibians,
the ventricles are primarily filled by contraction of
the atrium. In addition, some fishes, including the
elasmobranchs, may utilize suction filling of the Control of Contraction
ventricle, analogous to that seen in the hearts of From the preceding discussion it is clear that car-
arthropods. Elasmobranchs have a relatively rigid diac contraction must be precisely controlled in or-
pericardium. When the ventricle contracts, the vol- der to ensure coordinated unidirectional blood flow
ume of pericardial space occupied by the ventricle through the chambers of the heart. Unlike the neu-
decreases. This increases pericardial volume and rogenic hearts of the invertebrates that we dis-
decreases the pressure inside the pericardial cav- cussed previously, vertebrate hearts are myogenic;
ity. The sinus venosus and atrium are thin-walled their cardiomyocytes can produce spontaneous
chambers, and a very low pressure in the peri- rhythmic depolarizations that initiate contraction.
cardium causes them to expand, reducing the pres- But in order for the heart to contract in a coordi-
sure in the atrium and sucking blood into the heart. nated way, cardiomyocytes must be electrically
However, this mechanism will work only if pres- coupled via gap junctions so that the depolariza-
sure within the pericardium decreases below the tion in one cell can spread to adjacent cells,
pressure in the veins, and cardiovascular physiolo- triggering coordinated contractions. The rate
gists debate whether this mechanism actually oper- of the spontaneous depolarizations varies
ates in elasmobranchs under normal physiological among cardiomyocytes, with some having
403
Circulatory Systems
Right side of heart Left side of heart

120 120
Aorta
Pressure (mm Hg)
Pressure (mm Hg)

80 80
Left
ventricle
Right
40 Right ventricle 40
atrium Left
Pulmonary artery atrium
0 0
Time (msec) Time (msec)
Figure 22 Pressure changes in the heart and arteries of mammals such as

humans The left side of the heart, which supplies the systemic circuit, develops
substantially greater pressures than the right side of the heart, which supplies the pulmonary
circuit.
a relatively rapid rhythm and others depolarizing

more slowly. The cells with the fastest intrinsic 20
PCa
rhythm are termed the pacemaker cells, because
they determine the contraction rate for the entire
0 PK
heart. In fish, the pacemaker cells are located in
PCa
the sinus venosus, and in other vertebrates they –20
are located in an area of the right atrium called the
sinoatrial (SA) node, close to the point where the
–40 PNa
superior vena cava enters the right atrium. This
PK
structure is thought to be the remnant of the sinus
venosus of fish. –60
Pacemaker Action
potential potential
Pacemaker cells initiate the heartbeat
Time (msec)
Although derived from muscle cells, pacemaker
cells are small with few myofibrils, mitochondria, Figure 23 Pacemaker and action potentials In
myogenic hearts, the pacemaker cells have an unstable
or other organelles, and they do not contract. resting membrane potential (the pacemaker potential).
These cells have an unstable resting membrane Nonselective cation (“funny”) channels open, increasing the
potential (called the pacemaker potential) that permeability (P) of the membrane to Na , which causes the
slowly drifts upward from the starting potential membrane potential to increase gradually. As the membrane
approaches threshold, T-type Ca2 channels open, triggering
of about 60 mV until it reaches threshold
an action potential. After about 200 msec these channels
(about 40 mV) and initiates an action potential close and K channels open, repolarizing the cell, and the
(Figure 23). This slow depolarization is, in part, cycle begins again.
404
Circulatory Systems
the result of a slow inward movement of sodium, milliseconds after they open, these T-type Ca2
which is called the “funny” current (If) because of channels begin to close, and K channels open,
its unusual behavior. The funny current is the re- initiating the repolarization phase of the action po-
sult of the opening of a nonselective cation chan- tential in the pacemaker cell.
nel (sometimes called the “funny channel,” for
consistency with the term funny current). This
channel opens when the membrane is hyperpolar- The nervous and endocrine systems can
ized, allowing Na to enter the cell, and closes as modulate the rate of pacemaker potentials
the membrane gradually depolarizes. In addition, The rate of action potentials in the pacemaker sets
as in all other cells, there is a continuous leak of the heart rate. In most vertebrates, the nervous
potassium ions at the resting membrane potential. and endocrine systems can control heart rate by
In pacemaker cells, however, this potassium per- altering the rate of pacemaker potentials in the
meability decreases as the membrane depolarizes. cells of the sinoatrial node or sinus venosus. Nor-
The slow decrease in potassium movement con- epinephrine released from sympathetic neurons
tributes to the slow depolarization of the cell. The and epinephrine released from the adrenal
combination of reduced K efflux and increased medulla bind to adrenergic receptors on the
Na influx causes pacemaker potential. pacemaker cells (Figure 24). The receptors stimu-
When the membrane potential of the pace- late a cAMP-mediated signaling pathway that al-
maker cell reaches threshold, T-type voltage-gated ters the transport properties of the ion channels in
Ca2 channels open and Ca2 influx increases, the cell membranes. Funny and Ca2 channels
causing a further, more rapid, depolarization. open, increasing the influx of Na and Ca2 ions
Opening of these T-type Ca2 channels results in a and increasing the rate of depolarization of the
depolarization phase that is much less steep than cell. The increased depolarization rate increases
the depolarization of a neural action potential the frequency of action potentials in the pace-
(caused by influx of Na through voltage-gated maker cells, which ultimately increases heart rate.
Na channels; although it is faster than the depo- These effects of epinephrine and norepinephrine
larization caused by the funny current. About 200
Extracellular fluid Cardiovascular control center (medulla)
Norepinephrine
Funny T-type Ca2+ Sympathetic neurons
or epinephrine
channel channel
Norepinephrine Adrenal medulla

β receptor AC
Epinephrine
ATP cAMP Na+ Ca2+

Gs
β receptors of autorhythmic cells
Na+ and Ca2+ influx

Protein kinase
Depolarization Rate of depolarization
Cytoplasm Heart rate
Figure 24 The effects of norepinephrine on heart rate Norepinephrine

increases heart rate by binding to adrenergic receptors, activating an adenylate cyclase (AC)
signal transduction pathway that opens cation (funny) and T-type Ca2 channels, increasing the
rate of depolarization of the pacemaker potential.
405
Circulatory Systems
on the pacemaker cells explain the dangerous side potentials, which can then spread to adjacent
effects of drugs such as ephedrine and the herbal cells, propagating the impulse throughout the
supplement ephedra, which can bind to adrener- heart.
gic receptors and cause a rapid heart rate.
Acetylcholine, released from parasympathetic
Cardiac action potentials have an extended
neurons, binds to muscarinic receptors on the
depolarization phase
pacemaker cells of the heart (Figure 25). These re-
ceptors stimulate a signal transduction pathway The action potential of a contractile cardiomyocyte
that ultimately leads to increased K permeability. differs from the pacemaker potentials seen in the
The increased K efflux causes the pacemaker cell pacemaker cells of the sinus venosus or sinoatrial
to hyperpolarize. The pacemaker potential starts node. In the contractile cardiomyocytes, the action
at a more negative value, and thus takes longer to potential is initiated when a depolarization spread-
reach threshold potential. In addition, binding of ing from an adjacent cell depolarizes the cardio-
acetylcholine to its receptor leads to decreased myocyte beyond the threshold potential of the
Ca2 permeability, slowing the rate of the depolar- voltage-gated Na channel. At this point, the voltage-
ization during a pacemaker potential. Together gated Na channels open, causing the rapid depolar-
these effects decrease the number of depolariza- ization phase of the action potential. In this
tions per unit time, and thus slow the heart rate. respect, the action potential of the cardiomyocyte
is similar to that in neurons and in skeletal muscle
cells. However, the action potentials in contractile
Pacemaker depolarizations can spread via cardiomyocytes differ from those in skeletal
gap junctions muscles. They have an extended depolarization,
Cardiac cells are electrically connected to each called the plateau phase (Figure 26). At the time
other via gap junctions. Thus, the rhythmic depo- when the voltage-gated Na channel is inactivated
larization initiated in the pacemaker cells of the si- (closes), another channel, an L-type voltage-gated
nus venosus or sinoatrial node can spread from Ca2 channel opens, allowing Ca2 to
cell to cell via electrotonic current spread. In the enter the cell. This greatly lengthens the
adjacent cells, this depolarization triggers action depolarization phase of the action potential
Extracellular fluid Cardiovascular control center (medulla)
Parasympathetic neurons
T-type Ca2+ Acetylcholine K+

channel channel
Acetylcholine
Ca2+
Muscarinic K+
receptor Muscarinic receptors of
autorhythmic cells
K+ efflux, Ca2+ influx
Hyperpolarizes cell
Gi Gs
Time for depolarization
Cytoplasm Heart rate
Figure 25 The effects of acetylcholine on heart rate Acetylcholine decreases

heart rate by binding to muscarinic receptors, activating a signal transduction pathway that
closes Ca2 channels and opens K channels. This prevents Ca2 ions from entering the cell
and allows K ions to exit, causing a net hyperpolarization, which increases the time needed for
the pacemaker potential to depolarize the cell to threshold.
406
Circulatory Systems
PNa PK
in contractile cardiomyocytes. Note that this L-type
1
Ca2 channel is a distinct isoform from the T-type
2 PK PCa
Ca2 channel expressed in the pacemaker cells, ac-
0 Plateau phase
counting for the differences in their behavior.
0
The plateau phase of the contractile cardio-
3 PCa PK
PNa myocyte action potential corresponds to the re-
Repolarization fractory period of the cell, in which it cannot
Depolarization generate another action potential. This refractory
4 4
–90 period lasts almost as long as the entire muscle
twitch, preventing new contractions from occur-
0 100 200 300 400 ring until the previous one has finished. Thus, un-
Time (msec) like skeletal muscle, cardiac muscle cannot go into
(a) Cardiac action potential tetanus—a period of sustained contraction leading
to muscle fatigue.
The exact shape and duration of the action po-
tential varies substantially among organisms and
among cells from different parts of the heart (Fig-
SA node
ure 26b) as a result of variation in the expression
of ion channel isoforms. For example, small mam-
mals tend to have a rapid heart rate and cardiac
Atrium
action potentials with shorter plateau phases than
large mammals whose hearts beat more slowly.
AV node
Conducting pathways spread the

Bundle of
depolarization across the heart
His In a fish heart, in which the chambers are
arranged in a more or less linear way, impulse
conduction via gap junctions is sufficient to pro-
Ventricular
cardiomyocyte vide coordinated contraction of the chambers. The
depolarizing signal travels via gap junctions from
the sinus venosus to the atrium and then to the
ventricle, causing them to contract in series. How-
0 100 200 300 400
Time (msec)
ever, in addition to traveling from cell to cell via
gap junctions, depolarizations in vertebrate hearts
(b) Potentials in various parts of the heart
also spread via specialized conducting pathways.
Figure 26 The action potential in In mammals, these conducting pathways consist
cardiomyocytes (a) Phases of the action potential. of a series of cells that can be easily distinguished
Phase 0: The cell reaches threshold potential and voltage-
gated Na channels open, increasing Na permeability (PNa) microscopically because of their elongated, pale
and depolarizing the cell. Phase 1: The voltage-gated Na appearance. These conducting cells do not con-
channels inactivate and K channels open, causing a tract, but can undergo rhythmic depolarizations,
transient outward K current, resulting in a slight similar to pacemaker cells. Along most of their
repolarization. Phase 2: These inward rectifier K channels
close and L-type voltage-gated Ca2 channels open, causing length they are electrically insulated from the rest
the plateau phase of the action potential. Phase 3: L-type of the myocardium by a fibrous sheath. All verte-
voltage-gated Ca2 channels close and K channels open, brate hearts appear to contain fast electrical con-
causing repolarization. Phase 4: The cell returns to the ducting pathways, although in nonmammalian
resting membrane potential. (b) Pacemaker and action
potentials in various types of cardiomyocytes in the
vertebrates these conducting cells are not mor-
mammalian heart. The shapes of the pacemaker and action phologically distinguishable as electrically isolated
potentials differ across the parts of the heart as a result of cells. Instead, some of the trabeculae in the spongy
the expression of different channel isoforms. myocardium in fishes, amphibians, and reptiles
appear to play this fast conducting role.
407
Circulatory Systems
Figure 27 shows how electrical signals move cates the electrical signal to the ventricle. The
through the heart of a mammal. After the pace- contractile cells of the atrium and ventricle do not
maker cells in the sinoatrial (SA) node initiate an form gap junctions with each other, and thus are
action potential, the depolarization spreads rap- not electrically coupled, so the depolarization
idly via the internodal pathway through the walls cannot spread directly from the atrium to the ven-
of the atria. At the same time, the depolarization tricle, but instead can only pass through the AV
spreads more slowly through the contractile cells node. The AV node transmits signals a little more
of the atrium via gap junctions, causing the slowly than the other cells of the conducting path-
atrium to contract. After traveling through the in- ways, so the signal gets delayed slightly. This sig-
ternodal pathway, the depolarization reaches the nal delay allows the atrium to finish contracting
atrioventricular (AV) node, which communi- before the ventricle starts to contract. The signal
travels from the AV node through the bundles of
His (pronounced Hiss), which splits into the left
and right bundle branches that conduct electrical
signals to the ventricles. The electrical signal then
SA node
spreads into a network of conducting pathways
Internodal pathways
called the Purkinje fibers. From the Purkinje
fibers, the signal spreads from cell to cell in the
AV node
ventricular myocardium via gap junctions. The
Bundle
of His contraction of the ventricle begins at the bottom
(or apex) of the heart and spreads up through the
Purkinje
fibers myocardium, pushing blood upward toward the
arteries.
1 SA node depolarizes and the
depolarization spreads rapidly
via the internodal pathway. The integrated electrical activity of the
heart can be detected with the EKG
The depolarization of cardiac muscle produces a
strong electrical signal that travels through the
body and can be detected using an instrument
2 The AV node delays the signal. called an electrocardiograph. These instruments
The depolarization spreads use electrodes applied to various areas on the sur-
through atria via gap junctions,
and causes the atria to face of the body to generate an electrocardiogram
contract. (abbreviated EKG for the original German spelling,
or ECG for the English spelling). Clinicians gener-
ally perform EKGs on humans using 12 electrodes,
but you can generate an interpretable EKG using as
3 The depolarization spreads few as three electrodes (in humans these electrodes
rapidly through the bundles of are placed one on each wrist, and one on an ankle).
His and Purkinje fibers.
An EKG is a composite recording of all the action
potentials in the various parts of the heart, includ-
ing the pacemakers, the conducting pathways, and
the contractile cells (Figure 28). The deflections on
the chart are not action potentials, and do not rep-
4 The depolarization spreads resent specific depolarizations of any given cell. In-
upward through ventricle,
causing the ventricle to
stead, they are markers of the electrical activity of
contract. the heart as a whole. The small P wave is the result
of the spread of depolarization through the atria.
The large QRS complex is the result of ventricular
depolarization and atrial repolarization. The T
Figure 27 Electrical conduction in the wave is caused by ventricular repolarization. The
mammalian heart EKG can be very useful clinically to diagnose prob-
408
Circulatory Systems
of the heart. The heart sounds, which can be de-

1 mV 1 sec
tected with a stethoscope, represent the opening
R and closing of the valves. The center and top
T
P graphs show the pressure and volume changes
within the left ventricle over the course of the
QS
cardiac cycle.
(a) Normal At the beginning of the cardiac cycle, the ven-
tricle fills passively. Then the depolarization of the
SA node spreads through the atrium, initiating
atrial contraction, and pumping some additional
blood into the ventricle, which reaches its end-
diastolic volume. The depolarization then spreads
(b) Ventricular fibrillation
to the ventricle, which begins to contract. The in-
creased pressure caused by this contraction forces
Figure 28 EKG tracings (a) In the EKG of a normal the AV valves shut. Pressure then increases rap-
cardiac rhythm, the P wave indicates atrial depolarization.
The QRS complex indicates ventricular depolarization and
idly during the isovolumetric ventricular contrac-
atrial repolarization, and the T wave indicates ventricular tion phase, quickly becoming high enough to open
repolarization. (b) During ventricular fibrillation, the EKG the semilunar valves. The first heart sound is the
is disorganized and no consistent waves are observed. result of the AV valves shutting and the semilunar
valves opening. At this point, the ventricle begins
to empty and aortic pressure increases. Initially,
lems with the conducting system or the depolariza- pressure in the ventricle continues to increase, de-
tion of the heart muscle. For example, ventricular spite the reduced volume, because ventricular
fibrillation, which represents uncoordinated con- contraction continues, but ventricular pressure
traction of the ventricle, appears as a series of ran- quickly reaches a peak and begins to fall. Shortly
dom, apparently unrelated waves in the EKG. thereafter, the ventricle begins to relax, entering
Ventricular fibrillation is potentially deadly because ventricular diastole. When ventricular pressure
uncoordinated contraction of the ventricle results falls below the pressure in the aorta, the aortic
in ineffective pumping of blood to the tissues. The valve closes. The closing of the aortic valve causes
resulting oxygen deprivation kills tissues such as a brief episode of turbulent flow and a small in-
the brain within a few minutes. Ventricular fibrilla- crease in aortic pressure, called the dicrotic notch.
tion can sometimes be treated using an electronic Ventricular pressure falls rapidly, and once it is
defibrillator. These machines deliver an intense lower than atrial pressure, the AV valves open.
pulse of current to the body, causing all of the cells The second heart sound is the result of the aortic
of the heart to depolarize simultaneously. Defibril- valve closing and the AV valves opening. At this
lation gives the pacemaker cells of the heart a point, blood flows from the atrium into the ventri-
chance to take over and initiate a normal heartbeat, cle, reducing the atrial pressure, and initiating
because these cells are likely to be the first to depo- ventricular filling.
larize again following defibrillation. However, de-
fibrillation will not be effective if the pacemaker
cells or the conducting pathways have irreversible
defects or injuries. Cardiac output is the product of heart rate
and stroke volume
The amount of blood that the heart pumps per unit
The heart functions as an integrated organ
time is called the cardiac output (CO), and is a
The electrical and mechanical events of the product of the heart rate (HR) and the amount of
heart fit together, allowing the heart to function blood the heart pumps with each beat, or the
as an integrated organ. The diagrams at the bot- stroke volume (SV).
tom of Figure 29 depict the contractions and re-
CO HR × SV
laxations in the cardiac cycle, particularly in the
left ventricle. The EKG tracing just above the di- From this equation you can clearly see that an ani-
agrams shows the timing of the electrical events mal can modulate cardiac output by regulating heart
409
Circulatory Systems
polarization along the conducting

120
pathways of the heart, a phenomenon
Aorta
known as dromotropy.
Pressure in left heart (mm Hg)
80
Left The nervous and endocrine

ventricle systems can modulate stroke
volume
40
Left Both the nervous and endocrine
atrium
systems can also modulate the cont-
ractility (or rate and strength of
0 contraction) of the heart by altering
Left ventricular volume (ml)
130 some of the properties of cardiac

excitation-contraction coupling, a
phenomenon known as inotropy. If
100 the heart contracts more forcefully, it
will pump more blood with each beat,
increasing the stroke volume. Norepi-
70 nephrine released by sympathetic
neurons and circulating epinephrine
released by the endocrine system in-
Heart sounds crease contractility (Figure 30). These
signaling molecules bind to 1 adren-
ergic receptors on contractile car-
EKG diomyocytes. Binding of these
molecules to the receptor activates a
cAMP-mediated signal transduction
Ventricular Ventricular pathway that activates a protein ki-
diastole diastole
nase that phosphorylates a variety of
Atrial proteins, resulting in increased con-
systole tractility via four mechanisms.
Isovolumetric
Isovolumetric Ventricular relaxation
contraction systole • Phosphorylation of L-type Ca2
channels on the cell membrane al-
lows increased Ca2 into the cell in
response to depolarization.
• Phosphorylation of proteins in the
membrane of the sarcoplasmic
Figure 29 A summary of the electrical and mechanical events of reticulum causes it to release
the cardiac cycle more Ca2 in response to an ac-
tion potential.
rate, stroke volume, or both of these parameters. We • Phosphorylation of myosin increases the
have already seen how the nervous and endocrine rate of the myosin ATPase, increasing the
systems can modulate heart rate by changing the rate of cross-bridge cycling and the speed of
properties of the pacemaker cells of the sinoatrial contraction.
node. Decreases in heart rate are termed brady-
• Phosphorylation of the sarcoplasmic reticu-
cardia, whereas increases in heart rate are termed
lum Ca2 ATPase enhances Ca2 reuptake
tachycardia. Regulation of heart rate by changes in
into the sarcoplasmic reticulum, increasing
the rate of depolarization of the sinoatrial node is of-
the rate of relaxation.
ten referred to as chronotropy. Alternatively, the
sympathetic nervous system can also increase heart The net result of these four mechanisms is that the
rate by increasing the speed of conduction of the de- cardiomyocytes contract faster and more strongly
410
Circulatory Systems
Extracellular fluid 1 Binding of norepinephrine or

epinephrine changes the shape of
the β1 adrenergic receptor, which
Norepinephrine activates an associated G protein.
or epinephrine
1 L-type Ca2+
Ca2+
channel
2 The G protein ∝ subunit activates
adenylate cyclase.
β1 receptor AC
2 3 Adenylate cyclase catalyzes the

3 conversion of ATP to cAMP.
Ca2+
G protein ATP cAMP 5
4 The cAMP activates protein kinase A.
Inactive Active
4 5 The protein kinase phosphorylates
protein protein
Ca2+ L-type Ca2+ channels, allowing Ca2+
kinase kinase
to enter the cell, which stimulates
6 contraction.
7
6 The protein kinase phosphorylates
8 Ca2+ channels on the sarcoplasmic
Actin reticulum, allowing Ca2+ to move to
the cytoplasm, which stimulates
contraction.
Sarcoplasmic
reticulum
Ca2+ 7 The protein kinase phosphorylates
ATPase Ca2+ myosin, stimulating contraction.
Myosin
8 The protein kinase phosphorylates
the sarcoplasmic Ca2+ ATPase,
speeding the removal of Ca2+ from
the cytoplasm during relaxation,
Cytoplasm which decreases relaxation time.
Figure 30 Effects of norepinephrine and epinephrine on cardiomyocyte

contractility Norepinephrine and epinephrine increase contractility by binding to
receptors on the cardiomyocyte and activating an adenylate cyclase (AC)–mediated signal
transduction pathway that activates protein kinases, which phosphorylate various proteins and
cause an increase in the rate and strength of contraction.
in response to sympathetic stimulation, increasing cle pumps more forcefully, and stroke volume in-
the stroke volume of the heart. creases (Figure 31)—a phenomenon known as the
In contrast, stimulation of the parasympa- Frank-Starling effect. The Frank-Starling effect is
thetic nervous system causes a decrease in stroke a result of the length-tension relationship for mus-
volume by activating signal transduction pathways cle. Stretching a muscle changes the force of con-
that reduce the intracellular Ca2 signal. In mam- traction by altering the degree of overlap between
mals, parasympathetic effects are relatively weak actin and myosin within the sarcomere. Cardiomy-
in the ventricle, but tend to be strong in the atria. ocytes differ from other types of striated muscle in
that they are normally shorter than the length
needed for optimal contraction so that as you
End-diastolic volume modulates stroke stretch a cardiomyocyte, the strength of
volume contraction increases. When blood enters the
In addition to the extrinsic regulation of heart rate ventricle, the increased volume causes the
and stroke volume by the nervous and endocrine ventricle to stretch, and the more blood that enters
systems, the heart also undergoes autoregulation the heart at the end of diastole, the greater
by intrinsic regulatory mechanisms. If you experi- the degree of stretch. Thus, the end-diastolic
mentally increase end-diastolic volume, the ventri- volume (the maximum volume during the
411
Circulatory Systems
protects the heart from abnormal increases in vol-

Stroke volume (ml)
ume. Under normal physiological conditions the
heart is never stretched to the point that force gen-
eration falls. However, this can occur in some
pathological situations.
Extrinsic controllers such as the nervous sys-
tem act in addition to the autoregulatory mecha-
nisms of the Frank-Starling effect; they simply
shift the position of the cardiac muscle length-
End-diastolic volume (ml) tension relationship (Figure 31b). Increased
(a) Frank-Starling effect sympathetic activity shifts the curve upward
(representing an increase in the force of contrac-
tion at a given end-diastolic volume), while de-
Increased
sympathetic creased sympathetic activity shifts the curve
Stroke volume (ml)
activity downward (representing a decrease in the force

Basal level of contraction).
Decreased
sympathetic
activity
13. What is the difference between a neurogenic
End-diastolic volume (ml) heart and a myogenic heart?
(b) Effects of sympathetic activity on the 14. Compare and contrast the molecular events of
Frank-Starling effect
the action potential in the pacemaker cells of the
Figure 31 The Frank-Starling effect sinoatrial node to those in a ventricular
(a) Stroke volume increases as end-diastolic volume contractile cardiomyocyte.
increases. When end-diastolic volume is low, cardiomyocytes 15. How does the nervous system modulate
are shorter than the optimal length needed for maximal heart rate?
contraction. Increasing end-diastolic volume stretches the
muscle, increasing its length and increasing force
16. What is the connection between the length-
generation. The greater the force generated, the greater the tension relationship for cardiac muscle and the
stroke volume. (b) Changes in sympathetic activity alter the Frank-Starling law of the heart?
position of the curve. An increase in sympathetic activity
shifts the curve upward, whereas a decrease in activity shifts
the curve downward.
Regulation of Pressure
cardiac cycle) is an index of the amount of stretch and Flow
imposed on the cardiomyocytes.
The Frank-Starling effect allows the heart to Upon leaving the heart, the blood enters the circu-
automatically compensate for increases in the lation. The pressure as the blood leaves the heart
amount of blood returning to the heart. Consider provides the primary driving force for flow
what would happen in the absence of the Frank- through the circulatory system. Thus, maintaining
Starling effect. If stroke volume remained constant this pressure within appropriate limits is one of
in the face of an increase in venous return to the the most important requirements for the proper
heart, then the heart would pump a smaller frac- functioning of the circulatory system. The other
tion of the blood returning to the heart. Assuming fundamental requirement for the proper function-
that heart rate remained constant, blood would be ing of the vertebrate circulatory system is the abil-
“left over” in the ventricle after each beat and ity to appropriately direct flow to the organs,
would slowly build up in the heart, increasing its depending on their metabolic needs. In this part of
volume. Eventually, this might cause the ventricles the chapter we examine the regulation of blood
to distend to the point that they could no longer flow and blood pressure in vertebrate circulatory
contract effectively. Thus, the Frank-Starling effect systems.
412
Circulatory Systems
Regulation of Flow muscle to contract, constricting the arteriole. The

decrease in arteriolar diameter increases the re-
The circulatory system must regulate the distribu- sistance and decreases the flow, decreasing the
tion of flow to the tissues. Highly aerobically active pressure, which causes the smooth muscle to re-
tissues have a greater demand for oxygen than do lax. Thus, myogenic autoregulation tends to main-
less active tissues, and thus require greater blood tain constant blood flow to a tissue. But the
flow. The metabolic demands of a tissue can also metabolic activity of a tissue and its demand for
change greatly with time. For example, the meta- oxygen can vary with time, and thus the need for
bolic rate of aerobic skeletal muscle can increase blood flow varies. For example, when you are sit-
as much as 10-fold between rest and intense exerting still, the muscles of your legs have relatively
cise. In general, these changes are regulated by allow demand for oxygen, and little blood flows to
tering the diameter, and thus the resistance, of them, whereas when you are jogging, your mus-
blood vessels leading to the capillary beds. cles require more oxygen, so more blood must
flow to the tissue. Other mechanisms for control-
ling blood flow come into play when the needs of
The arterioles control blood distribution
the tissue change.
Arterioles play the primary role in the distribution
of flow within the circulatory system because they
can vasoconstrict and vasodilate, altering their re- The metabolic activity of the tissue
sistance and thus the flow of blood to the capillary influences blood flow
beds. Because the arterioles leading to the various The vascular smooth muscle cells surrounding the
capillary beds are arranged in parallel, an animal arterioles are sensitive to the conditions in the ex-
can redistribute blood flow to the various organs. tracellular fluid that surrounds them. They con-
For example, during exercise the arterioles of the tract or relax in response to changes in the
gut and kidney vasoconstrict, whereas the arteri- concentrations of substances such as oxygen, car-
oles of aerobically active skeletal muscles vasodi- bon dioxide, H , K , and a variety of paracrine sig-
late, decreasing flow to the internal organs and nals (Table 1). In general, changes in the
increasing flow to the active skeletal muscles. extracellular fluid that are associated with in-
As with the regulation of the heart, both extrin- creased activity cause vasodilation, while changes
sic factors (such as the nervous and endocrine sys- that are associated with decreased activity cause
tems) and intrinsic factors (including the metabolic vasoconstriction. Thus, decreases in oxygen or in-
state of the tissue) control the diameter of the arte- creases in carbon dioxide tend to cause vasodila-
rioles, and thus regulate the proportion of blood tion. Vasodilation increases blood flow to the
flow going to specific tissues. Intrinsic control tissue, bringing more oxygen and carrying away
mechanisms are particularly important in regulat- waste products. This reduces the signal to the
ing flow to the heart, brain, and skeletal muscle, muscle cell, in a negative feedback loop, stopping
while extrinsic factors are the most important con- the flow from increasing beyond what is needed
trollers of blood flow to organs such as the gut. (Figure 32).
Paracrine signaling molecules released from
the vascular endothelium also have a profound
Myogenic autoregulation maintains effect on vascular smooth muscle (Table 1). For ex-
blood flow ample, the gas nitric oxide is an important va-
Some of the smooth muscle cells surrounding the sodilator. Vascular smooth muscle cells actually
arterioles are sensitive to stretch and contract release a small amount of nitric oxide all the time,
when the blood pressure within the arteriole in- which helps to keep the arterioles dilated. How-
creases. This myogenic autoregulation acts as a ever, nitric oxide production is strongly induced by
negative feedback loop that helps to maintain histamine, bacterial lipopolysaccharides, and
blood flow to a tissue at a constant level. When other substances that are associated with damage
flow through the arteriole increases, the pressure to the vascular endothelium. The increased nitric
on the arteriolar wall increases, stretching the oxide causes vasodilation, increasing blood flow to
smooth muscle. This stretch causes the smooth damaged areas. This is an important mechanism
413
Circulatory Systems
Table 1 Factors influencing vasoconstriction and vasodilation.
Substance Source Type

Vasoconstriction
Stretch on arteriolar walls Increased blood pressure Myogenic autoregulation
Norepinephrine ( receptors on Sympathetic neurons Neural
arterioles in most tissues except
skeletal and cardiac muscle, which
express 2 receptors)
Endothelin Vascular endothelium Paracrine
Serotonin Platelets Paracrine
Vasopressin Posterior pituitary Endocrine
Angiotensin II Plasma Endocrine
Vasodilation
Hypoxia Multiple tissues Metabolite
Increased CO2 Multiple tissues Metabolite

H Multiple tissues Metabolite

K Multiple tissues Metabolite
Nitric oxide Endothelium Paracrine
Atrial naturietic peptide Atrial myocardium Endocrine
Histamine Mast cells of immune system Paracrine (systemic actions at high levels)
Substance P Damaged tissue Paracrine
Prostacyclin Damaged tissue Paracrine
Epinephrine (2 receptors in Adrenal medulla Endocrine
skeletal muscle arterioles)
Acetylcholine (muscarinic receptors) Parasympathetic neurons Neural
leading to erectile tissue of
clitoris or penis
Bradykinin Multiple tissues Paracrine
Adenosine Hypoxic cells Paracrine
underlying inflammation. Nitric oxide is also re- terioles of the penis. Sildenafil prevents the cGMP
leased in the arterioles of skeletal muscles during from breaking down, prolonging the effects of ni-
exercise, causing vasodilation that increases the tric oxide and causing vasodilation in the vessels
supply of oxygen to the working muscle. of the penis, leading to a sustained erection.
Nitric oxide activates the enzyme guanylate
cyclase in the vascular smooth muscle. Guanylate
cyclase catalyzes the conversion of GMP to cGMP,
The nervous and endocrine systems
which triggers the muscle cell to relax, causing va-
regulate arteriolar diameter
sodilation. The cGMP is quickly broken down by In addition to intrinsic and local control mecha-
the enzyme phosphodiesterase, preventing the ar- nisms, the arterioles respond to extrinsic con-
teriole from staying permanently dilated and al- trollers such as the nervous and endocrine
lowing it to constrict or dilate as necessary. The systems. The sympathetic nervous system controls
drug sildenafil (Viagra) specifically targets an iso- the smooth muscle surrounding the arterioles. In
form of phosphodiesterase that is found in the ar-
414
Circulatory Systems
Tissue metabolic rate

smooth muscles on the arterioles leading to the
gut and kidneys to contract, and the resulting
vasoconstriction reduces flow. This sympathetic
O2 stimulation also tends to cause vasoconstriction
CO2 of the arterioles leading to the skeletal muscle
Waste and in the coronary arteries. However, local
paracrine factors, such as nitric oxide and adeno-
sine released by these muscles, cause a vasodila-
Arteriolar
smooth muscle tion that outweighs the vasoconstriction
mediated by the sympathetic nervous system.
Thus, the overall result is a vasodilation of the ar-
Vasodilation terioles leading to the skeletal muscles and heart,
and a vasoconstriction of the arterioles leading to
– the kidneys and gut.
Resistance Three other hormones also affect vascular
Negative smooth muscle. Vasopressin (also called ADH) re-
feedback
leased from the posterior pituitary gland, and an-
Blood flow
giotensin II, a hormone involved in the regulation
of the kidney, promote generalized vasoconstric-
O2 delivery tion, while atrial natriuretic peptide promotes a
CO2 removal generalized vasodilation.
Waste removal The nervous and endocrine systems work to-
gether with the paracrine signals that relate to
metabolic activity to influence arteriolar diameter
Tissue O2
and alter blood flow. As a result, blood flow to each
Tissue CO2
Tissue waste
tissue of the body is almost always carefully con-
trolled in order to deliver the amount of blood that
Figure 32 The response of arteriolar smooth the tissue needs.
muscle to an increase in metabolic activity
vertebrates, the sympathetic nervous system al- 2 C O NC E P T C H E CK

ways maintains a certain degree of vasomotor 17. Does myogenic autoregulation play an important
tone so that the arterioles are slightly constricted. role in changing blood flow to tissues as oxygen
Increases or decreases in the activity of these sym- demand increases? (Justify your answer.)
pathetic neurons can alter the degree of vasomo- 18. What is vasomotor tone?
tor tone by acting on the smooth muscles 19. Why, during the fight-or-flight response, do the
surrounding the arterioles. Norepinephrine re- arterioles leading to active skeletal muscles dilate
leased from sympathetic neurons binds to adren- even though sympathetic stimulation causes
ergic receptors on these muscle cells, activating a vasoconstriction?
phosphatidylinositol second messenger system,
and causing vasoconstriction. So increases in sym-
pathetic activity tend to cause vasoconstriction,
whereas decreases in sympathetic activity tend to
Regulation of Pressure
cause vasodilation. As shown in Figure 33, blood pressure differs in the
The sympathetic nervous system is stimu- different parts of the circulatory system. Notice that
lated as part of the fight-or-flight response. Dur- blood pressure in the left ventricle also changes
ing this response, blood is directed away from greatly over time. During ventricular systole, the
organs such as the gut and kidneys, and toward ventricular pressure is very high, and during dias-
the skeletal muscles and heart, readying the body tole it is low. The high systolic pressure in the left
for action. Norepinephrine released from the
sympathetic nervous system causes the vascular
415
Circulatory Systems
ventricle forces blood out into the aorta. The aorta The velocity of blood flow also varies greatly
is a large vessel with relatively low resistance, so across the circulatory system (Figure 33). Blood
pressure remains relatively high as blood travels velocity is greatest in the arteries and veins, and
through this and subsequent arteries. Because ar- lowest in the capillaries, because blood velocity is
terioles are relatively narrow vessels (compared to inversely proportional to the total cross-sectional
arteries) and are relatively few in number (com- area of the circulatory system at any given point.
pared to capillaries), they have the highest resis- The low velocity of the blood, combined with the
tance of any part of the circulatory system. Thus, thin walls of the capillaries, allows for efficient ex-
pressure drops greatly as blood travels through the change of substances between the capillaries and
arterioles, and continues to drop as blood proceeds the tissues.
through the capillaries, venules, and veins. By the
time the blood returns to the heart, its pressure is
barely above ambient. The pressure gradient be-
The arteries dampen pressure fluctuations
tween the left ventricle and the right atrium causes Notice that the pressure fluctuations in the arter-
blood to flow through the system according to the ies are far smaller than those in the left ventricle.
law of bulk flow. The aorta (and the bulbus arteriosus of a bony
fish) acts as a pressure reservoir and dampens the
fluctuations in blood pressure that occur during
le
ric
s
s
rie
le
the cardiac cycle (Figure 34). During systole, the

nt
es
illa
rio
rie
ve
ul
ns
te
ap
te
n
ft
ventricle rapidly pushes blood into the aorta. Be-

i
Ve
Ar
Ar
Le
Ve
C
120 cause the aorta splits into progressively narrower

blood vessels, the exit from the aorta has relatively
Blood pressure (mm Hg)
100
high resistance, so instead of simply flowing out
80 into the rest of the circulatory system, the blood
60
40 Left Aorta Arterioles

ventricle
20
0
35
30
velocity (cm/sec)
Flow Flow
Average blood
25
20
15
10
5 (a) Ventricular contraction
0
5000
Total cross-sectional
4000
Flow
3000
area (cm2)
2000
(b) Ventricular relaxation
1000
0 Figure 34 The aorta as a pressure reservoir
(a) Blood flows rapidly into the aorta during the ejection
Figure 33 Pressure, velocity, and total cross- phase of ventricular contraction, pushing out on the walls of
sectional area across a vertebrate circulatory the aorta and causing it to expand. (b) As the heart relaxes,
system Pressure is variable in the ventricle, high and blood flow into the aorta ceases, but flow out into the
more constant in the arteries, and drops greatly across the arterioles continues, reducing the aortic pressure. Elastic
arterioles. Blood velocity is inversely proportional to total recoil of the arterial walls helps to push blood through the
cross-sectional area of that part of the circulatory system. vasculature, maintaining pressure and flow.
416
Circulatory Systems
tends to back up and exert pressure on the thick, systolic pressure, to its minimum, the diastolic
elastic walls of the aorta. This pressure causes the pressure. Table 2 shows some typical values for
aorta to expand. Because the walls of the aorta are systolic and diastolic pressure in a few represen-
elastic, they act very much like a spring that stores tative vertebrates. Physiologists often consider the
energy as it is stretched. mean arterial pressure (MAP), or the average
When the heart enters diastole, blood ceases blood pressure in the arteries across the cardiac
flowing into the aorta. But blood continues to flow cycle, which allows them to ignore the pulsatile
out of the aorta into the arterioles, reducing the nature of blood pressure and apply to the cardio-
pressure inside the aorta. This is equivalent to re- vascular system the simple physical principles of
leasing a spring, and the aortic walls snap back fluid flow. MAP in humans can be approximated as
into place. This elastic recoil propels the blood follows:
through the circulatory system and maintains an
MAP 2/3 diastolic pressure
aortic pressure that is higher than the diastolic
1/3 systolic pressure
pressure in the ventricle, dampening the pressure
fluctuations associated with the cardiac cycle. This Thus, using the data from Table 2, we can calculate
elastic recoil also helps to maintain relatively con- that the mean arterial pressure in humans is typi-
tinuous flow of blood into the arteries throughout cally around 93 mm Hg at rest. However, the length
the cardiac cycle. Because of the elastic nature of of diastole varies depending on the heart rate, so at
the aorta, the aortic pressure is higher than the high heart rates MAP is better approximated as the
ventricular pressure during some parts of the car- average of systolic and diastolic pressures.
diac cycle, but the aortic semilunar valve prevents
backflow of blood from the arteries to the heart.
The skeletal muscle and respiratory
pumps aid venous return to the heart
Mean arterial pressure is determined By the time the blood enters the veins it is under
by systolic and diastolic pressures relatively low pressure, and little driving force re-
The pressure in the aorta is called the arterial mains to return blood to the heart. Two major
blood pressure. Although the pressure fluctuations pumps assist in moving blood back to the heart:
in the aorta are not as large as those in the ventri- the skeletal muscle and respiratory pumps. When
cle, arterial blood pressure still varies with the skeletal muscles contract, they squeeze the veins,
phases of the cardiac cycle from its maximum, the increasing the pressure inside these blood vessels
Table 2 Systolic and diastolic pressure in representative animals.
Species Systolic pressure (mm Hg) Diastolic pressure (mm Hg)

Homo sapiens (human) 120 80
Equus caballus (horse) 100 60
Rattus norvegicus (rat) 130 90
Canis familiaris (dog) 140 80
Loxodonta africana (African elephant) 120 70
Columba livia (pigeon) 135 100
Turdus migratorius (robin) 118 80
Pseudemys scripta (turtle—red-eared slider) 31 25
Rana catesbeiana (bullfrog) 32 21
Oncorhynchus mykiss (rainbow trout) 45 33
Ictalurus punctatus (channel catfish) 40 30
Octopus vulgaris (octopus) 27 15
417
Circulatory Systems
(Figure 35). Veins that are located outside of the pushes the blood in the other direction, toward the
thoracic (chest) cavity contain valves. The in- heart.
creased pressure as a result of the contraction of
skeletal muscles forces the valves farthest from the
heart to close and the valves closest to the heart to
The veins act as a volume reservoir
open, pushing blood toward the heart. The rhyth- The veins have highly compliant walls that stretch
mic contraction of this skeletal muscle pump helps easily; small increases in blood pressure lead to
to drive blood toward the heart, increasing venous large changes in the volume of the veins compared
return to the heart. to the volume of the arteries (Figure 36). As a re-
Respiratory movements can also help to draw sult, the veins can act as a volume reservoir for
blood toward the heart. In terrestrial vertebrates blood. In fact, in mammals the veins typically hold
the thoracic cavity expands during inhalation, more than 60% of the total volume of blood in the
causing the pressure in the thoracic cavity to drop, body. The sympathetic nervous system regulates
and drawing air into the lungs. This low thoracic the proportion of blood in the venous versus arte-
pressure helps to draw blood into the veins of the rial systems by altering the venomotor tone. The
thoracic cavity, acting as a respiratory pump. Dur- smooth muscles surrounding the venules and
ing exhalation, the pressure in the thoracic cavity small veins contain adrenergic receptors. Nor-
increases, but the valves in the veins outside the epinephrine released from sympathetic neurons
thoracic cavity prevent backflow of blood out of the binds to these receptors, causing the smooth mus-
thoracic cavity. Instead, this increased pressure cle to contract, reducing the diameter of the veins.
Because the majority of the blood is contained in
these numerous smaller blood vessels, a decrease
in the volume of the venules and small veins de-
To heart To heart
creases the volume of the venous reserve. This in
turn increases venous return to the heart, increas-
ing cardiac output and forcing blood into the arte-
rial side of the circulation.
Valve Valve
open closed
Peripheral resistance influences pressure
Skeletal
We can rewrite the law of bulk flow as follows to
muscle specifically apply to vertebrate circulatory systems:
Vein
Valve Valve
closed open
Veins
Volume
(a) Skeletal muscle (b) Skeletal muscle

contracted relaxed
Figure 35 The skeletal muscle pump (a) When a

skeletal muscle contracts, it puts pressure on the vein, Arteries
pushing blood in both directions. The resulting pressure opens
the proximal one-way valve and closes the distal one-way
valve, squeezing blood toward the heart and preventing
backflow. (b) When the skeletal muscle relaxes, the one-way Pressure
valves are in the opposite configuration. The relaxation
reduces pressure on the distal valve, which opens and allows Figure 36 Compliance of arteries and veins
blood to flow in. Back pressure from the blood in the proximal Veins are far more compliant than arteries and thus they
segment of the vein closes the proximal valve, preventing stretch easily, increasing their volume in response to
backflow. increases in pressure.
418
Circulatory Systems
CO MAP/TPR circulatory system. Figure 37 provides a summary

of the major factors involved in the homeostatic
where cardiac output (CO) is a measure of the toregulation of MAP.
tal flow (Q) through the system, and TPR (total pe-
ripheral resistance) is the summed resistances
of all the blood vessels in the body and is a mea-
The baroreceptor reflex is the primary
sure of the resistance (R) of the circulatory system.
means of regulating MAP
We can approximate the pressure gradient across Baroreceptors are stretch-sensitive mechanore-
the circulatory system (P) using the mean arterial ceptors that are located in the walls of many of the
pressure (MAP). The actual change in pressure major blood vessels. The most important of these
across the circulatory system is MAP minus the baroreceptors are located in the carotid artery and
central venous pressure (CVP, the pressure in the aorta, although the large systemic veins, the pul-
superior vena cava near the right atrium). CVP is monary arteries, and the walls of the heart also
usually low relative to MAP, so MAP is approxi- contain baroreceptors. The carotid artery is the
mately equal to the pressure gradient across the major artery leading to the head, and thus the
circulatory system. carotid body baroreceptors monitor blood pres-
The body varies CO and TPR to maintain MAP sure to the brain. The aorta is the primary artery
within very narrow boundaries. TPR is set prima- leading to the systemic circulation, so the aortic
rily by the state of vasoconstriction and vasodila- body baroreceptors monitor mean arterial pres-
tion of the arterioles, which is in turn set largely by sure. Under normal conditions these barorecep-
the metabolic needs of the tissue. CO (and thus tors fire a steady stream of action potentials,
heart rate and stroke volume) varies in response sending signals via primary afferent neurons to
to these changes in TPR in order to maintain MAP the central nervous system. The cardiovascular
within a narrow range. Thus, the metabolic de- control center in the medulla oblongata of the
mand of the tissues is the ultimate regulator of the central nervous system integrates these inputs,
MAP
Number of
red blood
CO TPR cells
HR SV Arteriolar Blood
tone viscosity
– + + +
Para- Sympathetic EDV Metabolites Sympathetic Vasopressin

sympathetic nervous + nervous angiotensin II
nervous system paracrines system
system + + +
epinephrine epinephrine
Venous
return
+ + +
Blood Respiratory Skeletal

volume pump muscle
pump
Balance between Salt + water Kidneys

interstitial fluid balance
and blood
Figure 37 Factors affecting mean arterial pressure (MAP) CO: cardiac output;
TPR: total peripheral resistance; HR: heart rate; SV: stroke volume; EDV: end-diastolic volume.
419
Circulatory Systems
and sends out efferent signals via autonomic neu- sure. Increases in blood pressure stretch the mem-
rons that control heart rate, stroke volume, and va- brane of the baroreceptors in the aortic and carotid
somotor and venomotor tone, thus influencing bodies, increasing the firing rate of the receptor and
blood pressure. Increases in blood pressure cause the frequency of action potentials traveling to the
the walls of the arteries to stretch, increasing the fir- medullary cardiovascular control center in the cen-
ing rate of the baroreceptors, and causing signals tral nervous system. The control center integrates
that result in a reduction of blood pressure. De- the sensory input, and produces an efferent output
creases in blood pressure cause the walls of the ar- carried by autonomic neurons. There is a decrease
teries to relax, decreasing the firing rate of the in sympathetic output, resulting in vasodilation. This
baroreceptors. The decrease in baroreceptor firing decrease in sympathetic output in combination with
causes efferent signals that result in increased blood an increase in parasympathetic output results in a
pressure. Thus, the baroreceptor reflex is a negative decrease in the force of cardiac contraction and a
feedback loop that homeostatically regulates blood decrease in heart rate. Together, these factors lead
pressure within a relatively narrow range. to a decrease in peripheral resistance and cardiac
Figure 38 shows the major steps of the barore- output, and a concomitant decrease in blood pres-
ceptor reflex following an increase in blood pressure. The medullary cardiovascular center also de-
creases the secretion of the hormones vasopressin
and angiotensin in response to increased blood
MAP
pressure. Because these hormones constrict arteri-
oles, decreasing their secretion reduces total periph-
Baroreceptor eral resistance.
firing
The kidneys play a major role
in maintaining blood volume
Afferent
neurons In a closed system, pressure and volume are inti-
mately related. If you increase the volume of a fluid
inside a vessel with a fixed volume, the pressure in-
Cardiovascular
control center side that vessel will increase. (This is the principle
(medulla) behind the isovolumetric contraction of the heart.)
Therefore, increases in blood volume will lead to an
–
increase in blood pressure, whereas decreases in
Sympathetic
output
Negative blood volume will lead to a decrease in blood pres-
feedback sure. The veins are compliant, and can act as a vol-
ume reservoir, but their capacity is not infinite. Any
NE release changes in blood volume that exceed the capacity of
the veins to act as a buffer will alter blood pressure.
The kidneys play a major role in maintaining blood
Arteriolar Ventricular SA node volume, and thus these organs are an important
smooth muscle myocardium
component of the homeostatic regulation of blood
pressure. Figure 39 illustrates how changes in
Vasodilation Force of Heart mean arterial pressure can lead to changes in blood
contraction rate volume by altering kidney function, and how
changes in blood volume can lead to changes in ar-
terial pressure.
Peripheral Cardiac
resistance output
Blood pressure can force fluid out
of the capillaries
MAP
In addition to the critical importance of regulating
Figure 38 The baroreceptor reflex MAP: mean arterial pressure in order to maintain the driv-
mean arterial pressure; NE: norepinephrine; SA node: ing force for movement of blood through the verte-
sinoatrial node. brate circulatory system, it is also critical to maintain
420
Circulatory Systems
Arterial pressure
The direction of fluid flow across a capillary wall
is the result of the net filtration pressure (NFP),
which can be expressed as
Kidneys
NFP (Pcap Pif) (cap if)
This relationship, called the Starling principle of
Excretion of fluid exchange, allows us to quantify the movement
Na+ and H2O
of fluid across a capillary. The hydrostatic pressure
in the capillary is the major driving force pushing
Plasma volume
fluids from the blood and into the interstitial spaces.
If hydrostatic pressure in the capillary is larger than
the hydrostatic pressure in the interstitial fluid, then
– Blood volume fluids will be forced out of the capillary. Continuous
capillaries are permeable only to small molecules,
Negative so that plasma proteins and blood cells remain be-
feedback
Venous pressure hind in the blood, causing the blood to have a
higher osmotic pressure than the interstitial fluid.
Because salts and other small molecules are present
End-diastolic volume
in roughly equal concentration in the blood and the
interstitial fluid, the difference in osmotic pressure
Cardiac muscle between these two compartments is due largely to
contractility the presence of proteins in the blood. An osmotic
(Frank-Starling effect)
pressure that is due to proteins is termed an
oncotic pressure. The higher oncotic pressure in
Stroke volume
the capillaries tends to suck fluids back into the
blood. The balance between these two forces influ-
ences the rate and direction of fluid movement.
Cardiac output Figure 40 illustrates how these forces change
as fluids move along capillaries from the arterial
Figure 39 The relationship between arterial side to the venous side. The osmotic pressure of the
pressure and blood volume blood and interstitial fluid remains fairly constant
across a capillary bed, but the hydrostatic pressure
blood pressure to ensure appropriate of the blood declines substantially as it travels from
fluid balance at the capillaries.
Because of the presence of pores
Pcap Pcap = Capillary hydrostatic pressure
Pressure (mm Hg)
between the cells of the capillary

36 π cap = Capillary osmotic pressure
wall, fluids can move from the capil-
laries to the interstitial fluids by bulk
25
flow. Four forces (called Starling
π cap
forces after the physiologist Ernest
15
Starling, who discovered this princi-
ple in 1896) influence the bulk flow of
Blood
fluids across the capillaries: flow
1. Hydrostatic pressure in the Pcap > π cap Pcap = π cap π cap > Pcap
capillary (Pcap) (the transmural
pressure)
2. Hydrostatic pressure in the in-
Net filtration Net reabsorption
terstitial fluid (Pif)
3. Osmotic pressure in the capil- Figure 40 Net filtration pressure along a generalized capillary At
the start of the capillary, hydrostatic pressure (P) exceeds capillary osmotic pressure
lary (cap) (π), resulting in a net filtration pressure that forces fluid out of the capillary. At the end
4. Osmotic pressure in the intersti- of the capillary, hydrostatic pressure is less than capillary osmotic pressure, resulting
tial fluid (if) in net reabsorption that returns some of the fluid to the capillary.
421
Circulatory Systems
the arterial to the venous end of the capillary bed be- Lymphatic capillaries
cause of the frictional resistance of the capillary
Lymph node
walls. At the arterial end of the capillary the net fil-
tration pressure is positive, indicating that fluid will
flow out into the interstitial fluid. At the venous end
of the capillary, the net filtration pressure is negative,
indicating that fluid will flow back into the capillary.
This balance of forces is true for an idealized
capillary, but many capillaries show filtration across
their entire length, and some specialized capillaries Pulmonary circuit
in the intestinal mucosa reabsorb fluids along most
of their length. Whatever the capillary, however, the
important issue to consider is the balance of Starling
forces. Vertebrates have good control over capillary Valve
pressure, mostly through vasoconstriction and va-
sodilation of the blood vessels leading to capillary
beds, and changes in these parameters will lead to
changes in the rate of fluid filtration.
Under normal circumstances in humans al-
most 20 liters of fluid per day filters out of the cap-
illaries, or almost six times the total volume of the Heart
plasma in an average human being. About 17 liters
of this fluid is usually reabsorbed into the blood, but
this leaves an excess of almost 3 liters of fluid per Systemic circuit
day that could accumulate in the interstitial fluid.
The lymphatic system returns filtered

fluids to the circulatory system
The lymphatic system collects the filtered fluid and
returns it to the circulatory system (Figure 41). Fluid
Lymph node
enters the lymphatic system via the blind-ended
lymphatic capillaries. The lymphatic capillaries co- Figure 41 Relationship between the
alesce into progressively larger vessels termed mammalian circulatory and lymphatic systems
Some fluid leaving the capillaries enters the lymphatic
lymphatic veins and lymphatic ducts that contain
system. This fluid, lymph, flows through the lymph nodes and
valves to prevent backflow of the lymph, and are sur- lymphatic ducts, returning to the venous part of the
rounded by smooth muscle, which propels the circulatory system near the right atrium. The lymphatic ducts
lymph forward. In addition, fish, amphibians, rep- contain valves that ensure unidirectional flow.
tiles, and bird embryos have lymph hearts that help
to propel the lymph through the body. In birds and Anything that alters the balance between filtra-
mammals, the lymphatic ducts lead to small bean- tion and reabsorption of fluids across the capillary
shaped organs called lymph nodes. All vertebrates beds or the function of the lymphatic system may
have lymph nodes in the thoracic cavity, abdomen, lead to accumulation of fluids in the tissues—a con-
and pelvis. In addition, mammals have so-called ex- dition called edema. For example, sitting in one po-
ternal lymph nodes located in their necks and at the sition for a long period of time (such as in an
point where the limbs and torso join (the armpit and airplane) can reduce blood flow in the veins and
groin areas in humans). The lymph nodes filter the cause blood to pool in the capillaries of the ankles
lymph, and contain specialized blood cells called and feet. The pooled blood leads to increased capil-
lymphocytes that kill pathogens and cancerous cells. lary hydrostatic pressure, which leads to increased
From the lymph nodes, the filtered lymph travels filtration of fluids and ankle edema. Liver disease
through the efferent lymphatic vessels that drain into also affects capillary pressure, because the majority
the circulatory system at the veins of the neck. of plasma proteins are produced in the liver. If
422
Circulatory Systems
plasma protein concentration drops, plasma os-

motic pressure will drop, reducing the reabsorption
P1
of water at the venous end of the capillaries, and in-
creasing net filtration, leading to generalized h ΔP = P2 – P1 = ρgh
edema. Alternatively, removal of the lymph nodes P2
(for example, as a part of cancer treatment) can
compromise the function of the lymphatic system, (a) Hydrostatic pressure
preventing the removal of fluid filtered from the cap-
illaries, which leads to edema of the affected tissues. Heart
Pulmonary edema, in which fluids accumulate
in the tissues of the lungs, is one of the most dan-
gerous forms of edema. When fluid accumulates in 13.5 kPa 13.6 kPa 13.3 kPa
the lungs, it becomes more difficult for oxygen to (b) Measured blood pressure when prone
diffuse from the lungs to the blood. As a result, pul-
monary edema can be fatal. Anything that increases kPa mm Hg
the net filtration pressure in the lung capillaries has 4 50
the potential to cause pulmonary edema, if the rate 60
70
of filtration exceeds the rate at which the lymphatic 80
8
system can remove the fluid. For example, if a heart 90
Mean arterial pressure

attack damages the muscle of the left ventricle but 100
Heart 110
spares the right ventricle, the right side of the heart 12
120
may pump more blood per beat than the left side of 130
the heart. This causes blood to back up into the 140
16 150
lungs, and increases the hydrostatic pressure in the
160
capillaries, which increases the net filtration pres- 170
sure and can lead to pulmonary edema. 20 180
190
200
Changes in body position can alter blood

(c) Measured blood pressure when standing
pressure and flow
Figure 42 The effects of gravity on blood
Because of the effects of gravity, an unobstructed pressure Blood pressure is generally measured either in
vertical column of fluid exerts a pressure, termed kilopascals (kPa), the SI unit of pressure, or in millimeters of
the hydrostatic pressure, on objects below it mercury (mm Hg), the unit most commonly used in medical
(Figure 42a). The hydrostatic pressure exerted by diagnostics. 100 mm Hg is equal to 13.3 kPa. (a) Hydrostatic
pressure is the result of the gravitational potential energy of
a fluid column is thus a function of the effects of the fluid column. (b) When a human is lying down, arterial
gravity and the height of the column. We can ex- blood pressure is highest at the heart and lowest at the feet.
press this relationship mathematically as follows: (c) In a standing human, arterial blood pressure is highest in
the feet and lowest in the head.
¢P rg h
where P is the difference in pressure between amount by which the pressure of the blood ex-
two points in the fluid column, ρ is the density of ceeds the ambient atmospheric pressure. For ex-
the fluid, g is the acceleration due to gravity, and h ample, the mean arterial blood pressure near the
is the height of the fluid column (Figure 42a). As human heart is approximately 13.6 kPa, but the
you can see from this equation, hydrostatic pres- actual pressure is 13.6 kPa plus approximately
sure is a measure of the gravitational potential en- 101 kPa (the atmospheric pressure at sea level),
ergy of the fluid column. for a total of 114.6 kPa. The pressure gradient be-
When a person is lying down (Figure 42b), this tween the heart and the rest of the body drives
gravitational component is absent, and mea-sured blood flow around the circuit.
pressure in the feet and head is slightly lower than In contrast, Figure 42c shows the blood pres-
in the heart. We usually report blood pressure rel- sure in various parts of a human body when
ative to the surrounding atmospheric pressure, so standing. When standing, the pressure measured
the pressure shown in the figure is actually the in the ankles is higher than pressure near the
423
Circulatory Systems
heart. If liquids flow from areas of high pressures closer to the brain than in most other snakes. This
to areas of low pressures, how can the heart pump placement helps to make sure that blood reaches
blood down to the feet? This anomaly is explained the brain regardless of body position.
by the fact that the pressure measured in the an- Physiologists have long been fascinated by the
kles is the sum of the pressure exerted by the heart circulatory dynamics of very tall animals, such as
plus the hydrostatic pressure exerted by the blood the giraffe (Figure 43). A giraffe’s head can be as
in the circulatory system “pushing down” on the much as 2 m above its heart, while its legs are 2 m
blood in the ankles. The hydrostatic pressure ac- below the heart. Thus, there is a large gravita-
tually represents the gravitational potential energy tional potential energy barrier to overcome in
of the column of blood, and potential energy is pumping blood up to the head. It is possible that
highest at the top of the fluid column. Fluids tend some or all of this energy is recovered via a siphon
to flow from areas of high potential energy to ar- effect, as the blood moves downward back to the
eas of low potential energy. In essence, blood heart. However, comparative physiologists do not
“falls” downward in the circulatory system. currently agree on whether this effect is physiolog-
As blood returns up the body to the heart it must ically relevant. Whatever the case, clearly the very
move against a gradient of gravitational potential long blood vessels will have high resistance.
energy. This hydrostatic pressure component is ab- A giraffe has an extremely large and muscular
sent when a person lies down (as in Figure 42b). heart and the highest blood pressure known for any
mammal. With a systolic pressure of up to 280 mm
Hg and a diastolic pressure of 180 mm Hg at heart
Changes in body position can cause level, its blood pressure is twice that of a typical hu-
orthostatic hypotension man. A resting giraffe also has a very high heart
When you stand upright, gravity tends to push
blood downward, because the effects of gravity on 4
the column of blood in the blood vessel exert a hy- 75 mm Hg

drostatic pressure on the parts of the circulatory
system below. Thus, when we stand up, a certain
amount of blood normally pools in our ankles and
legs. This pooling causes a slight decline in venous 3
return to the heart. Because of the Frank-Starling
effect, reduced venous return leads to decreased
stroke volume and a momentary drop in arterial
blood pressure. This drop in blood pressure brings
Height (m)
the baroreceptor reflex into play, setting in motion 2

all of the changes that bring blood pressure back to 60 250 mm Hg
normal. If these reflexes do not act quickly enough, mm Hg
we can experience orthostatic hypotension, or low 100

mm Hg
blood pressure due to a vertical body position. This
lowered blood pressure can lead to reduced blood 1
flow to the brain, which can cause fainting. People
who have inefficient baroreceptor reflexes often
feel dizzy or faint if they stand up too quickly.
The effects of changes in body position are not 200 400
usually as profound for animals other than hu- mm Hg mm Hg
mans, since in most animals the head and heart

Figure 43 The effects of gravity on the
are at similar elevations. However, the problems of circulatory system of a giraffe Animals with a very
gravity can be acute for some animals. For exam- long neck must have relatively high mean arterial pressure at
ple, tree-dwelling snakes often orient themselves the heart in order to pump blood to the head. The long legs of
almost vertically with their heads up when climb- the giraffe also greatly increase the hydrostatic pressure in
the legs, potentially causing a problem with peripheral
ing up a tree, but can also hang with their heads
edema. To combat this high hydrostatic pressure, giraffes
down as they watch prey passing below them. The have extremely tight skin on their legs that exerts an inward
heart of a tree-dwelling snake is located much pressure that opposes the hydrostatic pressure due to gravity.
424
Circulatory Systems
rate (about twice that of humans, or approximately Blood

170 beats per minute versus 70 bpm). This obser-
vation is particularly surprising because heart rate Blood and hemolymph, the circulating fluids of
tends to decrease with size in mammals. These car- closed and open circulatory systems, respectively,
diac specializations may be needed to pump blood are complex fluids consisting of many components.
through the systemic circuit of a giraffe. These circulating fluids play a variety of roles, pro-
The high blood pressure of a giraffe, combined viding a relatively constant internal environment
with the effects of gravity on the hydrostatic pres- and transporting nutrients, oxygen, waste products,
sure within the circulatory system, would tend to immune cells, and signaling molecules around the
force blood out of the capillaries into the intersti- body. These fluids can also play noncirculatory roles.
tial fluid in the ankles, causing peripheral edema For example, the hydrostatic pressure exerted by the
in the absence of mechanisms to prevent this hemolymph helps spiders to extend their limbs. You
problem. Giraffes have unusually thick-walled and may have noticed that injured or dead spiders al-
muscular arteries in their legs that help to control ways have their legs bent inward, curled around
the flow of blood. But the most important differ- their bodies. Spiders extend their limbs by contract-
ence between a giraffe and other mammals is that ing muscles in the thorax. This muscle contraction
the skin on a giraffe’s legs is extremely tight. This increases the hydrostatic pressure of the hemolymph
tight skin helps the skeletal muscle pump to func- in the thorax, pumping fluid into the legs, and caus-
tion efficiently, and increases the interstitial fluid ing the legs to extend outward. Injured or dead spi-
pressure, reducing the risk of edema. ders can no longer control the hydrostatic pressure
When a giraffe bends down to drink, the head of the hemolymph, and the legs return to the con-
goes from being several meters above the heart to tracted
several meters below it. The resulting increase in position—curled around the body. Similarly, earth-
the hydrostatic pressure in the head could cause worms and other annelids use a hydrostatic skeleton
blood to pool in the veins, potentially causing for locomotion. In insects, increases in the hydro-
edema in the tissues of the head. Like pulmonary static pressure of the hemolymph are involved in
edema, cerebral edema (or accumulation of fluid molting and the unfurling of the wings as an insect
around the brain) can be life threatening. However, emerges from its pupa.
a giraffe has an intricate network of highly elastic
blood vessels near the brain that act as a pressure
reservoir that expands to accommodate excess
blood when the head is lowered, preventing it from Composition of Blood
pooling in the venous system. In addition, unlike in Blood and hemolymph are primarily composed of
other mammals, the jugular vein (leading from the water containing dissolved ions and organic solutes
head) contains a series of one-way valves that pre- and are thus similar in composition to interstitial
vent backflow of the blood away from the heart fluid. However, these circulatory fluids also contain
when the giraffe’s head is down. Together these blood cells and relatively high concentrations of
mechanisms help to regulate blood flow to the proteins. Many animals maintain the composition
head, regardless of the giraffe’s position. of their blood and interstitial fluid quite distinct
from the external environment, homeostatically
regulating the composition of the blood. However,
2 CO NC E P T C HE C K in some animals the composition of body fluids
varies in concert with the environment.
20. Explain how the large arteries (such as the aorta)
dampen pressure fluctuations and even out blood
flow across the cardiac cycle. Blood contains proteins
21. What is the influence of the skeletal muscle
pump on venous return to the heart? Interstitial fluid typically has a low protein concen-
tration (ranging from 0.2 to 2.0 g/l). In contrast, the
22. Outline the response of the cardiovascular
system to a drop in mean arterial pressure. circulatory fluids of animals with closed circulatory
23. What would happen to the production of lymph if systems often contain a rather high concentration
capillary hydrostatic pressure doubled? of proteins. For example, protein concentration
425
Circulatory Systems
may be 10–90 g/l of hemolymph in decapod crus- GATA factors are involved in the development of
taceans, 30–80 g/l of blood in vertebrates, and up these cells. This similarity suggests that blood cells
to 110 g/l of blood in cephalopod molluscs. In the may have a common origin in all animals.
invertebrates, these proteins are primarily
respiratory pigments that are used to transport Erythrocytes transport oxygen
or store oxygen. In the vertebrates, the respiratory
Erythrocytes, or red blood cells, are the most
pigments are located within cells, and thus the
abundant cells in the blood of vertebrates. Eryth-
principal proteins dissolved in the circulatory fluids
rocytes contain high concentrations of respiratory
are carrier proteins such as albumin and the
pigments such as hemoglobin, and their major
globulins, and proteins involved in blood clotting.
function is the storage and transport of oxygen.
Only a few groups of invertebrates—including the
Blood contains cells phoronid worms, five families of polychaetes, two
The diverse cell types found in the circulatory fluid classes of molluscs, and some echinoderms—have
of many animals are called hemocytes. Hemo- respiratory pigments contained within erythro-
cytes perform a wide variety of functions in differ- cytes. Because these groups are not closely re-
ent animals, including oxygen transport or lated, cells containing respiratory pigments are
storage, nutrient transport or storage, phagocyto- thought to have evolved independently several
sis of damaged cells, immune defense, and blood times in animals. Interestingly, the erythrocytes of
clotting. In many species, the coelomic fluid also invertebrates are almost always located outside
contains cells called coelomocytes that are in- the circulatory system, in the interstitial fluid,
volved in the immune system. Figure 44 compares possibly because the presence of cells in the
the hemocytes of insects and vertebrates to pro- circulatory fluid increases the viscosity of
vide an overview of the great variety of these cells. the solution too much to allow it to be pumped
Although the hemocytes of vertebrates and insects by the relatively weak hearts of these groups.
appear to be quite distinct, developmental biolo- However, in horseshoe worms (phylum
gists have recently discovered that in both of these
taxa, a group of transcription factors called the
Insect (Drosophila) Vertebrates: Fish Frog Mammal
Erythrocytes
Plasmatocyte Lymphocytes
(e.g., T cells, B cells)
Monocytes/macrophages
Lamellocyte
Leukocytes
Granulocytes
(e.g., neutrophils,
eosinophils, basophils)
Crystal cell
Thrombocytes
(e.g., platelets)
Figure 44 Hemocytes Left: Insects such as mammals they lack nuclei. Monocytes and granulocytes
Drosophila have three main classes of hemocytes. perform functions similar to those of invertebrate
Plasmocytes are small cells that use phagocytosis to engulf hemocytes, engulfing or destroying invading particles using
foreign invaders. Lamellocytes are large cells produced in enzymes, and are thus part of the nonspecific immune
response to parasitic infections. Crystal cells contain response. In addition, the vertebrates have lymphocytes,
enzymes that they use to lyse foreign invaders. Right: which are involved in adaptive (or specific) immunity, allowing
Vertebrate hemocytes can be divided into erythrocytes, or vertebrates to mount an immune response tailored to a
cells that contain hemoglobin, and leukocytes, which do not. particular pathogen, and thrombocytes, which are involved in
Erythrocytes vary in size among vertebrate groups, and in blood clotting.
426
Circulatory Systems
Phoronida) the erythrocytes are found in the cir- ganelles. However, mammals, some fish, and
culatory system. These tube-dwelling worms typi- some amphibians have enucleated erythrocytes.
cally live in very low-oxygen environments such as In fact, mammalian erythrocytes lack nuclei, mito-
muddy benthic habitats, and the ability to circu- chondria, and other organelles including ribo-
late erythrocytes through the blood vessels of their somes. As a result, a mammalian erythrocyte
respiratory surfaces may improve their ability to cannot perform protein synthesis or cell division.
obtain oxygen. Erythrocytes are generally round or oval in
shape, although most mammalian erythrocytes
are shaped like biconcave disks (disks with inden-
Vertebrate Blood tations on both sides). The biconcave shape in-
When vertebrate blood is centrifuged, it separates creases the surface area of the erythrocyte,
into three main components (Figure 45). The possibly facilitating oxygen transfer.
plasma makes up approximately 55% of the whole Leukocytes, or white blood cells, lack hemo-
blood volume in normal humans. Erythrocytes globin. All vertebrate leukocytes are nucleated,
make up the other major component of the blood and possess all of the normal cellular machinery.
(approximately 45% of blood volume in humans). Leukocytes are found both in the blood and in the
The other blood cells, consisting of the various im- interstitial fluid, and are able to move across cap-
mune and blood-clotting cells, make up a small illary walls through pores between the cells. There
fraction of the blood. The fraction of the blood that are five major types of leukocytes in vertebrates
is made up of erythrocytes is termed the hemato- (Figure 46), each of which performs specific im-
crit. Hematocrit varies substantially among verte- mune functions. Neutrophils are the most com-
brates (from 20 to 65%), and can vary within an mon leukocyte in vertebrate blood. These immune
individual depending on physiological condition. cells engulf damaged cells, microorganisms, and
For example, acclimation of humans to high alti- other foreign pathogens by phagocytosis.
tude causes an increase in hematocrit. Eosinophils can perform phagocytosis, but their
The size and structure of erythrocytes varies main function is to act as delivery vehicles for cy-
greatly among vertebrates. For example, the totoxic (cell-killing) chemicals. Eosinophils are
largest vertebrate erythrocyte (that of the sala- usually rare in vertebrate circulatory systems
mander Amphiuma) is almost 2000 times larger (making up about 3% of all leukocytes), but their
than the smallest erythrocyte (that of the lesser numbers can increase greatly in response to a
mouse deer, Tragulus javanicus). In most verte- stimulus such as a heavy infection by parasitic
brates, erythrocytes have nuclei and other or- worms. Basophils leave the circulatory system
and accumulate in the interstitial fluid at the site
of an infection or other inflammation, releasing
toxic chemicals that kill invading microorganisms
and other parasites. In addition, they release
paracrine factors including histamines and
prostaglandins that increase blood flow to the site
of infection. Because they release these inflamma-
Whole blood Plasma tory chemicals, they play an important role in al-
(~55% of blood volume lergic reactions such as hay fever. Collectively, the
in humans)
neutrophils, eosinophils, and basophils are
Components termed granulocytes because of their grainy ap-
separated White blood cells
by centrifuge pearance when viewed using light microscopy.
(<1% of blood volume)
Monocytes circulate in the blood of most mam-
mals only briefly, quickly leaving the bloodstream
Red blood cells
(erythrocytes) and entering the interstitial fluid where they grow
(~45% of blood volume much larger and develop into macrophages. Like
in humans)
neutrophils, macrophages are phagocytic, engulf-
Figure 45 The composition of vertebrate blood ing foreign invaders and dead and dying cells.
Some macrophages are found in the walls of the
427
Circulatory Systems
Leukocyte
nity, in which the immune system forms a “mem-
Functions in immunity ory” of invading pathogens so that it can mount a
morphology
faster response to subsequent invasions. Adaptive
immunity is unique to the jawed vertebrates.
Uses phagocytosis to engulf
damaged cells, microorganisms, and Thrombocytes (Figure 44) play a key role in
other foreign particles. blood clotting. The thrombocytes of nonmam-
Neutrophil
malian vertebrates are spindle-shaped cells that
have a nucleus and are classified as leukocytes,
Delivers cytotoxic chemicals and but in mammals an anucleate cell fragment called
enzymes that kill parasites; are a platelet plays this clotting role. When a blood
involved in allergic reactions.
vessel is cut or damaged, the hole must quickly be
Eosinophil
plugged by a blood clot before loss of blood from
Leaves the circulatory system and the circulatory system leads to a precipitous drop
accumulates at sites of infection. in blood pressure. The process of clotting, or blood
Releases cytotoxic chemicals that
kill foreign particles. Involved in coagulation, occurs in three steps. When a blood
Basophil inflammation. vessel is damaged, local signals and activation of
the sympathetic nervous system induce the vessel
to vasoconstrict, reducing blood flow. Next a
platelet plug forms, temporarily sealing the open-
ing. Finally, a clot forms through a series of steps
Monocyte termed the coagulation cascade.
Monocytes mature into phagocytic
macrophages that engulf and
All blood cells form from a single type of stem
destroy foreign particles and dead cell, through a process called hematopoiesis
or dying cells. (Figure 47). In adult mammals, hematopoietic
stem cells are found only in bone marrow, but in
other vertebrates they can be found circulating in
the blood as well as in specific organs. In fishes,
Macrophage the kidney is the primary hematopoietic organ,
whereas in amphibians, reptiles, and birds,
There are multiple types of
lymphocytes. B cells secrete hematopoiesis can occur in the spleen, liver, kid-
antibodies. Helper T cells secrete ney, and bone marrow. The number of stem cells
molecules that activate other
lymphocytes. Killer T cells (cytotoxic found in the blood is highest in the fishes, and de-
Lymphocyte T cells) secrete cytotoxic agents creases in the other vertebrate taxa, associated
that kill invaders or dying cells.
with an increasing role for the hematopoietic or-
gans. Specific signaling factors are involved in
Figure 46 Leukocytes Vertebrates have five different triggering the production of different types of
types of leukocytes, each with a different role in the immune blood cells. For example, erythropoietin is a hor-
response. mone released from the kidney in response to low
blood oxygen. Erythropoietin triggers the differen-
tiation of stem cells into erythrocytes.
blood vessels within the liver and the spleen

where they phagocytose dying erythrocytes.
A final group of leukocytes are the
lymphocytes, each with a different function in the 2 C O N C EP T CH E CK
immune system. B lymphocytes (B cells) make an- 24. What is the difference between blood and
tibodies. T lymphocytes (T cells) are involved in re- plasma?
cruiting macrophages and neutrophils to the site of 25. What is the function of a respiratory pigment?
infection, releasing cytotoxic agents to kill foreign 26. List the major cell types in the blood of
or dying cells, and helping B cells to produce anti- vertebrates.
bodies. In the jawed vertebrates, B cells and T cells 27. What is the function of erythropoietin?
provide a form of immunity called adaptive immu-
428
Circulatory Systems
Figure 47 Blood cell formation

Blood cells are derived from hematopoietic
stem cells that can differentiate to form any
type of hemocyte. The first round of
Hematopoietic stem cell differentiation forms two cell lines: the
myeloid stem cells, and the lymphoid stem
cells. Most hemocytes are derived from
myeloid stem cells. Lymphoid stem cells
are the precursors of the lymphocytes.
Myeloid stem cell Lymphoid stem cell
Monocyte Reticulocyte
Megakaryocyte
(Tissue)
Erythrocyte
Lymphocyte
Platelets Eosinophil Basophil Neutrophil Macrophage
Integrating Systems The Circulatory System During Exercise

Because of its important transport function, the circula- cle to relax. Muscles used for sustained exercise use
tory system plays an important role in the functioning of mitochondrial metabolism to replenish this ATP. Mito-
essentially every other physiological system. In this In- chondrial metabolism requires oxygen. Thus, input
tegrating Systems section, we examine how the nervous from the nervous system causes muscles to go from
system, endocrine system, muscular system, and circu- their resting state into a state of heightened aerobic me-
latory system work together when a vertebrate per- tabolism.
forms aerobic exercise. As a result of this increased demand for oxygen by
When a vertebrate begins to exercise aerobically, the skeletal muscles, the demands placed on the circu-
the brain sends a signal via motor neurons to the mus- latory system change greatly during the transition from
cles. The motor neuron releases ATP onto the nicotinic rest to exercise. In most humans, oxygen consumption
acetylcholine receptors on the motor end plate. The increases by nearly fivefold within a few minutes of the
muscle then generates an action potential, causing the onset of intense aerobic exercise. Figure 48 outlines
release of Ca2 from the sarcoplasmic reticulum, which the response of the cardiovascular system to exercise.
initiates contraction. The myosin ATPase rapidly hy- When we first begin to exercise, mechanoreceptors
drolyzes ATP to allow muscle contraction, and the sarin our muscles detect the change in the
coplasmic Ca2 ATPase hydrolyzes ATP to pump Ca2 tension of the muscle as a result of contraction. These
back into the sarcoplasmic reticulum to allow the mus-
429
Circulatory Systems
Figure 48 The response of the Higher brain Skeletal muscle

cardiovascular system to centers contraction
exercise
Reset arterial Stimulate O2

baroreceptors muscle CO2
upwards mechanoreceptors Release paracrines
Cardiovascular Stimulate Dilate

control center chemoreceptors arterioles
(medulla oblongata) in muscles in muscle
Muscle blood
Parasympathetic stimulation of heart
flow
Sympathetic stimulation of heart and
vasculature (except skeletal muscle)
mechanoreceptors send afferent sensory information to and limits end-diastolic volume. As a result, during the
our brain, activating the cardiovascular control center in later stages of exercise in mammals, increases in heart
the medulla oblongata. The cardiovascular control cen- rate contribute more to increases in cardiac output than
ter reduces the activity of the parasympathetic nervous do increases in stroke volume. In most terrestrial verte-
system and increases the activity of the sympathetic brates, increases in cardiac output in response to exer-
nervous system, changing the efferent signals going to cise are primarily the result of increases in heart rate,
the heart and the arteriolar smooth muscle. with a modest contribution from increases in stroke vol-
The change in parasympathetic and sympathetic ume. In contrast, in fish such as salmon, changes in
activity has dramatic effects on cardiac output. In fact, in stroke volume play the most important role in causing
humans cardiac output can increase by between four the increase in cardiac output during exercise. However,
and eight times the value at rest (depending on the type not all fish are stroke volume regulators. For example,
and intensity of the exercise and the fitness of the indi- tuna typically increase cardiac output by increasing
vidual). A trained thoroughbred horse can achieve as heart rate and keeping stroke volume fairly constant.
much as a 10-fold increase in cardiac output during Thus, different animals use different strategies to
maximal exercise. Recall that cardiac output is the achieve the same goal: increasing the delivery of oxygen
product of heart rate and stroke volume. So which of to the working muscles during exercise.
these factors is the most important in causing the in- In addition to changes in cardiac output, there are
crease in cardiac output? At the onset of exercise large changes in the patterns of blood flow during exer-
parasympathetic activity decreases, causing an in- cise. At rest, the skeletal muscles receive only about 20%
crease in heart rate. At the same time, the increase in of the total cardiac output, whereas they receive 88% of
muscular activity and breathing improves the function the cardiac output during exercise. Notice that total car-
of the respiratory and skeletal muscle pumps, causing diac output also increases dramatically, so that flow to the
an increase in venous return to the heart. Because of skeletal muscles actually increases from about 1.2 l/min
the Frank-Starling effect, the resulting increase in end- at rest to over 22 l/min during exercise. At the same time,
diastolic volume causes an increase in stroke volume. blood flow to organs such as the kidney decreases, both in
Thus, during the initial stages of exercise, the in- relative and absolute terms. At rest, approximately 19% of
creases in cardiac output are a result of both increases the total cardiac output flows through the kidneys (or
in heart rate and increases in stroke volume. Next, sym- about 1 l/min), whereas during intense exercise only 1%
pathetic stimulation of the heart increases, resulting in of the total cardiac output flows through the kidneys (or
increases in both heart rate and contractility. In princi- about 0.25 l/min). These changes in blood flow are the re-
ple, the increase in contractility should cause an in- sult of vasodilation of the arterioles leading to the skele-
crease in stroke volume, but the large increase in heart tal muscle and heart and vasoconstriction of the
rate reduces the time available for filling of the heart, arterioles leading to the other organs. The increase in the
430
Circulatory Systems
activity of the sympathetic nervous system causes a gen- pressure would trigger the baroreceptor reflex, and
eralized vasoconstriction, as sympathetic neurons re- bring blood pressure back to normal by decreasing car-
lease norepinephrine onto the vascular smooth muscle diac output or total peripheral resistance. Recent data
surrounding the arterioles leading to the organs. The nor- suggest that the afferent signal from the muscle
epinephrine binds to its receptors and causes the smooth mechanoreceptors changes the set point of the barore-
muscles to contract. In skeletal muscle, however, local ceptor reflex, or alters its sensitivity, allowing blood
release of paracrine factors causes the vascular smooth pressure to increase slightly with exercise.
muscle to relax by opposing the vasconstrictive effects of Feedforward regulation also plays an important role
adrenergic receptor stimulation. Together, these fac- in the response of the circulatory system to exercise. The
tors cause an intense local vasodilation, increasing blood circulatory changes that accompany exercise occur
flow to the muscles. more rapidly if you ask an experimental subject to re-
Recall that mean arterial pressure is the product of peatedly contract a muscle, compared to what happens
cardiac output and total peripheral resistance. During when you electrically stimulate that muscle. This sug-
exercise, cardiac output increases greatly, which you gests that descending input from higher brain centers
might expect to cause a large increase in mean arterial helps to cause circulatory changes in anticipation of the
pressure. However, the vasodilation of the arterioles need for more oxygen by the working muscles, even be-
leading to the skeletal muscles more than offsets the fore metabolic end products begin to build up. Thus, it is
vasoconstriction of the arterioles leading to the other or- clear that the circulatory responses to exercise repre-
gans, so total peripheral resistance falls dramatically. As sent a delicate integrated response involving the ner-
a result, blood pressure increases only slightly during vous system, the endocrine system, the musculoskeletal
exercise. Ordinarily, even this modest increase in blood system, and the cardiovascular system. 2
Summary
Characteristics of Circulatory Systems k In closed circulatory systems the circulatory
k Diffusion occurs quickly over short distances fluid is called blood.
but is slow over long distances.
k Blood remains within the blood vessels through
k To avoid the limitations of diffusion, animals the complete circuit.
use bulk flow of fluids through a circulatory sys-
k Vertebrates also have a lymphatic system that
tem to transport substances quickly across long
pumps lymph, a fluid formed from blood by
distances.
ultrafiltration.
k In bulk flow, fluids move from areas of higher
k Sponges, cnidarians, and flatworms lack a spe-
pressure to areas of lower pressure.
cialized circulatory system, but transport water
k In order to generate bulk flow, all animal circu- or interstitial fluids through their bodies by
latory systems contain one or more pumps (e.g., bulk flow.
a heart), channels through which a fluid can
k Most molluscs and all insects have relatively sim-
flow (e.g., blood vessels), and a specialized cir-
ple open circulatory systems, but decapod crus-
culatory fluid (e.g., blood).
taceans have complex open circulatory systems.
k Circulatory systems use diverse pumping struc-
k Cephalopods, most annelids, and most verte-
tures, including chambered hearts, skeletal
brates have closed circulatory systems.
muscles, and contractile blood vessels.
k In most organisms, closed circulatory systems
k Circulatory systems can be either open or closed.
have evolved in parallel with increased demand
k In open circulatory systems, the circulatory for oxygen. One exception is the insects, which
fluid is called hemolymph. have very high oxygen demand, but relatively
simple open circulatory systems.
k At some points in the circulatory system, he-
molymph flows out of the blood vessels into k Insects do not depend on their circulatory sys-
large sinuses where it bathes the tissues. tem for oxygen transport.
431
Circulatory Systems
k Vertebrates share a common circulatory plan in k The total flow in a circulatory system is constant
which the heart pumps blood to arteries, arteri- at all levels within the system. The total flow in
oles, capillaries, venules, and then veins, which the arteries is the same as the total flow in all of
return blood to the heart. the capillaries.
k Vertebrate blood vessels have complex walls k Fluids flow along the path of least resistance.
with many layers. Blood vessels can alter the proportion of flow
along alternative pathways arranged in parallel
k The inner layer, the tunica intima, is present in by vasoconstricting or vasodilating and thus al-
all blood vessels and consists of the vascular entering resistance.
dothelium, but the thickness of the two outer
layers, the tunica media and tunica externa, k Flow rate and the velocity of flow are not the
varies among different types of vessels. same. The velocity of flow is proportional to the
rate of flow divided by the total cross-sectional
k Arteries have thick, elastic walls that allow area of the vessels.
them to act as a pressure reservoir.
k Blood pressure exerts a force on the walls of a
k Veins have thinner, more compliant walls that blood vessel, and this force varies depending on
allow them to act as a volume reservoir. the radius of the vessel and the thickness of the
vessel walls.
k Muscular arteries and arterioles have a thick
layer of smooth muscle that allows them to con- Hearts
trol the flow of blood. k The pumping action of a heart is divided into
two phases: systole (contraction) and diastole
k Capillaries have thin walls that promote ex-
(relaxation).
change of substances.
k Arthropod hearts are neurogenic, and require
k The structure of the circulatory system is not
nervous input to initiate contraction.
static, but instead changes over time through
processes such as angiogenesis, which allows k Arthopod hearts fill by suction, and empty as a
new blood vessels to grow into areas with in- result of the increased pressure from contraction.
creased demand for oxygen.
k Mammalian hearts consist of an outer peri-
k The organization of the vertebrate circulatory sys- cardium, an epicardium, a myocardium, and an
tem relates to the respiratory mode of the animal. endocardium.
Water breathers have a single-circuit circulation, k The structure of the myocardium varies among
whereas most air breathers have a double circu- vertebrates. Birds and mammals have only com-
lation (although there is some mixing between pact myocardium. Lampreys have only spongy
these circulations in amphibians and reptiles, myocardium. But most species have a combina-
whereas they are completely separated in birds tion of both compact and spongy myocardium.
and mammals).
k Compact myocardium receives oxygen via the
k Flow in the circulatory system can be approxi- coronary arteries, but spongy myocardium gen-
mated using Poiseuille’s equation (Q Pr4/ erally receives oxygen from the blood flowing
8L). Thus, flow increases when the pressure dif- through the heart.
ference or the radius of the tube decreases.
k The chambers of the fish heart are arranged in
k The total resistance of a circuit differs depend- series. Blood flows from the sinus vensosus, to
ing on whether the resistors are arranged in se- the atrium, to the ventricle, and then to the bul-
ries or parallel. bus arteriosus (or the conus arteriosus in carti-
laginous fish).
k Capillary beds, which consist of many small
blood vessels arranged in parallel, typically k In the mammalian heart, the pathway for blood
have relatively low resistance to flow compared flow is via the right atrium, the right AV valve,
to arterioles, which are fewer in number. the right ventricle, the pulmonary semilunar
432
Circulatory Systems
valve, the pulmonary artery, the capillary beds Regulation of Pressure and Flow
of the lungs, the pulmonary veins, the left k The arterioles control blood distribution by al-
atrium, the left AV valve, the left ventricle, the tering their radius, and thus their resistance.
aortic semilunar valve, the aorta, and the blood
vessels of the systemic circulation. k There are four main ways in which the body
regulates arteriolar diameter: myogenic au-
k The vertebrate ventricle fills during ventricular toregulation, paracrine signals of the metabolic
diastole, reaching its maximum volume (the activity of the tissue, signals from the nervous
end-diastolic volume) at the end of this period. system, and signals from the endocrine system.
In most vertebrates, ventricular filling is pas-
sive, but atrial contraction (during atrial sys- k Blood pressure and blood velocity vary in differ-
tole) pushes some additional blood into the ent parts of the circulatory system because of
ventricle. the structure of the blood vessels.
k Some animals, however, may use suction filling k Myogenic autoregulation acts to maintain a
to assist venous return to the heart. constant blood flow, but the other mechanisms
k At the beginning of ventricular contraction, all can be used to alter blood flow in response to
of the heart valves are closed. tissue demand.
k Once the pressure in the ventricle exceeds that k Blood pressure in the heart and arteries is pul-
in the arteries, the semilunar valve opens, initi- satile because the systolic pressure is higher
ating ventricular ejection. than the diastolic pressure.
k The valves play a critical role in the function of k The arteries act to dampen pressure fluctua-
the heart, but they are passive, opening and tions, and as a result, the pulsatility of blood
closing in response to the applied pressure. flow declines along the course of the circulatory
system.
k The right ventricle pumps much less forcefully
than the left ventricle in mammals. k Blood pressure declines as blood moves
k A pacemaker controls heart rate. In neuro- through the circulatory system.
genic pacemakers the nervous system initi- k Skeletal and respiratory muscle pumps help to
ates the rhythm, whereas in myogenic return venous blood to the heart.
pacemakers specialized cardiomyocytes initi-
ate the rhythm. k The body maintains close homeostatic control
over mean arterial pressure by altering cardiac
k The depolarization then spreads through the
output and total peripheral resistance.
heart via gap junctions. In addition, the verte-
brates have specialized conducting pathways to k The baroreceptor reflex is the primary means
help spread the depolarization through the heart. of regulating mean arterial pressure in the
In mammals, these pathways are very distinct, short term.
but in fishes, these depolarizations spread
k In the long term, blood volume regulation by the
largely through the spongy myocardium.
kidneys is critical.
k Myogenic pacemaker cells have an unstable rest-
ing membrane potential due to changes in K con- k Blood pressure can force fluid out of the capil-
ductance and the action of non-selective Na+ laries by bulk flow.
channels that are responsible for the so-called k The lymphatic system recycles this fluid, but
“funny” current. any imbalance in these processes can lead to
k The nervous system and the endocrine systems edema.
can modulate the rate of the pacemaker poten-
k Body position can affect the functioning of the cir-
tial. Norepinephrine and epinephrine increase
culatory system, because of the effects of gravity.
the rate of pacemaker potentials, whereas
acetylcholine decreases the rate of pacemaker k Animals with very long necks (such as giraffes)
potentials. have specialized mechanisms to ensure blood
433
Circulatory Systems
flow to the brain, and to prevent edema in the k Mammalian erythrocytes lack nuclei and most
lower extremities. organelles, but the erythrocytes of other verte-
brates are less specialized.
Blood
k Blood is a complex aqueous fluid containing k Erythrocytes vary greatly in size among species.
ions, proteins, and cells. It is also considered to
k Leukocytes are vertebrate immune cells.
be a connective tissue.
k Thrombocytes (or platelets in mammals) are in-
k In some species, oxygen-transporting respira-
volved in blood clotting.
tory pigments are found in erythrocytes,
whereas in other species they are found dis- k All types of blood cells form from a single popula-
solved in the blood. tion of stem cells by the process of hematopoiesis.
Review Questions
1. Compare and contrast the circulatory systems 8. What is the Frank-Starling effect? Explain its
of fish, amphibians, and mammals. significance in cardiovascular physiology.
2. Trace the movement of a drop of blood 9. Would resistance be higher in an arteriole or a
through the human circulatory system, listing vein, and why?
all of the structures it passes (including all of 10. What is the difference between the velocity of
the parts of the heart). the blood and the rate of blood flow? How are
3. Name the layers of the walls of a mammalian these two concepts related?
heart and describe their structure. 11. Describe the mechanisms that control the ra-
4. What is the significance of the difference in dius of the arterioles.
pressure developed by the right and left atria 12. Outline some of the functions of the lymphatic
of a mammalian heart? system.
5. Compare the mechanism of filling of a mam- 13. What is the importance of the skeletal muscle
malian heart and an insect heart. and respiratory pumps?
6. Why is the lengthy refractory period of a con- 14. Outline the baroreceptor reflex and discuss its
tractile cardiomyocyte important for the func- importance.
tion of the mammalian heart?
7. Define heart rate, stroke volume, and cardiac
output. Explain how changes in heart rate or
stroke volume affect cardiac output.
Synthesis Questions
1. What are some possible advantages of a dou- blocked (in a way that didn’t directly affect any
ble circulation over a single-circuit circulation? other parts of the heart)?
2. Explain the changes in blood pressure as 6. During an experiment dogs were given the
blood flows through the mammalian circula- drug atropine, which abolishes parasympa-
tory system. thetic nerve transmission. What effects would
3. Aortic blood flow starts to increase only some you expect on the heart and why?
time after the initiation of ventricular contrac- 7. Tom suffers from high blood pressure. Which
tion. Similarly, aortic blood flow continues at a of the following might help deal with this prob-
relatively high level well into the diastolic pe- lem? Remember to explain your answer.
riod. Explain why. (a) A drug that stimulates 1 receptors
4. Increased heart rate can greatly reduce dias- (b) A drug that blocks receptors
tolic filling time, but has less impact on systolic (c) A drug that blocks 1 receptors
ejection time. Why? (d) A drug that blocks acetylcholine receptors
5. What would happen if the connection between 8. After a heart transplant, there is no direct con-
the AV node and the bundle of His were nection between the nervous system and the
434
Circulatory Systems
heart. However, the cardiac output of patients exercise). How could this be possible? Would
with heart transplants can vary in response to you expect this regulation to be as efficient as
changes in metabolic demand (such as during in a patient with an intact heart?
1. Below is a schematic diagram of the mam- 3. Use this figure to answer the following questions:
malian cardiovascular system.
R2 = 12
Left heart
A B
R1 = 1 R3 = 12 R5 = 2
R4 = 12
Lungs Body
A B C D
PA = 100 mm Hg
PD = 0 mm Hg
D C
Right heart (a)What is the flow through this network?

(b)What are the pressures at points B and C?
(c)What is the flow in vessel 3?
If mean pressure at A 2 mm Hg, B 80 mm (d)If another vessel is added in parallel to ves-
Hg, C 5 mm Hg, and D 10 mm Hg, and sels 2–4, with a resistance R6 18 mm
cardiac output 5 l/min, calculate Hgmin/ml, then what is the flow through the
(a) the resistance of the systemic circulation system (assuming P remains the same)?
(b) the resistance of the pulmonary circula- (e) If vessel 4 becomes completely occluded
tion. What are the units you have used for (blocked) (i.e., R4 is now infinite), what is
resistance? the flow through the network?
2. The radius of the aorta in humans is about 4. Using the information in Figure 8.29, at what
1 × 102 m and the velocity of blood flowing point in the cardiac cycle is ventricular ejec-
through it is about 0.3 m/sec. What is the av- tion velocity highest?
erage speed of blood in the capillaries given 5. If during exercise heart rate increases from
average capillary diameter is only 8 × 106m, 70 beats/min to 150 beats/min and the stroke
and the total cross-sectional area of the capil- volume increases from 70 ml/beat to 120
laries is about 2 × 101 m (the cross-sectional ml/beat, what will be the difference in cardiac
area of a blood vessel is approximately πr2). output between rest and exercise?
For Further Reading

See the Additional References section at the end knowledge and concepts, W. H. Dantzler, ed.
of the chapter for more readings related to the (Section 13: Comparative Physiology), vol. 1,
topics in this chapter. 215–308. Bethesda, MD: American
Physiological Society.
Characteristics of Circulatory Systems
The comprehensive chapter below provides an The following detailed review highlights some of
in-depth look at the physiology of vertebrate the seldom-appreciated complexity of the
cardiovascular systems at a level suitable for circulatory systems of insects.
advanced undergraduates and graduate Hertel, W., and G. Pass. 2002. An evolutionary
students. treatment of the morphology and physiology of
Burggren, W., A. Farrell, and H. Lillywhite. 1997. circulatory organs in insects. Comparative
Vertebrate cardiovascular systems. In Biochemistry and Physiology, Part A:
Handbook of physiology: A critical, Molecular and Integrative Physiology 133:
comprehensive presentation of physiological 555–575.
435
Circulatory Systems
This fascinating paper, which includes several The following reviews outline the nature of ion
wonderful images of crustacean circulatory channels and the basis of excitability in
systems such as the one used in the opening vertebrate cardiac tissues.
essay of this chapter, demonstrates that a simple Irisawa, H., H. F. Brown, and W. Giles. 1993.
classification of circulatory systems into “open” Cardiac pacemaking in the sinoatrial node.
or “closed” cannot capture their full diversity. Physiological Reviews 73: 197–227.
McGaw, I. J., and C. L. Reiber. 2002. Kaupp, U. B., and R. Seifert. 2001. Molecular
Cardiovascular system of the blue crab diversity of pacemaker ion channels. Annual
Callinectes sapidus. Journal of Morphology Review of Physiology 63: 235–257.
251: 1–21.
Roden, D. M., J. R. Balser, A. L. George Jr.,
The reviews below highlight some of the and M. E. Anderson. 2002. Cardiac ion
important evolutionary transitions in the channels. Annual Review of Physiology 64:
circulatory systems of the vertebrates. 431–475.
Burggren, W. W., and K. Johansen. 1986. The review below outlines some of the
Circulation and respiration in lungfishes mechanisms involved in the regulation of heart
(Dipnoi). Advances in Comparative and rate and stroke volume in fish hearts.
Environmental Physiology 21: 175–197.
Farrell, A.P. 1984. A review of cardiac
Farrell, A. P. 1991. From hagfish to tuna: A performance in the teleost heart: intrinsic and
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Physiological Zoology 64: 1137–1164. Zoology. 62: 523-536.
White, F. N., and J. W. Hicks. 1987.
Cardiovascular implications of the transition The following review outlines some of the recent
from aquatic to aerial respiration. In work on the genetics of heart development in
Comparative physiology: Life in water and on vertebrates.
land, P. Dejours, L. Bolis, C. R. Taylor, and Warren, K. S., J. C. Wu, F. Pinet, and M. C.
E. R. Weibel, eds., Fidia Research Series, Fishman. 2000. The genetic basis of cardiac
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Anatomical organization and physiological Royal Society of London, Series B: Biological
significance. Journal of Experimental Zoology Sciences 355: 939–944.
275: 172 -185.
Burggren, W.W. 1987. Form and function Regulation of Pressure and Flow
in reptilian circulations. American Zoologist The comprehensive review below discusses the
27: 5-19. mechanisms involved in the regulation of mean
Burggren, W.W. and A.W. Pinder. 1991. arterial pressure, contrasting the mechanisms of
Ontogeny of cardiovascular and respiratory acute regulation to those involved in longer term
physiology in lower vertebrates. Annual regulation.
Review of Physiology 53: 107-135. Cowley, A.W. Jr. 1992. Long-term control of
Hicks, J.W. 2002. The physiological and arterial blood pressure. Physiological Reviews
evolutionary significance of cardiovascular 72: 231-300.
shunting patterns in reptiles. News in The following review outlines how the
Physiological Sciences 17: 241-245. baroreceptor reflex varies among animals.
Hearts Van Vliet, B. N., and N. H. West. 1994.
Phylogenetic trends in the baroreceptor
The review below provides a clear description of
control of arterial blood pressure.
the anatomy and physiology of the heart in
Physiological Zoology 67: 1284–1304.
crustaceans.
Cooke, I. M. 2002. Reliable, responsive These interesting papers debate the nature of the
pacemaking and pattern generation with effects of gravity in closed circulatory systems,
minimal cell numbers: The crustacean cardiac and outline the anatomy and physiology of the
ganglion. Biological Bulletin 202: 108–136. circulatory system of the giraffe.
436
Circulatory Systems
Badeer, H. S. 1997. Is the flow in the giraffe’s Blood

jugular vein a “free” fall? Comparative This fascinating review highlights the
Biochemistry and Physiology, Part A: unanticipated similarities in blood cell formation
Molecular and Integrative Physiology 118: between vertebrates and invertebrates.
573–576.
Evans, C. J., V. Hartenstein, and U. Banerjee.
Hargens, A. R., R. W. Millard, K. Pettersson, and 2003. Thicker than blood: Conserved
K. Johansen. 1987. Gravitational mechanisms in Drosophila and vertebrate
haemodynamics and oedema prevention in the hematopoiesis. Developmental Cell 5: 673–690.
giraffe. Nature 329: 59–60.
Hicks, J. W., and Badeer, H. S. 1989. Siphon Exercise
mechanism in collapsible tubes: Application The following reviews summarize our current
to circulation of the giraffe head. American understanding of the regulation of the human
Journal of Physiology 256: R567–R571. cardiovascular system during exercise.
Recordati, G. 1999. The contribution of the Delp, M. D., and D. S. O’Leary. 2004. Integrative
giraffe to hemodynamic knowledge: A unified control of the skeletal muscle microcirculation
physical principle for the circulation. in the maintenance of arterial pressure during
Cardiologia Roma 44: 783–789. exercise. Journal of Applied Physiology 97:
1112–1118.
This accessible review outlines the role of Thomas, G. D., and S. S. Segal. 2004. Neural
elasticity in the circulatory system. control of muscle blood flow during exercise.
Shadwick, R. E. 1998. Elasticity in arteries. Journal of Applied Physiology 97: 731–738.
American Scientist 86: 535–541. The brief reviews listed below take a historical
perspective to summarize some of the classic
The entertaining and accessible book listed experiments demonstrating that the baroreceptor
below presents detailed information about the reflex is re-set during exercise.
physiology of circulatory systems using examples
and approaches that make circulatory physiology Joyner, M.J. 2006. Baroreceptor function during
come to life. exercise: resetting the record. Experimental
Vogel, S. 1992. Vital circuits: On pumps, pipes,
and the workings of circulatory systems. Raven, P.B., P.J. Fadel, and S. Ogoh. 2006.
Oxford: Oxford University Press. Arterial baroreflex resetting during exercise: a
current perspective. Experimental Physiology
91: 37–49.
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Circulatory Systems
Abel, D. C., W. R. Lowell, J. B. Graham, and R. Shabetai. Korsmeyer, K. E., N. C. Lai, R. E. Shadwick, and J. B.
1987. Elasmobranch pericardial function II. The influence Graham. 1997. Heart rate and stroke volume contribution
of pericardial pressure on cardiac stroke volume in horn to cardiac output in swimming yellowfin tuna: Response to
sharks and blue sharks. Fish Physiology and Biochemistry exercise and temperature. Journal of Experimental
4: 5–15. Biology 200: 1975–1986.
Barrionuevo, W. R., and W. W. Burggren. 1999. O2 Lai, N. C., N. Dalton, Y. Y. Lai, C. Kwong, R. Rasmussen, D.
consumption and heart rate in developing zebrafish Holts, and J. B. Graham. 2004. A comparative
(Danio rerio): Influence of temperature and ambient O2. echocardiographic assessment of ventricular function in
American Journal of Physiology 276: R505–R513. five species of sharks. Comparative Biochemistry and
Burggren, W. W. 1987. Form and function in reptilian Physiology, Part A: Molecular and Integrative Physiology
circulations. American Zoologist 27: 5–19. 137: 505–521.
Burggren, W. W. 2004. What is the purpose of the embryonic McMahon, B. R. 2001. Control of cardiovascular function and
heart beat? Or how facts can ultimately prevail over its evolution in Crustacea. Journal of Experimental
physiological dogma. Physiological and Biochemical Biology 204: 923–932.
Zoology 77: 333–345. Moorman, A. F., and V. M. Christoffels. 2003. Cardiac
Burggren, W. W., and D. A. Crossley. 2002. Comparative chamber formation: Development, genes, and evolution.
cardiovascular development: Improving the conceptual Physiological Reviews 83: 1223–1267.
framework. Comparative Biochemistry and Physiology, Sedmera, D., M. Reckova, A. deAlmeida, M. Sedmerova, M.
Part A: Molecular and Integrative Physiology 132: Biermann, J. Volejnik, A. Sarre, E. Raddatz, R. A.
661–674. McCarthy, R. G. Gourdie, and R. P. Thompson. 2003.
Cho, N. K., S. L. Keye, E. Johnson, J. Heller, L. Ryner, F. Functional and morphological evidence for a ventricular
Karim, and M. A. Krasnow. 2002. Developmental control conduction system in zebrafish and Xenopus hearts.
of blood cell migration by the Drosophila VEGF pathway. American Journal of Physiology 284: H1152–H1160.
Cell 108: 865–876. Shigei, T., H. Tsuru, N. Ishikawa, and
Cripps, R. M., and E. N. Olson. 2002. Control of cardiac K. Yoshioka. 2001. Absence of endothelium in invertebrate
development by an evolutionarily conserved blood vessels: Significance of endothelium and
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reptiles. News in Physiological Sciences 17: 241–245. depolarization of the cog-wheel valve and pulmonary-to-
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Credits
348 Iain J. McGaw and Carl L. Reiber, Image courtesy of Iain
J. McGaw and Carl L. Reiber.
349 Library of Congress.
349 Photo Researchers, Inc., Martin Dohrn/Royal College of
Surgeons/SPL/Photo Researchers, Inc.
438
439
Respiratory Systems
In his book Into Thin Air: A Personal Account of the Mt. Ever- gen. In fact, fewer than 5% of all the people who have
est Disaster, Jon Krakauer tells the gripping story of one of reached the summit of Everest have done so without using
the deadliest attempts to scale Mt. Everest: the 1996 expe- bottled oxygen.
ditions in which eight climbers died in a single day at- Humans seldom live permanently at altitudes higher
tempting to reach the Everest summit. Located in the than 4500 m, which is the typical upper limit for farming, al-
Himalayas, Mt. Everest is the highest mountain peak in the though the nomadic peoples of the Tibetan plateau spend
world, at 8850 m. Altitudes greater than 8000 m are compart of the year in the surrounding mountains at altitudes
pletely inhospitable to human beings because of low tem- between 4800 and 5500 m. But many animals other than hu-
peratures, strong winds, and thin air. The air at the summit mans can easily reach greater altitudes without suffering
of Everest has only one-third the oxygen per unit volume as any ill effects. Pikas (genus Ochotona) are small mammals
does air at sea level—far too little for most humans to ob- related to rabbits. They are found only at high altitudes or
tain enough oxygen to perform any kind of vigorous activ- latitudes, and permanent populations exist at elevations
ity. Mountain climbers have named these altitudes “the higher than 6000 m. Pikas are able to extract oxygen from air
death zone,” because it is impossible for people to survive far more efficiently than other mammals, which allows them
there for more than a few hours without supplemental oxy- to live and breed at high altitudes. The highest altitude colo-
440
Respiratory Systems
Bar-headed geese.
nized by any animal appears to be approximately 6700 m;

Mudskippers.
jumping spiders (family Salticidae) have been observed by
climbing expeditions that high in the Himalayas. As little else
lives this high up, what these predatory spiders eat is a mys- yet understand the complete suite of adaptations that al-
tery, although some scientists have speculated that they low birds to thrive at high altitudes, these animals differ
may subsist on aerial plankton—small insects carried up to from mammals in their ability to obtain oxygen from the at-
high altitudes by air currents. mosphere, to tolerate low blood oxygen levels, and to cope
Bar-headed geese (Anser indicus) nest and breed on with changes in blood carbon dioxide and pH.
the shores of high-altitude lakes in the Himalayas and the Aquatic organisms also regularly experience low-
Tibetan plateau. They then migrate to their winter feeding oxygen environments, both in high-altitude habitats and at
grounds on the shores of lowland lakes in central and sea level. At sea level, aquatic hypoxia is usually caused by
southern India. During their migration they fly over the Hi- the presence of aquatic plants. During the day, plants pho-
malayas, sometimes directly over the summit of Everest, tosynthesize and produce oxygen, but at night plants
reaching altitudes of nearly 9400 m. Airplane pilots have respire and consume oxygen, which can cause drastic de-
also observed other species of birds at very high altitudes, clines in the dissolved oxygen content of enclosed bodies of
including whooper swans (Cygnus cygnus) at 8300 m, and water such as lakes and ponds. Fish that are tolerant of
bar-tailed godwits (Limosa lapponica) at 6100 m. The alti- habitats with low levels of dissolved oxygen exhibit a wide
tude record for a bird is held by the Ruppell’s griffon (Gyps range of adaptations, including behavioral alterations,
rueppellii), obtained when one of these African vultures changes in oxygen extraction efficiency, and changes in
was sucked into a jet engine at 11,500 m—more than 2 km metabolism. Some fish, such as mudskippers, are even ca-
higher than the summit of Mt. Everest. Although we do not pable of emerging from the water and breathing air. 2
441
Respiratory Systems
Overview Diffusion through water or air
Water Air
Most animals depend on mitochondrial respira-
tion to supply the ATP that they need to perform O2 diffuses O2 dissolves
and diffuses
normal cellular functions. During mitochondrial
respiration, mitochondria oxidize carbohydrates,
amino acids, or fatty acids to produce ATP, con- Unicellular and small thin animals
suming oxygen and producing carbon dioxide in
the process. Thus, animals must obtain oxygen Bulk flow of water
from the environment and dispose of the resulting

carbon dioxide in order to meet their metabolic Bulk
flow
needs. The entire sequence of events that results in
the exchange of oxygen and carbon dioxide be-
Diffusion
tween the external environment of an animal and
the mitochondria within its cells is often termed
respiration. However, we prefer the term external
respiration to distinguish this process from mito-
Sponge Cnidarian
chondrial respiration.
During mitochondrial respiration, mitochon- Bulk flow of air
dria consume oxygen and act as oxygen sinks, de-
Bulk flow O2 dissolves
pleting the local concentration of oxygen. Thus, or diffusion and diffuses
there is an oxygen gradient from the outside of the through trachea at tracheoles
cell to the mitochondrion. Oxygen molecules move
down this gradient into the mitochondria (and
carbon dioxide moves in the opposite direction).
Unicellular organisms and small multicellular or-
ganisms living in aquatic environments can utilize Bulk flow or
diffusion through
this diffusion gradient to drive gas exchange with spiracles
the environment (Figure 1). Animals that obtain Insect
oxygen from air need an additional step: gaseous
Diffusion/gas transport
oxygen must first dissolve before it can cross the
cell membrane. Water Bulk flow in Air O2 dissolves
Diffusion alone is too slow to maintain the circulatory and diffuses
O2 diffuses system
rates of gas exchange needed to support the me-
tabolism of larger organisms, because diffusion
Diffuses
occurs slowly over long distances. Instead, larger to tissues
organisms rely on a combination of bulk flow and Bulk
diffusion for gas exchange (Figure 1). Some ani- flow in
Diffusion circulatory
mals, such as sponges and cnidarians, move the to tissues system
Leech Earthworm
external medium (seawater) by bulk flow through
an internal body cavity. Oxygen diffuses from the Ventilation/gas transport
seawater into the cells of the organism, and car- Bulk flow in circulatory system
bon dioxide diffuses out of the cells into the
Diffusion
seawater. The seawater circulating through the to tissues
body cavity by bulk flow carries the carbon diox-
ide out into the environment. Insects use a
conceptually similar system. In these animals, a
series of hollow tubes called trachea penetrate Bulk flow
into all parts of the body. Air moves through O2 dissolves and diffuses
these tubes either by diffusion or bulk flow, Vertebrate
and at the tissues oxygen from the air dissolves in
Figure 1 Respiratory strategies of animals
extracellular fluid and diffuses to the
442
Respiratory Systems
mitochondria, while carbon dioxide diffuses out of cm2/sec), and A is the area of the membrane (e.g.,
the cells and into the trachea where it moves out in cm2). The Fick equation is often expressed in
to the external environment by either diffusion or terms of dC/dx—the difference in concentration
bulk flow (depending upon the species). per unit distance (or the concentration gradient).
Many animals have a circulatory system that This gradient is more accurately described as an
transports oxygen by bulk flow through the body. In energetic gradient, which may be due to differ-
some animals, such as leeches and earthworms, ences in concentration, electrical charge, tempera-
oxygen simply diffuses across the skin and then is ture, or pressure. When we apply the Fick equation
carried by bulk flow through the circulatory system, to gases, we usually express the energy gradient in
but many organisms have a specialized respiratory terms of the pressure gradient of the gas, rather
organ with a large surface area, either gills or lungs, than the concentration gradient, because gases
which they use for gas exchange. Animals with in- have special properties such that they dissolve, dif-
ternal gills or lungs often move the external medium fuse, and react according to their pressure, not
by bulk flow across the respiratory surface—a necessarily according to their concentration.
process called ventilation. In these animals, respi- From the Fick equation you can see that the
ration is divided into four steps: (1) bulk flow of the rate of diffusion will be greatest when the diffusion
medium across the respiratory surface, (2) diffusion coefficient, area of the membrane, and energy gra-
across this surface, (3) bulk flow in the circulatory dients are large, but the diffusion distance is small.
system (a process termed gas transport), and (4) dif- These constraints greatly influence the structures of
fusion into the tissues. gas exchange surfaces so that they are typically thin
In this chapter, we first examine the respira- and often fragile, and have a large surface area.
tory strategies used by animals to obtain oxygen
from the environment and to dispose of carbon
dioxide. Then we take a closer look at the Gases exert a pressure
processes of ventilation and gas transport. We end
The total pressure exerted by a gas is related to the
the chapter with a discussion of the regulation of
number of moles of the gas and the volume of the
respiratory systems and the response of this sys-
chamber, according to the ideal gas law:
tem to environmental changes such as high alti-
tude and diving. PV ⫽ nRT
where P is the total pressure, V is the volume, n is
the number of moles of gas molecules, R is the gas
Respiratory Strategies constant, and T is the temperature in Kelvin. Air is
a mixture of gases, containing nitrogen (⬃78%),
Because the processes of diffusion, dissolution, oxygen (⬃21%), argon (⬃0.9%), carbon dioxide
and bulk flow are fundamental in shaping the res- (⬃0.03%), and a variety of trace gases. Dalton’s
piratory strategies of animals, we begin this chap- law of partial pressures states that in a gas mixture
ter by focusing on the physical principles that each gas exerts its own partial pressure. The
underlie these processes. sum of the partial pressures of the gases in a gas
mixture yields the total pressure of the gas mixture
(Figure 2a). Just as with total pressure, the partial
pressure of a gas is proportional to the number of
The Physics of Respiratory Systems gas molecules.
We can quantify the rate of diffusion using the Fick By rearranging the ideal gas law to the form
equation: n/V ⫽ P/RT, we can see that the concentration of the
gas (number of moles per unit volume, or n/V) is
dQ/dt ⫽ D ⫻ A ⫻ (dC/dx) proportional to the pressure at a constant temper-
where dQ/dt is the rate of diffusion (or the mass ature. If temperature increases, and volume is not
flux—the quantity of substance moving per unit fixed, volume will increase, keeping the pressure
time, e.g., in mol/sec), D is the diffusion coefficient constant but causing the concentration to change.
(an index of the ease of diffusion of a particular The effect of temperature on the concentration of a
substance through a given medium, e.g., in gas is one reason we usually express the Fick equa-
tion in terms of pressure when dealing with gases.
443
Respiratory Systems
For example, consider the diffusion

of a gas across the cell membrane.
Gases are much more soluble in
PV = nRT lipids than they are in aqueous solu-
PO VO = nO RT tion. When the partial pressures are
2 2 2
PCO2VCO2 = nCO2RT at equilibrium, and are thus the
O2 Ptotal = PO2 + PCO2 same outside the cell, in the mem-
CO2 brane, and inside the cell, the con-
centration of gas will actually be
higher in the membrane than out-
(a) Ideal gas law side the cell, because of the higher
solubility of the gas in the mem-
Starting condition: At equilibrium brane lipids. Despite this concentra-
no O2 in solution tion gradient, there will be no net
movement of gas, because there is
no partial pressure gradient.
Notice that Henry’s law is actu-
ally just a modification of the ideal
PO2 = PO2 = 100 mm Hg gas law, where [G] is equivalent to
100 mm Hg [O2] = 5.2 mmol/l n/V, and (1/RT) represents the solu-
Oxygen bility of a gas in air. Using these re-
dissolves lationships, we can compare the
PO2 = in liquid PO2 = 100 mm Hg content of oxygen in air with the
0 mm Hg [O2] = 0.15 mmol/l content of oxygen in water. At sea
level at 20°C, the molar concentra-
(b) Henry’s law tion of oxygen in air is approximately
Figure 2 Partial pressure of gases (a) Molecular collisions of gas 9 mM, whereas the concentration of
molecules exert a pressure on the walls of a container, according to the ideal gas law. oxygen in water under these condi-
Each gas in a mixture contributes to this pressure in proportion to its concentration. tions is less than 0.3 mM. This dif-
(b) Henry’s law. Gases dissolve in solution according to their partial pressure and ference has important implications
solubility. Because the solubility of oxygen in aqueous solutions is low, the
concentration of oxygen dissolved in water is much lower than the concentration of for the respiratory strategy of an or-
oxygen in air, even when the partial pressures in the two media are at equilibrium. ganism. To obtain the same amount
of oxygen, an animal that uses wa-
ter as its respiratory medium must
Henry’s law describes how gases dissolve move 30 times more fluid across its respiratory
in liquids surface than an equivalent organism that uses air
In order to diffuse into a cell, gas molecules in air as its respiratory medium.
must first dissolve in liquid (such as water or ex- The solubility of oxygen in water decreases by
tracellular fluid). Henry’s law states that the almost 50% when temperature is raised from 0 to
amount of gas that will dissolve in a liquid is de- 40°C, causing a large decrease in oxygen concentra-
termined by the partial pressure of the gas and the tion. This effect makes it more difficult for aquatic
solubility of the gas in the liquid. We can write organisms to obtain sufficient oxygen from their en-
Henry’s law as follows: vironments at high temperatures—a particularly
acute challenge for animals such as fish whose body
[G] ⫽ Pgas ⫻ Sgas
temperature and oxygen demand increase with in-
where [G] is the concentration of gas dissolved in creasing environmental temperatures. The solubil-
the liquid, Pgas is the partial pressure of the gas in ity of gases also decreases with increasing ion
the atmosphere above the liquid, and Sgas is the concentration in a fluid. For example, the solubility
solubility of the gas in that liquid (Figure 2b). The of oxygen in seawater is 20% less than in freshwa-
effect of solubility on gas concentration is another ter at the same temperature. Together, these two ef-
reason we usually express the Fick equation in fects cause seawater at 20°C to have almost the
terms of pressure rather than concentration. same oxygen content as freshwater at 30°C.
444
Respiratory Systems
Gases diffuse at different rates 20°C. By substituting these values into the equa-
tion above, we can calculate that oxygen diffuses
Graham’s law states that when gases are dis-
almost 300,000 times more slowly in water than
solved in liquids, the relative rate of diffusion of a
in air at 20°C.
given gas is proportional to its solubility in the liq-
uid and inversely proportional to the square root
of its molecular weight (MW). Fluids flow from areas of high to low
Diffusion rate r solubility> 2MW
pressure
Substances move across long distances much
This relationship has important consequences for
more quickly by bulk flow than by diffusion. Thus,
the diffusion of respiratory gases. Oxygen is lighter
the bulk flow of a fluid medium can transport dis-
than carbon dioxide (32 atomic mass units com-
solved substances such as gases, moving them
pared to 44 for carbon dioxide). These two gases
across long distances much more quickly than is
are equally “soluble” in air, so oxygen diffuses ap-
possible with diffusion alone. Fluids, including
proximately 1.2 times faster in air than does carbon
both liquids and gases, move by bulk flow if the to-
dioxide. However, carbon dioxide is approximately
tal pressure in one area differs from the total pres-
24 times more soluble in aqueous solutions than oxy-
sure in another. We have already discussed the
gen. By substituting these numbers into Graham’s
factors affecting the bulk flow of liquids but for
law, we find that carbon dioxide diffuses about
gases, pressure is related to volume according to
20 times faster than oxygen in water.
Boyle’s law:
By combining the Fick equation with Henry’s
and Graham’s laws, we can derive the following P1V1 ⫽ P2V2
equation for the rate of diffusion of a gas through where P1 and V1 equal the initial pressure and vol-
a medium at a constant temperature: ume, and P2 and V2 equal the final pressure and
D ⫻ A ⫻ ¢Pgas ⫻ Sgas volume. Thus, if you increase the volume of a
Diffusion rate r sealed chamber containing a gas, the pressure
X ⫻ 2MW within that chamber will decrease (Figure 3a).
Thus, at a constant temperature the rate of diffu- If you then open the chamber to the surround-
sion of a gas in a fluid is proportional to (1) the dif- ing atmosphere (which is at higher pressure),
fusion coefficient (D) of the gas in the medium, (2) the gas will move down the pressure gradient un-
the cross-sectional area (A), (3) the partial pres- til the external pressure and the pressure inside
sure gradient (⌬Pgas), and (4) the solubility of the the chamber are equal, and no further net move-
gas in the fluid (Sgas), but is inversely proportional ment of gas occurs. The lungs of terrestrial ani-
to (5) the diffusion distance (X) and (6) the molec- mals work in this way. For example, when you
ular weight of the gas (MW). Table 1 provides val- breathe in, your chest expands, increasing the vol-
ues for the diffusion coefficients and solubilities of ume of your lungs, and decreasing the pressure,
oxygen and carbon dioxide in air and water at causing air to flow into the lungs.
Table 1 The physical properties of air and water and their effects on the respiratory gases.
Property Air (20°C) Water (20°C) Ratio (water/air)

⫺9
Oxygen diffusion coefficient (m /sec × 10 )
2
20,300 2.1 ⬃1:10,000
Carbon dioxide diffusion coefficient (m2/sec × 10⫺9) 16,000 1.8 ⬃1:10,000
Oxygen solubility (ml/l) 1000 33.1 1:30
Carbon dioxide solubility (ml/l) 1000 930 ⬃1
Oxygen concentration (mM) (at 1 atm) 8.7 .3 1:30
Carbon dioxide concentration mM (at 1 atm) .01 .01 ⬃1
Density (kg/m )3
1.2 998 ⬃800:1
⫺2
Viscosity (poise × 10 ) .02 1 50:1
445
Respiratory Systems
Air Gas
Valve
moves
by bulk
Pull on Pressure flow
Open
piston valve
Piston
Gas molecule V=1 V=2 V=2

Volume
10 molecules/volume 5 molecules/volume 10 molecules/volume

(a) Sealed chamber containing gas (external pressure = 1)
Water Liquid
moves
by bulk
Pull on Pressure Open flow
piston valve down
pressure
gradient
Volume constant Volume
10 molecules/volume 10 molecules/volume 10 molecules/volume

(b) Sealed chamber containing liquid
Figure 3 The effects of changes in volume on volume of a sealed chamber containing a liquid, the volume
changes in pressure (a) Boyle’s law. Increasing the will not change. However, pressure will decrease within the
volume of a sealed chamber filled with gas decreases the chamber. If you then open the valve, liquid will move into the
pressure within the chamber. When the chamber is opened, chamber by bulk flow, increasing the volume of the chamber
gas will flow into it down this pressure gradient until the until the pressures are equalized.
pressures are equalized. (b) If you attempt to increase the
Boyle’s law does not apply directly to liquids, 2 C O N C EP T CH E CK

because liquids are incompressible (Figure 3b);
the intermolecular forces holding molecules to- 1. Use the Fick equation to explain why respiratory
gether in liquid form are too strong to be disrupted surfaces usually have high surface area and are
very thin.
by physiologically relevant changes in pressure.
2. In a gas mixture consisting of nitrogen, oxygen,
However, if you exert a force on a liquid, the pres-
and carbon dioxide, if the total pressure is
sure within that liquid will change without a 100 kPa, the partial pressure of nitrogen is
change in volume. These pressure changes result 80 kPa, and the partial pressure of carbon
in the bulk flow of the liquid from the area of dioxide is 0.03 kPa, what is the partial
higher pressure to the area of lower pressure. pressure of oxygen?
3. Compare and contrast the bulk flow of liquids
and gasses.
Resistance opposes flow
Frictional resistance opposes the bulk flow of fluids.
The relationship between flow, pressure, and resis-
tance can be quantified using the law of bulk flow Types of Respiratory Systems
(Q ⫽ ⌬P/R). As in the circulatory system, flow in res- Only very small animals can rely solely on diffusion
piratory systems often occurs in tubes. In tubes, re- of oxygen to support metabolism. As organisms
sistance increases in direct proportion to the length grow larger, their ratio of surface area to volume de-
of the tube and the viscosity of the fluid, but decreases, limiting the area available for diffusion.
creases in inverse proportion to the radius to the Moreover, oxygen must diffuse across greater dis-
fourth power. Because of this relationship, small in- tances within the animal, increasing the time
creases in the radius of a tube cause large de- needed for diffusion. Consider a hypothetical animal
creases in resistance. shaped like a sphere (Figure 4). A sphere has a
446
Respiratory Systems
not increase as quickly as oxygen demand when the

radius of an animal increases. By using the Fick
r=3 equation, we can calculate the maximum possible
oxygen supply to a spherical animal with a given ra-
r=1 dius, and this oxygen supply must be the upper limit
of aerobic metabolic rate.
Sphere A Sphere B Since the ratio of surface area to volume de-
4 3
creases as volume increases, the maximum meta-
Volume = ––
3 πr bolic rate of each gram of tissue must decrease as
Surface area = 4πr 2 volume increases. Data from real unicellular or-
ganisms that rely on diffusion for oxygen supply
Surface area
–––––––––––– 3 (4πr 2) 3 conform to these predictions; metabolic rate per
= ––––––– = ––
Volume 4πr 3 r
gram of tissue declines as size increases. In gen-
Surface area
–––––––––––– eral, using this reasoning, we can conclude that an
for sphere A = 3
Volume
actively metabolizing spherical animal living in
Surface area
–––––––––––– water can be no more than about a millimeter in
for sphere B = 1
Volume
diameter before it begins to be limited by the dif-
3.5 fusing capacity of its surface.
Ratio: surface area/volume
3
Up to this point in the discussion, we have not
considered the distance that oxygen must diffuse
2.5
from the environment to the animal’s body surface.
2 In a perfectly stagnant (unmixed) environment, an
1.5 organism rapidly depletes the oxygen in the imme-
diate area, forming a stagnant boundary layer at
1
its surface. Of course, real environments are almost
0.5 never entirely still. Instead, environmental fluids
0 typically move by bulk flow, as a result of tempera-
0 10 20 30 40 50 60
ture differences or the movement of other organ-
Radius
isms through the fluid. These actions mix the fluid
Figure 4 Relationships between surface area and reduce the size of the boundary layer around
and volume For a sphere, the ratio of surface area to the organism, reducing the effective diffusion dis-
volume declines as the radius increases.
tance between the surface of the organism and the
well-mixed regions of the environmental fluid. En-
volume of 43␲r3 , and a surface area of 4␲r2 . Thus, vironments with more extensive flow will have bet-
the surface area (s) of a spherical organism is pro- ter mixing than environments with low flow. As a
portional to r2 whereas its volume (v) is proportional result of this effect, organisms that live in swiftly
to r3, and the ratio of surface area to volume must be flowing fluids will have a smaller boundary layer
proportional to 1/r. As a result of this relationship, around their surface and can be somewhat larger
as the radius of the organism increases, the ratio of than organisms that live in motionless fluids. How-
surface area to volume decreases. At the same time, ever, the maximum diameter of a spherical organ-
as the sphere increases in size, the distance from the ism in a swiftly flowing fluid is still only a few
external world to the center of the sphere increases. millimeters. Some organisms have cilia or flagella
First, let’s consider the ratio of surface area to on their surface whose beating causes fluids to
volume, without addressing the rate of diffusion move past them by bulk flow, which also acts to re-
within the animal. If we assume that mitochondrial duce the boundary layer, and increases the maxi-
density and activity are uniform across the organ- mum possible size of a spherical organism.
ism, oxygen demand must increase in proportion to
the volume of the animal. However, we know from
the Fick equation that oxygen supply by diffusion is
Very thin animals can rely on diffusion
related to the surface area available for gas ex-
alone for gas exchange
change. Since the ratio of surface area to volume Of course, organisms are not necessarily spheri-
decreases as radius increases, oxygen supply does cal; their bodies may be long and thin, or their
447
Respiratory Systems
body surface may be highly folded so that the re- terrestrial arthropods. Most aquatic invertebrates,
lationships of surface area to volume relevant to terrestrial annelid worms, and some vertebrates
spherical animals no longer apply. Under these such as frogs and salamanders use the second
circumstances, surface area and volume might in- strategy, which is termed cutaneous respiration.
crease equally as the size of the animal increases. The lungless salamanders (family Plethodontidae)
In this case, surface area may be sufficient for dif- are among the largest animals to rely upon cuta-
fusion to supply the oxygen needs of even quite neous respiration. These animals live in moist
large organisms. For example, some soil nema- woodland habitats, and obtain all of their oxygen
todes (roundworms) can be as much as 7 mm long, by diffusion across the skin. The eggs of birds rep-
a few marine species reach 5 cm, and some horse- resent a special case of this respiratory strategy.
hair worms (phylum Nematomorpha) can reach Bird eggs can be extremely large (up to 15 cm in
up to 1 m in length. All of these organisms rely on diameter in the case of an ostrich egg), but all gas
diffusion across their body surfaces for gas ex- exchange with the environment must occur by dif-
change. The marine turbellarian flatworms are fusion through pores in the eggshell.
among the largest of the animals that rely primar- The strategy of cutaneous respiration has sev-
ily on diffusion for gas exchange, reaching as eral limitations. First, the very thin skin necessary
much as 60 cm in length and 20 cm in width. to minimize the diffusion distance and maximize
However, there is an additional factor that the rate of diffusion leaves the animal vulnerable
must be taken into account when considering the to predation or physical damage. Second, because
limitations to diffusion.The time needed for diffu- this thin barrier must remain moist so that dis-
sion increases with the square of the distance over solved oxygen can diffuse into the cell, animals
which a substance must diffuse, according to the that use cutaneous respiration are generally con-
following equation: fined to aquatic or very moist terrestrial habitats.
Third, as a result of these first two constraints, the
t ⫽ x2/4D
surface area of the skin is usually quite limited.
where t is the time needed for a given amount of a Some species that rely on cutaneous respiration
substance to diffuse across distance x, and D is the have skin with unusually high surface area. For ex-
diffusion coefficient for the substance. The net re- ample, the skin of the Lake Titicaca frog (Telmatobius
sult of this relationship is that diffusion occurs culeus) is highly folded to increase the area available
rapidly over short distances, but is extremely slow for gas exchange (Figure 5). Capillaries penetrate
over long distances. None of the species that rely into these skin folds, decreasing the diffusion
solely on diffusion for gas exchange are more than distance between the air and the blood. Similarly,
a few millimeters thick, such that all of the cells of adult male hairy frogs (Trichobatrachus
the body are within about a millimeter of the ex- robustus) develop a series of highly
ternal medium. Organisms that are larger than a
few millimeters in thickness must rely on bulk flow
to transport gases.
Most animals use one of three major

respiratory strategies
Animals that are more than a few millimeters
thick use one of three major strategies to facilitate
bulk flow of gases from the external environment
to every cell in the body: (1) circulating the exter-
nal medium through the body, (2) diffusion of
gases across all or most of the body surface accom-
panied by transport of gases in an internal circu-
latory system, or (3) diffusion across a specialized
Figure 5 Lake Titicaca frog (Telmatobius
respiratory surface accompanied by circulatory culeus) These frogs, which live in a high-altitude lake in
transport (see Figure 1). The first strategy is found Peru, use the skin for gas exchange. The highly folded skin
in the sponges and cnidarians as well as in many surface increases the area of the respiratory surface.
448
Respiratory Systems
vascularized hairlike projections of the skin around water for ventilation, but most species expend en-
their thighs and sides of the body during the mating ergy to actively ventilate their respiratory surfaces.
season, when metabolic demands are highest. Nondirectional ventilation occurs when the
These projections are thought to increase the sur- medium flows past the gas exchange surface in an
face area available for respiration. However, the unpredictable pattern. Animals that wave their gills
strategy of increasing the overall body surface area through the external medium are an example of a
is rather rare. Instead, many organisms confine nondirectional ventilation pattern. Animals with in-
their gas exchange with the environment to a small ternalized gills or lungs often utilize tidal ventila-
region of the body, but greatly increase the surface tion. Tidal ventilation occurs when the external
area of this region. This specialization allows the medium moves in and out of the respiratory cham-
respiratory surface to be moist, thin, and have a ber in a back-and-forth movement, whereas in uni-
large surface area, while allowing the rest of the directional ventilation the respiratory medium
body to be covered with a thick protective layer. enters the respiratory chamber at one point and ex-
Specialized respiratory surfaces can be classi- its via another, causing the medium to flow in a sin-
fied as either gills or lungs. Gills originate as out- gle direction across the respiratory surface.
pocketings (evaginations) of the body surface and The anatomy of the respiratory surface usually
can be external or located within a respiratory determines the type of ventilation that an animal
cavity protected by a flap or other covering. Lungs uses, and thus animals generally do not switch
originate as infoldings (invaginations) of the body from one ventilatory pattern to another. Instead,
surface, forming an internal body cavity that con- animals respond to changes in environmental oxy-
tains the external medium. Gills are most com- gen or metabolic demands by altering the rate or
monly used for gas exchange in water, whereas pattern of ventilation rather than its direction.
lungs are most commonly used for gas exchange Table 2 describes some of these patterns.
in air, but as we discuss later in this chapter, there
are several exceptions to this general rule.
Perfusion of the respiratory surface
affects gas exchange
Gas exchange surfaces are often ventilated Most animals that have specialized respiratory
Most animals ventilate their respiratory surfaces, surfaces also have a circulatory system that
moving the external medium across the surface by moves fluids (such as blood) by bulk flow through
bulk flow. Ventilation of the respiratory surface re- the body. The circulatory system allows oxygen
duces the formation of static boundary layers that from the respiratory surface to be transported
become oxygen depleted, improving the efficiency of across long distances by bulk flow. Just as venti-
gas exchange with the environment. Some animals lating the respiratory surface is important for ef-
with external gills rely on natural movements of the ficient gas exchange, the movement of blood
Table 2 Patterns of ventilation.
Term Definition Examples

Eupnea Normal breathing
Apnea No breathing During diving in air breathers
Hyperpnea Increased ventilation frequency or volume
associated with increased metabolism Exercise
Tachypnea Increased ventilation frequency, usually
with a decrease in ventilatory volume Panting
Dyspnea Difficult, labored, or uncomfortable Anxiety or panic attacks, excessive
breathing exercise, various diseases (e.g., emphysema)
Hyperventilation Increased ventilation in excess of that Anxiety or panic attacks, response to
required to meet metabolic needs blood acid-base disturbance
Hypoventilation Decreased ventilation Asthma, various lung diseases
449
Respiratory Systems
through the respiratory surface can also affect exchange surface can approach that of the inhaled
change efficiency. medium (Figure 6e). As blood flows through the
In animals that utilize nondirectional ventila- gas exchanger it becomes progressively more oxy-
tion, the partial pressure of oxygen (PO2) in the genated, whereas the medium becomes progres-
blood leaving the gas exchanger can approach the sively deoxygenated as it travels in the opposite
PO2 in the medium, if the medium is very well mixed direction. Because the medium and blood are
(Figure 6a). Any factor that increases diffusion dis- flowing in opposite directions, a partial pressure
tance will decrease oxygen exchange efficiency, and gradient that favors diffusion of oxygen into the
reduce the PO2 in the blood leaving the gas ex- blood is maintained across essentially the entire
changer (Figure 6b). For example, if ventilation is gas exchange surface, and the PO2 of the blood
inefficient, an oxygen-depleted boundary layer will leaving the respiratory organ can approach the PO2
form at the respiratory surface, increasing the ef- of the inhaled medium.
fective diffusion distance. Similarly, in vertebrates The efficiency of a countercurrent exchanger
that use cutaneous respiration, the skin is typically depends on the flow rates of the blood and the ex-
much thicker than the lining of other gas exchange ternal medium. Countercurrent exchange of gases
surfaces such as gills or lungs. In these situations, is most efficient when flow of both fluids is rela-
the PO2 in the blood leaving the gas exchanger can tively slow. When flow is rapid or poorly matched,
be much lower than that in the external medium. respiratory systems that use countercurrent flow
Animals that tidally ventilate are generally un- may not differ substantially in efficiency from sys-
able to completely empty their respiratory cavity tems using concurrent flow.
with each ventilatory cycle. As an animal breathes In crosscurrent flow, multiple capillaries are
in, incoming fresh medium mixes with the resid- arranged at an angle to the flow of the external
ual oxygen-depleted medium in the respiratory medium. After they exit the gas exchange surface,
cavity. Thus, the PO2 in the respiratory cavity is these capillaries coalesce into an efferent blood
lower than that of the external medium. The PO2 of vessel (Figure 6f). The PO2 of the efferent vessel
the blood equilibrates with that of the medium in leaving the gas exchange surface is generally
the respiratory cavity. This equilibrated medium is higher than would be seen with concurrent flow,
then exhaled. The PO2 of the blood exiting the gas but lower than that seen with countercurrent flow.
exchange surface in an organism will thus be ap- In a crosscurrent system, the first vessel that
proximately in equilibrium with this exhaled crosses the gas exchange surface encounters a
medium (Figure 6c), if the diffusion distance fully oxygenated medium, yielding a high PO2 in
across the respiratory surface is small. the capillary, but subsequent capillaries en-
With unidirectional ventilation, the blood can counter a progressively oxygen-depleted medium,
flow in one of three ways relative to the flow of the and thus have somewhat lower PO2. The blood
medium. The blood may flow in the same direction mixes as the capillaries merge, reaching a PO2 that
as the medium, in which case it is called is approximately the average of the PO2 of the
concurrent (or cocurrent) flow. Alternatively, the blood in all the capillaries. The exact PO2 in the
blood and medium may flow in opposite direc- blood leaving the respiratory surface with cross-
tions, in which case it is referred to as countercurrent exchange depends on the relative rates of
current flow. Finally, the blood may flow at an flow between the medium and the blood. If the
angle relative to the flow of the external medium, flow of the medium is high relative to the flow of
in which case it is called crosscurrent flow. blood, the PO2 of the medium will not be greatly
Concurrent flow allows the PO2 of the blood to depleted as it travels through the gas exchanger,
equilibrate with the PO2 of the respiratory medium and blood PO2 may begin to approach the PO2 of the
(Figure 6d). As deoxygenated blood enters the gas inhalant medium. In contrast, if the flow of the
exchange surface, it comes into contact with the medium is low relative to blood flow, then the PO2
fully oxygenated external medium. As the blood of the medium will decline sharply across the res-
flows through the gas exchange surface, the PO2 piratory surface and blood PO2 will be lower. Thus,
gradually equilibrates between the two compart- as with countercurrent exchange, crosscurrent
ments and blood PO2 approaches that of the ex- exchange is more efficient than either tidal or con-
haled medium. With countercurrent flow, in current ventilation under only a restricted set of
contrast, the PO2 of the blood leaving the gas ex- circumstances.
450
Respiratory Systems
Flow of medium Inhalant Exhalant

Flow of medium medium medium
Flow of
medium
Respiratory surface Respiratory
Respiratory surface and boundary layer surface
Blood flow Blood flow Blood flow
Inhalant
Exhalant
Medium Medium
Medium
PO2
PO2
PO2
Blood
Blood Blood
Distance Distance Distance

(a) Nondirectional ventilation (fully mixed (b) Nondirectional ventilation (poorly (c) Tidal ventilation
medium and thin respiratory surface) mixed medium or thick respiratory surface)
Flow of medium Flow of medium

Respiratory
surface
Respiratory surface Respiratory surface
Flow of
medium
Blood flow Blood flow Blood flow
Medium Medium Medium
Blood
PO2
PO2
PO2
Blood
Blood
Distance Distance Distance

(d) Concurrent flow (e) Countercurrent flow (f) Crosscurrent flow
Figure 6 Effects of the orientation of the flow (c) In tidally ventilated respiratory structures, and in
of the external medium and the blood on gas unidirectionally ventilated respiratory structures with
exchange efficiency Both the mode of ventilation and concurrent flow (d), the PO2 of the blood approaches that
the orientation of the flow of the respiratory medium and of the exhaled medium. In unidirectional ventilation with
the blood affect the efficiency of gas exchange. (a) In countercurrent (e) or crosscurrent (f) flow, the PO2of the
nondirectional ventilation the PO2 of the blood may approach blood can be higher than that of the exhaled medium.
that of the respiratory medium, if diffusion distance is small. (Adapted from Piiper and Scheid, 1992.)
(b) If diffusion distance increases, efficiency decreases.
451
Respiratory Systems
The difference in solubility of oxygen and car-

bon dioxide also has important implications for the
4. What are the limitations on cutaneous relative levels of carbon dioxide in the blood of air
respiration? and water breathers. Water breathers must venti-
5. What is the difference between a gill and late the respiratory surface at a high rate to obtain
a lung? sufficient oxygen. As a result, they are ventilating
6. Explain why a respiratory structure with more than is necessary to eliminate the carbon
countercurrent flow could exhibit higher dioxide they produce. In contrast, air breathers do
efficiency of gas exchange than a respiratory
not need to ventilate the respiratory surface at such
structure with concurrent flow.
high rates to obtain oxygen, so they do not elimi-
nate as much carbon dioxide as do water
breathers. Because of this relative difference in
Ventilation and Gas Exchange ventilation with respect to carbon dioxide, water
breathers typically have an arterial PCO2 that is al-
Because the physical properties of air and water most 20 times lower than that seen in air breathers.
are substantially different (see Table 1), the strate-
gies animals use to ventilate the gas exchange sur-
face differ in air and water. Most animals that use
water as the respiratory medium have unidirec-
Ventilation and Gas Exchange
tionally ventilated gills, whereas most animals
in Water
that use air as the respiratory medium either have Animals use a variety of strategies for ventilation
tidally ventilated lungs or use a system of air-filled and gas exchange in water. Some aquatic animals
tubes as in insects. circulate the external medium through an internal
From the data in Table 1, you can see that the cavity that penetrates throughout the body (Figure
oxygen content of air is almost 30 times that of wa- 7a). In sponges (phylum Porifera) the beating of
ter at 20°C. Thus, water-breathing animals must flagellated cells called choanocytes moves water
ventilate their respiratory surface nearly 30 times through a series of pores called ostia and into a
more vigorously to move the same amount of oxy- central cavity called the spongocoel. This bulk flow
gen across the respiratory surface as do air-
breathing animals. Water is also much more dense
and viscous than air, and as a result, it takes much Osculum
Spongocoel
more energy to move a volume of water than the
same volume of air. In tidal ventilation, an animal Water Water
must expend energy to reverse the direction of the
medium into and then out of the respiratory cav-
ity. With unidirectional ventilation, an organism Choanocyte Mouth
need only expend energy to move the fluid in a sin-
Gastrovascular
gle direction. Unidirectional ventilation is thus less cavity
Ostia
costly than is tidal ventilation. Unidirectional ven-
tilation also makes possible a countercurrent
arrangement of blood flow, improving oxygen ex-
traction efficiency. For all of these reasons, aquatic
organisms generally have gills that they ventilate
unidirectionally.
For animals that use air as the respiratory (a) Sponge (Porifera) (b) Cnidarian
medium, oxygen availability is high, and the density Figure 7 Circulation of the external medium
of the medium is low, so the cost of ventilation is not through a digestive and respiratory cavity
the primary issue. Instead, these animals face the (a) The body wall of a sponge is full of pores (ostia) that lead
possibility of evaporation across the respiratory into an inner digestive and respiratory cavity called the
spongocoel. The beating of flagellated choanocytes propels
surface, and thus usually have internally located water through the ostia into the spongocoel and out the
gas exchange surfaces such as lungs that allow osculum. (b) Cnidarians use muscular contractions to propel
them to recover much of the evaporating water. water into the mouth and through the gastrovascular cavity.
452
Respiratory Systems
moves the water past essentially all of the cells in Gills

the sponge’s body. Oxygen diffuses from the water (ctenidia)
into the cells, while carbon dioxide diffuses out.

Water then exits the spongocoel via the osculum. Shell
Some flatworms use a similar system. The guts of
Mantle
these species are lined with ciliated flame cells, and cavity
the beating of these cilia moves water containing
oxygen and food molecules throughout the body.
In cnidarians (jellyfish, corals, sea anemones, Foot Water flow
and similar animals) muscle contractions move
water through the mouth into the gastrovascular
cavity (Figure 7b), which extends into all parts of (a) Gastropod mollusc (e.g., aquatic snail)
the body. As water passes the tissues, oxygen dif-
fuses into the cells, while carbon dioxide diffuses Shell
out. Water then flows back out of the gastrovascu- Mantle cavity
lar cavity via the mouth.
Most molluscs ventilate their gills Water flow

using cilia
All molluscs are built around the same generalized
body plan (Figure 8). The mantle, an outfolding of Foot
the body wall, surrounds the rest of the body, en-
closing an internal space called the mantle cavity, (b) Lamellibranch mollusc (e.g., clam)
which contains the gills, or ctenidia. In addition,

the mantle itself may act as a respiratory surface
in some species. In most molluscs, the gills are cil-
iated. Beating of these cilia propels water across
the gills, allowing unidirectional flow of the exter-
nal medium. In many species, blood flow through
the gills is arranged in a countercurrent pattern to
the flow of water. A group of bivalve molluscs Mantle cavity
Gill
known as the lamellibranchs, which includes
Water
clams, mussels, and oysters, have thin, flat, sheet- flow
like gills with multiple filaments that are length- (c) Cephalopod mollusc (e.g., squid)
ened and folded to form a series of W-shaped
structures. The gills in these species can be of the Figure 8 Respiratory systems of molluscs (a)
Aquatic snails ventilate their simple sheetlike gills using
filibranch type (found in mussels, scallops, and cilia. (b) Lammellibranch molluscs such as clams and
oysters), in which each filament is essentially sep- mussels have highly modified gills with pores and internal
arate and attached to the other filaments via small channels. Cilia move the water across the gills by bulk flow.
cross-connections, or they may be of the eu-lamel- (c) Cephalopods ventilate their gills using muscular
contractions of the mantle cavity.
libranch type (found in clams), in which the fila-
ments are fused together to form a nearly
continuous sheet. In a filibranch gill, water can lar contractions of the mantle propel water unidi-
move through the gill between the gill filaments, rectionally through the mantle cavity past the gills,
but in species with eulamellibranch gills the water allowing a countercurrent exchange mechanism
passes through pores, or ostia, in the gill and into to function in the gills. In some species of cephalo-
the water tubes that fill the intralamellar space. pod, water flow through the mantle cavity is used
These water tubes allow higher pumping rates for both respiration and locomotion. By rapidly
than are possible in filibranch gills. expelling water out of the mantle cavity via the
The gills of cephalopod molluscs such as octo- siphon, a cephalopod such as a squid can move by
puses and squid are not ciliated. Instead, muscu- jet propulsion.
453
Respiratory Systems
Crustacean gills are located called the madreporite, and pump this water
on the appendages around the water vascular system to move the
tube feet via a hydraulic mechanism. The thin skin
Crustaceans are the most common of the aquatic
of the tube feet, coupled with the water circulating
arthropods. Filter-feeding species, such as barna-
through them, makes them important sites of gas
cles, or very small species, such as copepods, typ-
exchange. The tube feet of some sea urchins are
ically lack gills, and instead rely on diffusion
specialized for this respiratory function, with a
across the body surface for gas exchange. The gills
countercurrent flow arrangement.
of shrimp, crabs, and lobsters are modified re-
gions of the appendages that are located within a
branchial cavity formed by the hard outer cover- Water flow
ing, or carapace, of the animal (Figure 9). Move-
ments of a specialized appendage, the gill bailer or Madreporite
scaphognathite, propel water out of the branchial

chamber. This movement of water causes a nega-
tive pressure within the branchial chamber, which
then sucks water across the gills. Various crus-
taceans have slightly different water-flow pat-
terns. In shrimp, water enters all along the back Respiratory
papulae
and side edges of the carapace, whereas in cray-
fish and lobsters water enters only at the base of
the legs, and in crabs water enters only at the base
Tube feet
of the claw.
Echinoderms have diverse respiratory

structures (a) Sea star
Echinoderms (sea stars, sea urchins, brittle stars,
sea cucumbers, and their relatives) have diverse
respiratory structures (Figure 10). Most sea stars Mouth
and sea urchins use their tube feet for gas ex-
change. The tube feet are small water-filled tubes
with suction cups on the end that are part of the
complex water vascular system that echinoderms
use for locomotion. Echinoderms suck water into
the water vascular system via a sieved opening
Gut
Scaphognathite
(gill bailer)
Carapace Respiratory
tree
Cloaca
Water
flow Anus
(b) Sea cucumber
Decapod crustacean (crayfish) Figure 10 Respiratory systems of echinoderms

(a) Sea stars use both external gills, called respiratory
Figure 9 Respiratory systems of crustaceans papulae, and the surface of their tube feet for respiration. (b)
Crustacean gills are modified from the appendages, and The respiratory tree of sea cucumbers develops as a pocket
are usually located under the carapace. Beating of the leading off the gut, and thus is an invagination of the body
scaphognathite (gill bailer) propels water anteriorly through surface that should be considered a lung rather than a gill.
the animal and out an opening near the mouth.
454
Respiratory Systems
Sea stars also have external gill-like structures Nostril

called respiratory papulae scattered across their
body surface. The retractable papulae are small
tufted evaginations of the body surface that project Mouth Gill opening
through holes in the dermal skeleton and function Gill sac
as external gills. The outer surfaces of the papulae Nostril Velum
are covered with cilia, which beat and ventilate
the respiratory surface. Cilia on the inner surface
move the internal coelomic fluid by bulk flow, al- Water
lowing countercurrent exchange. Sea urchins lack flow Mouth Gill opening
papulae, but many species have peristomial gills Water
flow
located around their mouths. Like the papulae of
sea stars, these peristomial gills are ventilated by (a) Hagfish (side view and longitudinal section)
the movements of cilia.

Brittle stars and sea cucumbers have a rather Gill openings
different respiratory strategy. Instead of external
gills, their respiratory surfaces are formed by in-
vaginations of the body surface, and thus should
more properly be termed lungs. In the brittle stars, Mouth (with grasping teeth)
these saclike structures are termed bursae, and Water Mouth Pharynx Gill pouch
open to the exterior of the body near the mouth via flow
small slits. The opening of a bursa is usually cili-
ated, and the beating of these cilia ventilates the Nonfeeding
respiratory surface. Many sea cucumbers have
particularly elaborate invaginated respiratory Water flow
sacs called respiratory trees that connect to the
cloaca, a portion of the intestine near the anus
Feeding
(Figure 10b). Muscular contractions of the cloaca
propel water into the trunks and branches, and
then the respiratory tree itself contracts to expel (b) Lamprey (side view and longitudinal section)
water back into the cloaca. Sea cucumbers use this
tidally ventilated lung to supplement cutaneous Figure 11 Respiratory systems of jawless
fishes (a) Hagfish ventilate their gills using a muscular
gas exchange. velum. Movements of the velum propel water through the
mouth across the gills, and out via one or more gill openings.
Flow through the gill sacs is unidirectional. (b) Lampreys
Feeding lampreys ventilate have multiple gill pouches, each with an external opening.
their gills tidally Expansion and contraction of the gill pouches ventilates the
gills. When the lamprey is feeding (and possibly at other
Lampreys and hagfish have multiple pairs of gill times as well) ventilation of the gill pouches is tidal, with
sacs, located toward the anterior end of the body water entering and leaving the gill pouches via the external
(Figure 11). In the case of hagfish, a muscular opening.
pumping structure called the velum propels water
through the respiratory cavity. Water enters the the pharynx, and then through the gill pouches
pharynx via the single dorsal nostril, and then and out via the outer gill openings. However, adult
travels through the gill pouches and out via one or lampreys are parasitic and feed by tightly attach-
more pairs of outer gill openings (depending on ing their round suckerlike mouth to the skin of a
the species). Flow through the gill pouches is uni- host species such as a bony fish, using their mul-
directional, and blood flow is arranged in a coun- tiple grasping teeth. The lamprey then secretes a
tercurrent pattern relative to the water flow. substance that dissolves the host tissue, and feeds
Ventilation in nonfeeding lampreys is thought on the dissolved tissue and blood. When feeding, a
to be similar to that in hagfish, since lampreys also lamprey cannot ventilate its gills by unidirectional
have a velum that can pump water unidirection- flow of water through the mouth. Under these cir-
ally across the gills. Water flows via the mouth into cumstances, the lamprey pumps water into the
455
Respiratory Systems
gills via the outer gill openings, and then back out past the gills and out via the external gill slits. Thus,
the same way. Thus, a feeding adult lamprey ven- the buccal cavity in this species acts as both a suc-
tilates its gills tidally. The lamprey may continue to tion pump and a force pump. Together, these two
use this tidal ventilation between bouts of feeding, phases of pumping action cause unidirectional but
or may convert to unidirectional ventilation pulsatile flow across the gills. Blood flow through
through the mouth during nonfeeding periods. the gills is arranged in a countercurrent fashion, in-
creasing the efficiency of gas exchange.
Elasmobranchs use a buccal pump
for ventilation Teleost fishes use a buccal-opercular
The elasmobranchs (sharks, skates, and rays) ven- pump for ventilation
tilate their branchial chambers by expanding the In a teleost fish the gills are located in the opercu-
volume of the buccal (mouth) cavity (Figure 12). lar cavities, chambers leading from the buccal
This increase in volume sucks fluid into the buccal cavity that are protected by the flaplike
cavity via the mouth and the spiracles, a pair of operculum (Figure 13a). Water flows from the
nostril-like structures on the top of the head. The mouth through the buccal cavity and into the op-
animal then closes its mouth and spiracles, and the ercular cavity, and then out through the slit
muscles surrounding the buccal cavity contract, re- formed by the operculum. Figure 13b shows the
ducing the volume of the cavity and forcing water ventilatory cycle in a typical teleost fish. The first
step in ventilation occurs when the fish lowers the
floor of the buccal cavity while its mouth is open.
This increase in the volume of the buccal cavity re-
sults in a decrease in pressure below that of the
external medium, sucking water into the buccal
Water
flow cavity via the mouth. During this phase the oper-
culum is closed, a skeletal muscle pump expands
the volume of the opercular cavity, and the pres-
sure in the opercular cavity decreases such that
Mouth the opercular cavity pressure is below that in the
buccal cavity. Thus, there is little or no backflow
Spiracle
from the opercular cavity into the buccal cavity
during this phase. During the next phase of the
ventilatory cycle, the fish closes its mouth and
raises the floor of the buccal cavity. This move-
Water ment decreases the volume of the buccal cavity, in-
flow
creasing the pressure and pushing water into the
Gill expanded opercular cavity. In the next phase of
the ventilatory cycle the fish opens its operculum,
causing water to flow from the buccal cavity,
Gill through the opercular cavity, and out into the en-
septum
vironment via the opercular slit. At this stage, the
operculum moves inward and begins compressing
the opercular cavity, increasing the pressure in the
Gill opercular cavity and forcing water out via the
slit open opercular valve. At this point, the pressure
within the buccal cavity is still high, so there is lit-
Shark’s head (horizontal section)
tle or no backflow from the opercular cavity to the
Figure 12 Respiratory system of sharks buccal cavity. The final phase of the ventilatory cy-
To inhale, a shark expands the volume of the buccal cavity, cle, which occupies only a small fraction of the to-
and the resulting decrease in pressure sucks water into the
buccal cavity via the mouth and spiracles. The shark then
tal ventilatory cycle, occurs when the fish again
closes its mouth and raises the floor of the buccal cavity, opens its mouth and begins to expand the buccal
forcing water across the gills. cavity. At this point, the operculum is still com-
456
Respiratory Systems
Mouth
Operculum
(covers gills)
Buccal cavity
Mouth
Operculum
Gill arches Opercular cavity
(under Gill
operculum) arch
Opercular
valve
(a) Teleost fish (lateral view and horizontal section)
Water Water
enters enters
buccal Opercular Water enters Water flows buccal
cavity cavity opercular out of cavity
expands, cavity opercular
pressure cavity
drops
Some
backflow
1 • Mouth open 2 • Mouth closed 3 • Mouth closed 4 • Mouth open

• Opercular valve • Opercular valve • Opercular valve • Opercular valve
closed closed open open
• Buccal cavity • Buccal cavity • Buccal cavity • Buccal cavity
expanded compressed compressed expands
• Opercular cavity • Opercular cavity • Opercular cavity • Opercular cavity
expands expanded compressing compressed
(b) Ventilatory cycle of teleosts
Figure 13 Respiratory systems of teleost fish (a) The gills of a teleost fish are
located within the opercular cavity, underneath a muscular flaplike cover called the operculum.
(b) Teleost fish use a buccal-opercular pump that ensures unidirectional and almost continuous
flow across the gills.
pressed, and pressure in the opercular cavity is the careful coordination of the action of the buccal
high. The high opercular pressure continues to and opercular pumps. In general, the opercular
force water out into the environment via the pump sucks while the buccal pump fills, and the
opened opercular valve, but because of the low- buccal cavity pumps when the opercular cavity
ered pressure in the buccal cavity there may be empties, reducing the possibility of backflow.
some backflow of water from the opercular cavity If a fish swims forward with its mouth open,
into the buccal cavity. The opercular and buccal water will flow across the gills without active
cavities then reset to their starting positions. Al- pumping by the muscles surrounding the buccal
though there may be brief periods of backflow in and opercular cavities. This strategy, termed ram
the last phase of the ventilatory cycle, flow is gen- ventilation, is used by many active fish species,
erally unidirectional and almost continuous including tunas and some species of sharks. Ram
through most of the ventilatory cycle because of ventilation is highly efficient because the fish does
457
Respiratory Systems
not use energy to ventilate the respiratory surface, illaries of the secondary lamellae is arranged in a
although this strategy may increase the drag on countercurrent pattern relative to the flow of wa-
the fish and thus increase the cost of locomotion. ter through the gills. When the flows through this
system are properly matched, oxygen extraction
from the water can reach as high as 70%.
Fish gills are arranged for The number of gill filaments and lamellae, and
countercurrent flow thus the total gill surface area, varies substantially
Teleost fish have complex gills with a very large among species of fish. More active species tend to
surface area for gas exchange (Figure 14). There have more lamellae and a larger surface area than
are four gill arches in each opercular cavity. The do less active species.
gill arches provide structural support for the two
rows of gill filaments that project from each gill
arch in a V shape. The tips of the filaments from
the adjacent arches overlap slightly, so that the
whole gill forms a sieve. Each filament is covered 7. What kinds of structures can water-breathing
with rows of interdigitated folds called secondary animals use to ventilate their respiratory
surfaces?
lamellae, which are perpendicular to the filament.
These thin-walled structures are highly vascular- 8. What is ram ventilation?
ized and are covered with a thin sheet of epithelial 9. Outline some of the structures or mechanisms
that allow the gills of teleost fishes to have very
cells that acts as the primary respiratory surface.
high gas exchange efficiency.
Each gill arch contains an afferent and an ef-
ferent blood vessel. The afferent blood vessel
branches into a series of afferent filament vessels
that travel down the filaments, carrying blood to
the respiratory surfaces. The afferent filament
Ventilation and Gas Exchange in Air
vessels then branch into many capillaries where Animals evolved in aquatic habitats, and thus air-
gas exchange takes place. The capillaries then breathing animals evolved from water breathers.
converge into an efferent filament vessel that car- In this chapter we examine two of the major ani-
ries oxygenated blood back to the efferent blood mal lineages that have colonized terrestrial habi-
vessel in the gill arch. Blood flow through the cap- tats: the vertebrates and the arthropods.
Opercular
cavity
Water Gill arches

flow
Primary
Gill arch Secondary
Afferent lamella
blood lamella
vessel Secondary
lamella
Efferent
blood
vessel
Water Direction
flow Direction of flow in
of flow in afferent
Gill arch Water capillaries vessel
flow Direction
Secondary Afferent of flow in
lamella Efferent vessel efferent
vessel vessel
Figure 14 Structure of a teleost gill
458
Respiratory Systems
Arthropods use a variety of mechanisms

for aerial gas exchange
The respiratory systems of the terrestrial and
semiterrestrial crabs are similar in many ways to
those of their marine relatives. Like marine crus-
taceans, these animals have gills located in a Spiracles
of book
branchial cavity, but the gills of terrestrial crabs lung
are stiff so that they do not collapse in air. In addi-
tion, the walls of the branchial cavity are often thin
and highly vascularized, acting as the primary site
of gas exchange in some species. Terrestrial crabs
ventilate their branchial cavity in much the same
way as do their aquatic relatives; beating of the Lamellae
scaphognathite propels air in and out of the of book lung
branchial chamber. In some terrestrial crabs, such

as the porcelain crabs (genus Petrolisthes), the
walking legs serve as an accessory respiratory Spiracle
surface. The carapace on part of the walking legs Figure 15 The book lungs of chelicerates Book
is very thin, allowing gas exchange. lungs are composed of a series of thin plates called lamellae.
Among the crustaceans, the terrestrial isopods Oxygen from air diffuses across the surface of the lamellae
(such as woodlice and sowbugs) have the most ex- into the hemolymph.
tensive specializations for gas exchange with air.
In some species, such as the seashore isopod with complex tracheal systems generally make lit-
Ligia, a thick layer of chitin on one side of the gill tle use of their circulatory systems for gas trans-
provides support, while the other side is a very port. Instead, oxygen diffuses in gaseous form
thin wall specialized for aerial gas exchange. In down the trachea and then dissolves in the inter-
other species, such as Armadillidium, the anterior stitial fluid before diffusing into the tissues. The
gills are modified and contain many branching normal body movements of a spider cause
air-filled tubules called pseudotrachea. Oxygen in changes in the pressure inside the body cavity,
gaseous form diffuses down the pseudotrachea which may help to ventilate the trachea. However,
and dissolves in the interstitial fluid. The circula- other scientists suggest that these movements in-
tory system then carries this oxygen to all parts of terfere with gas transport down the trachea, and
the body. may reduce ventilation.
Most of the air-breathing chelicerates (spiders, Some myriapods (centipedes and millipedes)
scorpions, and their relatives) have four book have tracheal systems similar to those in spiders,
lungs located within the body cavity (Figure 15). but the most extensive tracheal systems are found
Book lungs are derived from the book gills of in insects. As in chelicerates, the tracheal system
aquatic chelicerates such as horseshoe crabs. of insects is open to the outside air via a series of
Book lungs consist of a series of 10–100 very thin spiracles, which lead to the air-filled tracheae
lamellae that project into an air-filled cavity inside (singular: trachea) that penetrate deep into the
the body that opens to the outside via a spiracle. body (Figure 16). The tracheae branch and divide,
Air diffuses into the cavity via the spiracle and terminating in tiny thin-walled structures called
then across the walls of the lamellae into the he- tracheoles, which can be as small as 0.2 µm in di-
molymph, which then carries the oxygen through ameter. The ends of the tracheoles are filled with
the body. circulatory fluid called hemolymph. Oxygen dis-
In many spiders, the anterior pair of book solves in this fluid, and then diffuses across the
lungs is replaced by a tracheal system, consist- thin walls of the tracheoles.
ing of a series of air-filled tubes. Some species There is no clear functional distinction be-
(such as the Solifugae, or sun spiders) lack book tween tracheae and tracheoles, but they differ
lungs entirely and have only a tracheal system structurally and in size. Tracheae are relatively
that penetrates into all parts of the body. Species large tubes that are formed by joining together
459
Respiratory Systems
Fluid filled piratory systems are not very effi-

Tracheoles cient for gas exchange in water. In-
sects that have colonized aquatic
habitats use a variety of mechanisms
Trachea Trachea
to avoid using water as the respira-
tory medium (see Box 1, Evolution
and Diversity: Respiratory Strategies
of Aquatic Insects).
Spiracle Spiracle
Many insects actively ventilate
Muscle
the tracheae
Figure 16 Insect tracheal systems Air enters the tracheae via the The high diffusion coefficient of oxy-
spiracles and travels down the progressively branching tubes to the tracheoles. gen in air allows oxygen to diffuse
Oxygen then dissolves in the extracellular fluid within the tracheoles and diffuses into through the tracheal system and still
the tissues. support the metabolic needs of most
species of insects. However, many in-
several epithelial cells. In many species, the walls sects also ventilate the tracheal system actively ei-
of the tracheae are reinforced by structures called ther through contractions of the abdominal
taenidia. These thin bands of cuticle are wrapped muscles or through movements of the thorax.
in a spiral pattern around the walls of the tra- When the abdominal muscles contract, the volume
cheae. In some species, portions of the tracheae of the abdomen decreases, forcing air out of the
lack taenidia, and instead form air sacs, which are tracheae. When the muscles relax, the abdomen
involved in ventilating the tracheal system in these springs back to its normal volume, decreasing the
species. In contrast, tracheoles are formed by hol- pressure within the tracheae, and causing air to
lowing out a single cell, and thus have a wall that move into the tracheae by bulk flow. Similarly, in
consists only of two layers of cell membrane. Tra- the thorax as the wings beat, the thoracic muscles
cheoles are so numerous that an insect cell is sel- contract and relax, changing the volume of the tra-
dom more than a few hundred micrometers, or a cheae within the thorax, which causes the air to
few cell diameters, away from the nearest trache- move in and out of the tracheae by bulk flow. Oxy-
ole. In fact, in metabolically active cells such as gen then diffuses into the tracheoles, as is the case
flight muscle, tracheoles are located within invagi- in species that do not ventilate the tracheae.
nations of the muscle cell membrane. As a result, The direction of airflow through the tracheal
the average distance between tracheoles may be system varies among insects. Insects with rela-
as little as 3 µm. The walls of insect tracheoles are tively simple tracheal systems use tidal ventilation;
very thin, have an extremely high surface area, in others, the flow through the tracheae is unidi-
and are always moist—characteristics required rectional. For example, in cockroaches and locusts
for high-efficiency gas exchange. But because of air enters the anterior spiracles, passing through
these factors the tracheoles are also a potential large longitudinal tracheae and exiting the body
site for water loss, increasing the danger of desic- via the abdominal spiracles at the rear of the body.
cation, particularly in arid environments. In many This unidirectional ventilation may increase the
species of insects the spiracles can be opened and efficiency of gas exchange by providing a continu-
closed, which seals the tracheal system off from ous supply of fresh air to the respiratory surfaces,
the environment part of the time, potentially re- although even in these insects the smaller tra-
ducing water loss. cheae that branch off the large longitudinal tra-
Tracheal systems provide high-efficiency gas cheae are still ventilated tidally. Some flying
exchange in air because of the high diffusion coef- insects, such as cerambycid (or long-horned) bee-
ficients of gases in air compared to water. In fact, tles, take advantage of ram ventilation, which is
tracheal systems have evolved independently in also called draft ventilation in insects, to ventilate
several groups of terrestrial arthropods, suggest- the large longitudinal tracheae.
ing that there has been strong natural selection for Recent observations of living insects, using a
tracheal-like systems in air. However, tracheal res- novel technique called synchrotron X-ray imaging,
460
Respiratory Systems
suggest that the volume of the tracheae can substantially revise our understanding of how in-
change by as much as 50% in a rapid cycle of ex- sects obtain oxygen from the environment.
pansion and compression that occurs every one to Some insects use a ventilatory pattern known
two seconds (Figure 17) and that cannot be ac- as discontinuous gas exchange, particularly
counted for by changes in the volume of the ab- when they are at rest. Discontinuous gas exchange
domen or thorax. The resulting pressure changes occurs in three phases (Figure 18). During the first
within the tracheae move the air by bulk flow. This phase, called the closed phase, the spiracles re-
recently discovered, and entirely unanticipated, main shut, preventing gas exchange with the envi-
mechanism of respiration in insects is likely to ronment. As a result, the oxygen partial pressure
in the tracheoles drops as the mitochondria con-
sume oxygen. However, the partial pressure of
carbon dioxide does not increase nearly as much,
because the carbon dioxide produced by metabo-
lism reacts with water in the interstitial fluid to
form bicarbonate (HCO3⫺). This decline in oxygen
without an increase in carbon dioxide causes a
slight decrease in the total gas pressure within the
tracheae. During the next phase of the respiratory
cycle, called the flutter phase, the spiracles open
and close many times in rapid succession. The low
pressure within the tracheae causes air to enter
the insect’s body, moving by bulk flow down the
resulting pressure gradient. Eventually, as carbon
dioxide accumulates, and can no longer be stored
as HCO3⫺, the partial pressure of carbon dioxide
(a) begins to increase. At this point in the respiratory
cycle, the spiracles open completely, and carbon
dioxide is rapidly released.
The adaptive significance of discontinuous gas
exchange is a matter of active debate among insect
physiologists, and three main hypotheses have
been advanced to explain it.
• Discontinuous gas exchange may facilitate
tracheal ventilation by causing low total gas
pressure within the tracheae, or by induc-
ing a low PO2 that increases the PO2 gradient
between the tracheae and the environment,
assisting the diffusion of oxygen into the an-
imal. This could be particularly important
in insects that spend all or part of their life
(b)
cycle underground where environmental
PO2 is low and PCO2 is high.
Figure 17 X-ray synchrotron images of insect
tracheae A synchrotron, an instrument that can generate • Discontinuous gas exchange may help to
an extremely bright beam of light, can be used to generate minimize water loss across the tracheae,
high-resolution X-ray videos. Using this technique, scientists because water will be lost from the tracheae
have been able to visualize the movements of insect only during the short open phase of the res-
tracheae. In some species, the tracheae undergo rapid cycles
of expansion and contraction that are independent of piratory cycle.
movements of the rest of the body. These movements help to • Discontinuous gas exchange may protect in-
ventilate the tracheae. sects from the harmful effects of oxygen. Al-
(Reprinted with permission from Westneat, M. W. et al. 2003. Tracheal
respiration in insects. Science 299 (5606): 588–560. Copyright 2003 though oxygen is necessary for most animal
AAAS.) life, it is also a highly reactive chemical that
461
Respiratory Systems
Closed Flutter Open within the fishes. As a result of these

independent evolutionary events, fish
use a variety of structures for aerial
Rate of CO2 release
(mmol/g per min)
300
gas exchange. For example, mud-
skippers have specialized “rein-
150 forced” gills that do not completely
collapse in air, allowing some limited
0
gas exchange when the fish is out of
water. Many fish have specialized
atmospheric pressure)
Intratracheal pressure
accessory breathing organs that they

(kPa) (relative to
0 use in addition to, or instead of, gills

when breathing air. Electric eels use
–0.25 the mouth and pharyngeal cavity for
gas exchange. The inside of the
–0.5 mouth is highly vascularized, allow-
ing substantial gas exchange. Some
fish, including the armored catfish
(Liposarcus anisitsi), have a highly
PO2 in trachea
20 modified and vascularized stomach

(kPa)
15 that they use for aerial gas exchange.

10
Many air-breathing fish, including
5
bichirs (Polypteriformes), use spe-
1 2 4 6 cialized pockets off the gut for gas
Time (h) exchange.
Figure 18 Discontinuous gas exchange cycles in insects Some Lungfish have the most highly
insects keep their spiracles closed for long periods, only opening them briefly for gas developed air-breathing organ of
exchange. any fish. These lungs are highly
(Adapted from Hetz and Bradley, 2005.) complex, covered in folds and pock-
ets that increase their surface area.
can damage tissues. When an insect’s spir- There are three living genera of lungfish. The Aus-
acles are fully open, fresh air can diffuse tralian lungfish (Neoceratodus) has a single lung
deep into the body, and the PO2 at the ends and relatively well-developed gills, whereas the
of the tracheole approaches 20 kPa. In the African lungfish (Protopterus) and South Ameri-
vertebrates, internal tissues are seldom ex- can lungfish (Lepidosiren) have bilobed lungs and
posed to PO2 greater than 0.5 kPa, and expo- reduced gills. In addition to their highly developed
sure to high PO2 can cause tissue damage. lungs, lungfish have a two-circuit circulatory sys-
During discontinuous ventilation the tissues tem with a separate pulmonary circuit. This al-
are only exposed to high PO2 during the lows lungfish to separate oxygenated blood
short open phase, whereas tracheal PO2 re- coming from the pulmonary system and deoxy-
mains low during the rest of the ventilatory genated blood coming from the tissues. Animals
cycle. similar to lungfish are thought to be the common
ancestor of the tetrapods (amphibians, reptiles,
Further research is needed to determine
birds, and mammals).
which, if any, of these hypotheses accounts for the
Air-breathing fish ventilate their breathing or-
evolution of discontinuous gas exchange in insects.
gans using a buccal force pump similar to those of
other fishes (Figure 19). They drop the floor of the
buccal cavity, and the increase in volume causes a
Air breathing has evolved multiple times drop in pressure that draws air into the mouth. By
in the vertebrates closing the mouth and raising the floor of the buc-
Almost 400 species of extant fish are thought to ob- cal cavity, the fish then forces air down into the
tain all or part of their oxygen from air, and air breathing organ. In essence, air-breathing fish
breathing is thought to have evolved multiple times simply swallow air.
462
Respiratory Systems
Air Pneumatic
duct
Expand
buccal
cavity
Anterior
chamber of air-
breathing organ
Posterior
chamber of air-
breathing organ
1 • Mouth open 2 • Mouth closes 3 • Mouth closed 4 • Mouth closed

• Buccal cavity • Buccal cavity • Anterior chamber • Anterior chamber
expands compresses closed opens
• Air enters • Air enters anterior • Posterior chamber • Anterior chamber
buccal cavity chamber of air contracts contracts
breathing organ • Spent air exhaled • Air flows into
from posterior posterior chamber
chamber • Gas exchange
• Air exits via the occurs
operculum
Figure 19 The ventilatory cycle in an air-breathing fish
Amphibians ventilate their lungs exhaled stale air with the fresh air held in the buc-
using a buccal force pump cal cavity because inhaled air is held at the bottom
Amphibians use cutaneous respiration, external of the buccal cavity, while exhaled air flows out
gills, lungs, or some combination of these three through the upper regions of the buccal cavity.
methods of gas exchange depending on whether However, the exact degree of mixing is a matter of
they are obtaining oxygen from water or from air. some debate. The nares then close and the floor of
Amphibians have relatively simple bilobed lungs the buccal cavity rises, forcing air from the buccal
that form as outpocketings of the buccal cavity. In cavity into the lungs. The glottis then closes as a
some species they may be nothing more than a result of muscular contractions, sealing off the
pair of thin-walled, highly vascularized sacs; how- lungs and preventing air from escaping, allowing
ever, in the terrestrial frogs and toads the inner time for gas exchange.
surface of the lungs can be highly folded or divided Amphibians are typically intermittent breath-
by partitions called septa, which give the lungs a ers. They often pause for a substantial period be-
honeycombed appearance and increase the sur- fore beginning the respiratory cycle again. During
face area available for gas exchange. the time that the lungs are sealed off by the glottis,
An amphibian ventilates its lungs using a buccal a frog may pump air in and out of the buccal cavity
force pump, similar to that used by air-breathing multiple times. In fact, amphibians have a diverse
fish. In the first step of ventilation, the frog ex- ventilatory repertoire. The steps outlined above
pands its buccal cavity, drawing air in through the constitute a balanced breath, in which a roughly
open nares (nostrils) (Figure 20). At this point in equal amount of air leaves and then enters the
the ventilatory cycle, the glottis, a muscular ori- lungs with each ventilatory cycle. But amphibians
fice that acts as a valve for the lungs, is closed. As can also undergo inflation breaths, in which the
a result, the fresh air is held in a pocket of the buc- lung deflation step (Figure 20, step 2) is reduced or
cal cavity. The frog may make repeated buccal absent, or deflation breaths, in which more air
movements to fully refresh the air within the buc- leaves the lungs than is pumped back. Further in-
cal cavity. Next, the glottis opens. Elastic recoil of creasing the complexity of amphibian breathing,
the lung pushes the spent air into the buccal cav- there are some amphibian species in which the or-
ity and out the mouth and nares. Muscle contrac- der of the steps differs. For example, aquatic toads
tion in the chest wall may assist in this exhalation. such as Xenopus first empty both the lungs and the
There is thought to be relatively little mixing of the buccal cavity through the open glottis and nares,
463
Respiratory Systems
Nares Nares
(open) Buccal Glottis Glottis (closed) Glottis Glottis
cavity (closed) (open) (open) (closed)
Air Lung
Mouth
1 • Air enters pocket 2 • Glottis opens 3 • Nares close 4 • Glottis closes

of buccal cavity • Elastic recoil of • Floor of buccal • Gas exchange
lungs and cavity rises occurs in lungs
compression of • Air is pushed
chest wall reduces into lungs
lung volume
• Air forced out of the
lungs and out the

nares
Figure 20 The ventilatory cycle in a frog
then draw fresh air into the buccal cavity with the ing the pressure and causing air to enter the lungs.
glottis closed, and finally pump this air into the During expiration (exhalation), the volume of the
lungs with the glottis open and the nares closed (es- chest cavity decreases, increasing the pressure
sentially performing the steps in Figure 20 in the and causing air to exit the lungs.
order 2, 1, 3, 4). Reptiles use one of several mechanisms to
change the volume of the chest cavity during
Reptiles ventilate their lungs breathing (Figure 21). Snakes and lizards use the
using a suction pump intercostal muscles, which are located between
Most reptiles have two lungs, although in snakes the ribs. Contraction of a group of the intercostals
one of the lungs may be highly reduced or absent. lifts the ribs forward and outward, increasing the
The simplest, or unicameral, lung is a saclike volume of the chest cavity, sucking air into the
chamber with a honeycombed wall, similar to the lungs. In lizards, the intercostal muscles are also
most complex amphibian lungs. In highly active needed for locomotion; when a lizard runs it
species such as monitor lizards, as well as the moves its body back and forth laterally in an S-
turtles and crocodilians, the lungs are divided shaped pattern, a movement that involves the in-
into many chambers, greatly increasing the sur- tercostal muscles. Thus, the muscle contractions
face area available for gas exchange. Each of needed for locomotion may compromise lung ven-
these multicameral lungs has a stiffened tube tilation in some species. However, some lizards
called a bronchus (plural: bronchi) that allows are known to supplement ventilation with a buc-
airflow into the chambers of the lung. In some cal force pump similar to that used by amphib-
reptiles, the posterior part of the lungs is poorly ians, particularly during locomotion.
vascularized, and may act as a bellows to help in In turtles and tortoises (Figure 21b), the rib
lung ventilation. cage is fused to the rigid shell, and cannot be
Reptiles rely on aspiration (suction) pumps to moved to ventilate the lungs. Instead, these ani-
ventilate their lungs, rather than forcing air into mals have a pair of sheetlike abdominal muscles
the lungs using a buccal pump. This important that expand and compress the lungs. In addition,
evolutionary innovation separates the muscles movements of the limbs may assist in lung venti-
used in feeding from the muscles used in ventila- lation. However, as with the lizards, during loco-
tion and is also seen in birds and mammals. In all motion there may be some conflicts between the
of these groups, the ventilatory cycle is divided motions needed for ventilation and those needed
into two phases. During inspiration (inhalation), for locomotion. Turtles are not known to use a buc-
the volume of the chest cavity increases, decreas- cal force pump to assist in ventilating the lungs.
464
Respiratory Systems
In crocodilians (Figure 21c), a sheet of connec- the pressure in the lungs, and the resulting suction
tive tissue called the hepatic septum is tightly at- draws air into the lungs. In essence, the liver acts
tached to the anterior side of the liver, and divides like a piston that helps to alternately compress and
the visceral cavity into an anterior and a posterior expand the lungs.
space. The paired diaphragmaticus muscles run
from the hepatic septum to the pelvic girdle. When
Birds unidirectionally ventilate their lungs
these muscles contract, they pull on the hepatic In birds, the lung itself is stiff and undergoes little
septum and the liver, decreasing the volume of the change in volume during the ventilatory cycle. In-
abdominal cavity, and increasing the volume of stead, a series of flexible air sacs associated with
the lungs. This increase in lung volume decreases the lungs act as bellows (Figure 22a). Air enters
Inhalation: ribs move Exhalation: ribs move Primary bronchus

forward and outward, backward and inward, Syrinx
thorax expands thorax compresses
Lung
Airflow Airflow Trachea
Trachea
Lung Intercostal Anterior

muscles air sacs
(a) Lung ventilation in lizards
Posterior
air sacs
Movements of
Lung Carapace abdominal muscles
and limbs change
volume of thorax (a)
Ventrobronchus
Airflow Parabronchi
Trachea Plastron
(b) Lung ventilation in chelonians (turtles and tortoises)
Contraction and relaxation

of diaphragmaticus Bronchus
changes volume of thorax
Thoracic cavity Abdominal cavity Dorso-

bronchus
Blood
flow
Airflow Lung Hepatic Liver Posterior

Pelvic air sacs
septum Air
girdle Airflow in
Diaphragmaticus capillary
parabronchus
(c) Lung ventilation in crocodilians
(b)
Figure 21 Lung ventilation in reptiles
(a) Lizards ventilate their lungs using their intercostal Figure 22 Structure of bird lungs The respiratory
muscles. (b) Chelonians ventilate their lungs using system of birds consists of a pair of rigid lungs and a series of
movements of specialized abdominal muscles and the limbs. highly extensible air sacs. The stiff lung is made up of
(c) Crocodilians ventilate their lungs using the hexagonal arrays of parabronchi. Extensions of the
diaphragmaticus muscles. parabronchi, called air capillaries, are the site of gas exchange.
465
Respiratory Systems
the respiratory system via the nares and mouth, the lungs. The next inhalation causes this air to
passing down the cartilage-reinforced trachea. At move from the lungs into the anterior air sacs.
the syrinx, which acts as the bird voicebox, the Then, on the next exhalation, the air moves from
trachea divides into two primary bronchi, with the anterior air sacs back into the trachea and out
one bronchus leading to each lung. As the bronchi the mouth or nares. Note that although we have
enter the lungs they branch into secondary separated the ventilatory cycle into four steps for
bronchi, termed the dorsobronchi, and then into clarity, these processes actually occur simultane-
smaller tubes called parabronchi that are ously. Both sets of air sacs inflate during inhala-
arranged in parallel in a hexagonal array. The tion, but fresh air from the environment moves
parabronchi then lead into secondary bronchi into the posterior air sacs, while stale air from the
called the ventrobronchi, and back into the pri- lungs moves into the anterior air sacs. During ex-
mary bronchi (Figure 22b). The walls of the halation, both sets of air sacs deflate, and fresh air
parabronchi are folded to form hundreds of tiny from the posterior air sacs moves into the lungs,
blind-ended structures called air capillaries, while stale air from the anterior air sacs is exhaled
which are richly vascularized and act as the site of out the nares and mouth.
gas exchange. Air diffuses from the parabronchi Bird lungs are extremely efficient, and can ex-
into the air capillaries, and then into the blood. tract a high percentage of oxygen from the air. In
The thin walls of the air capillaries present a min- fact, the PO2 of the blood leaving the lungs is typi-
imal barrier to gas exchange by diffusion. cally higher than the PO2 of the exhaled air. As we
In birds, ventilation of the lungs requires two discussed earlier in the chapter, only a countercur-
cycles of inhalation and exhalation. Because of this rent or crosscurrent flow pattern in the lungs could
ventilatory pattern, airflow across the respiratory account for this observation. To distinguish be-
surfaces of the lungs is unidirectional and almost tween these possibilities, respiratory physiologists
continuous. Figure 23 follows a single breath of air experimentally reversed the direction of airflow
as it moves through the bird’s respiratory system. through a bird lung. If the flow was in a countercur-
A bird inhales by expanding the volume of its chest rent arrangement, reversing the flow of air should
using the rib muscles and muscles attached to the have greatly decreased the oxygen extraction effi-
sternum (breastbone). This movement increases ciency. Instead, the PO2 of the blood leaving the lung
the volume of the air sacs, and decreases the pres- was always higher than the PO2 of the exhaled air,
sure within them. Air flows through the trachea regardless of the direction of airflow. This observa-
and bronchi down this pressure gradient, and tion demonstrates that blood flow in a bird lung is
moves primarily into the posterior air sacs. Next, arranged in a crosscurrent pattern, providing high
the bird exhales by compressing its chest, increas- oxygen extraction efficiency. Such efficiency may be
ing the pressure within the air sacs. This pressure needed to power flight, and may play a role in the
gradient moves air from the posterior air sacs into ability of birds to tolerate high altitudes.
Air
Trachea
Lung
Anterior
air sacs
Expansion Compression Expansion Compression

of chest of chest of chest of chest
Posterior
air sacs
1 Expansion of the chest 2 Compression of the 3 Expansion of the chest 4 Compression of the
during the first chest during the first during the second chest during the
inhalation causes fresh exhalation pushes the inhalation causes stale second exhalation
air to flow through the fresh air from the air to flow from the pushes stale air from
bronchi to the posterier air sacs into lungs into the anterior the anterior air sacs
posterior air sacs. the lungs. air sacs. out via the trachea.
Figure 23 The ventilatory cycle in a bird
466
Respiratory Systems
The alveoli are the site of gas exchange lower respiratory tract consisting of the bronchi and
in mammals gas exchange surfaces (Figure 24). Air enters the
lungs via the mouth and nares, passing through
The mammalian respiratory system is located
the pharynx and larynx, and then entering the
within the chest cavity, or thorax, and is divided into
cartilage-reinforced trachea. The trachea branches
an upper respiratory tract, consisting of the mouth,
into two primary bronchi, which branch into suc-
nasal cavity, pharynx, larynx, and trachea, and a
cessively smaller tubes called the secondary and
Nasal tertiary bronchi, and then bronchioles. The bron-
cavity Bronchi Bronchiole
chioles terminate in thin-walled, blind-ended sacs
Trachea Diaphragm
called alveoli that are the site of gas exchange.
Nares
The alveolar epithelium is composed of two
types of cells. The thin Type I alveolar cells are
responsible for gas exchange. The much thicker
Type II alveolar cells are responsible for a variety of
functions, including maintaining the fluid balance
Mouth
across the lungs and secreting lipoproteins called
Buccal surfactants. The alveoli are wrapped with an ex-
cavity
tensive capillary network that covers 80–90% of the
Terminal bronchiole alveolar surface.
Both lungs are surrounded by the pleural sac
(Figure 25), which consists of two layers of cells
Atmospheric pressure
760 mm Hg
Chest wall
Respiratory Pleural sac:

bronchiole intrapleural
pressure
756 mm Hg
Alveoli
Alveoli:
intra-alveolar
Type cell pressure
760 mm Hg
Type cell Alveolar
pores
Lung Pleural sac Chest wall
Elastic Elastic
recoil of Force recoil of
lung due to chest
negative wall
intrapleural
Alveolar macrophage Capillaries
pressure
Figure 24 Structure of mammalian lungs
Mammalian lungs consist of conducting airways, not involved
in gas exchange, that terminate in a series of interconnected
blind-ended sacs called alveoli that form the respiratory Figure 25 The relationship between the lungs,
surface. The alveoli are polygonal in shape, with flattened pleura, and chest wall At rest, the intrapleural pressure is
walls, and are wrapped in blood vessels and suspended in a lower than atmospheric pressure. This low pressure pulls on
collagenous matrix. the lungs and keeps them expanded.
467
Respiratory Systems

Respiratory Strategies of Aquatic Insects
Tracheal systems are not very well suited

for aquatic respiration, because of the low oxy-
gen content and high density and viscosity of water, and
the relatively low rate of diffusion of oxygen in solution.
Aquatic insects cope with this problem in two ways.
Some insects have evolved structures termed tracheal
gills, which allow them to extract oxygen from water.
Other aquatic insects have developed strategies that
permit them to continue to breathe air despite their
aquatic habitat.
Like the gills of other species, tracheal gills are
evaginations of the body surface, generally arranged in
a series of plate-like structures. However, tracheal gills
are densely packed with sealed air-filled tracheae and
tracheoles, covered with only a very thin layer of cuticle.
These gills bring the tracheae into very close contact
with the water, allowing gas exchange by diffusion. Tra-
cheal gills are generally found in the immature stages
of insects and are typical of aquatic nymphs, the juve- Mosquito larvae breathing through siphons.
nile stages of insects that do not form pupae. These gills
can be located on various parts of the body, including
the abdomen, the base of the legs, the anus, and the often covered with water-repellent hydrofuge hairs. Some
rectum (the posterior portion of the gut). Mayfly and species also have hydrophobic lipids in the tracheoles that
dragonfly nymphs have tracheal gills on the outside of repel any water that may enter. Some fly (dipteran) larvae,
their abdominal segments, which can be moved to gen- including Chrysogaster and Notiphila, and the larvae of the
erate ventilatory water currents. Insects with rectal gills beetle Donacia, utilize a variant on this siphon strategy.
pump water in and out of the rectum for ventilation. These insects have a sharply pointed abdominal siphon,
Many species of aquatic insects simply avoid using wa- which they use to pierce the surface of aquatic plants and
ter as a respiratory medium. For example, some insects extract the oxygen produced by photosynthesis.
such as mosquito larvae remain near the water surface Insects that breathe through siphons must remain
and breathe air through a specialized structure that ex- close to an air source, which imposes severe limita-
tends above the surface of the water and acts as a siphon tions. Many beetles and bugs have adopted a different
or snorkel. To make sure that air and not water will enter strategy, that of bubble breathing. These insects dive
the siphon, the spiracles on these respiratory siphons are beneath the surface carrying a conspicuous bubble of
with a small amount of fluid between them, form- Low intrapleural pressure plays a critical role
ing a space called the pleural cavity. The pleural in maintaining the integrity of the lungs. Between
fluid lubricates the pleura and allows the two lay- breaths, the pressure inside the lung at rest is
ers to slide past each other during ventilation. The equivalent to atmospheric pressure, and thus is
pressure within the fluid of the pleural cavity (or higher than the intrapleural pressure. The rela-
the intrapleural pressure) is normally subatmo- tively low pressure outside the lungs tends to pull
spheric, because the chest wall pulls on the outer the small airways and alveoli open, preventing
layer of the pleura, whereas the elasticity of the these fragile structures from collapsing in on
lungs tends to pull on the inner layer of the pleura. themselves. If the pleural sac is punctured, the
These two opposing forces result in a subatmo- pressure within the pleural cavity increases, and
spheric pleural pressure. the small airways and alveoli collapse. This condi-
468
Respiratory Systems
air under their wings. This bubble acts as an air supply the bubble to decrease rapidly. Once the PO2 within the
while the animal is underwater. As the animal con- bubble drops below the external PO2, oxygen will start to
sumes oxygen from the bubble, the partial pressure of diffuse into the bubble, and the bubble will shrink more
oxygen within the bubble falls lower than that of the sur- slowly. However, it will continue to decrease in size as
rounding water. As a result, oxygen diffuses down this nitrogen diffuses into the water, forcing the insect to re-
partial pressure gradient from the water into the air turn to the surface.
bubble, providing additional oxygen to the animal. Some Some small aquatic beetles avoid returning to the
beetles increase this gas exchange by stirring the water surface by capturing the oxygen bubbles produced by
around the bubble with their legs. This reduces the size photosynthesizing algae and adding this gaseous oxy-
of the boundary layer around the bubble, and increases gen to their gas bubble. Other bugs and beetles use the
oxygen availability. strategy of hydrofuge hairs to prevent their bubbles
Because the PO2 within the bubble is lower than that from shrinking. In bugs such as Aphelocheirus aestivalis
in the water, and the total pressure remains similar to these hairs are arranged into a structure called a plas-
atmospheric pressure, the PN2 within the bubble intron, which consists of an extremely dense layer of hy-
creases slightly, causing nitrogen to diffuse out of the drofuge hairs containing as many as 2–3 million hairs
bubble and into the water. As a result, the bubble grad- per mm2. These hairs trap air bubbles as a thin film of
ually shrinks in size over time. Nitrogen is less soluble gas along the surface of the body. The hairs are not col-
in water than is oxygen, so nitrogen leaves the bubble lapsible, so the volume of the plastron is fixed. As the air
more slowly than oxygen enters, but over time the bub- bubble loses nitrogen to the water, the surface tension
ble will gradually shrink. Because CO2 is so soluble in of the air-water junction between the hairs holds the
water, it rapidly diffuses out of the bubble, and the CO2 bubble in place, preventing it from decreasing in size.
produced by metabolism does not help to stabilize the Thus, the hydrofuge hairs prevent the bubble from col-
size of the bubble. lapsing. The bubble then reaches an equilibrium in
Diffusion of oxygen into the bubble is a function of the which its volume is constant, but its internal pressure is
surface area of the bubble (according to the Fick equa- reduced. Some species of aquatic insects with plastrons
tion), so oxygen delivery declines as the size of the bub- can remain submerged almost indefinitely.
ble decreases. As a result, these insects must Other aquatic insects maintain large oxygen stores
periodically return to the surface to renew their bubble. within their bodies. For example, some species of
This problem is even more acute as the insect descends aquatic bugs have hemoglobin molecules in their he-
deeper into the water. Hydrostatic pressure increases molymph. As we see later in the chapter, hemoglobin
with depth, causing the volume of the bubble to de- acts as an oxygen storage and transport molecule in
crease, which causes an increase in PO2 and PN2 within many species. Insect hemoglobins are typically used as
the bubble. Under these circumstances both oxygen and an oxygen store, which can help aquatic insects remain
nitrogen diffuse out of the bubble, causing the size of submerged for prolonged periods.
tion, known as a pneumothorax, causes severe ward and upward and the diaphragm to move
shortness of breath because of the loss of the alve- down, expanding the volume of the thorax. This
oli as an efficient gas exchange surface. increase in volume decreases intrathoracic pres-
sure, which pulls on the outer layer of the pleural
sac, decreasing the pressure within the pleural
Mammals ventilate their lungs tidally cavity. This decrease in intrapleural pressure re-
Mammals exhibit a tidal pattern of ventilation. sults in an increase in the pressure difference
Inspiration begins when somatic motor neurons across the alveolar walls. This increase in the
trigger the contraction of the diaphragm and the transpulmonary pressure gradient causes the
external intercostal muscles of the rib cage. lungs to expand, decreasing the pressure in the
These contractions cause the ribs to move out- alveoli. The resulting pressure gradient between
469
Respiratory Systems
the atmosphere and the alveoli causes air to flow The work required for ventilation depends
into the lungs. on lung compliance and resistance
Expiration begins when the nerve impulses
The amount of energy needed to ventilate the
from the somatic motor neurons that innervate the
lungs depends on the elastic properties of the
external intercostal muscles and diaphragm stop.
lungs and chest wall and on the resistance to air-
This allows the muscles of the diaphragm and tho-
flow in the pulmonary airways. The ability of the
rax to relax. The thorax then returns to its original
lungs to reversibly change shape can be quantified
position, causing thoracic volume to decrease and
using two parameters: compliance, which ex-
intrapleural pressure to increase. Because the
presses how easy it is to stretch a structure, and
lungs contain elastic materials, when they are no
elastance, which expresses how readily the struc-
longer being actively stretched by the low in-
ture returns to its original shape. Lung compliance
trapleural pressure they tend to snap back to their
is simply defined as the magnitude of change in
original position. This elastic recoil of the lungs
lung volume produced by a given change in pres-
decreases lung volume, causing alveolar pressure to
sure. A highly compliant lung stretches more in re-
increase and air to flow out of the lungs. Figure 26
sponse to a pressure change than does a less
summarizes the pressure changes within the pleu-
compliant lung, and can be described by the fol-
ral cavity and lungs during quiet breathing. During
lowing equation:
rapid and heavy breathing such as that induced by
exercise, this passive expiration may not be suffi- C ⫽ ⌬V/⌬P
cient for ventilation. Under these circumstances, where C is the lung compliance, ⌬V is the change
contraction of the internal intercostal muscles and in lung volume, and ⌬P is the change in transpul-
the abdominal muscles compresses the thorax and monary pressure. The lower the lung compliance,
actively expels air from the lungs. the harder it is to expand the lungs and the higher
the energetic costs of inspiration.
Lung compliance can change as a result of dis-
Inspiration Expiration ease. For example, in fibrotic lung disease, which
can result from chronic inhalation of asbestos, sil-
Intra-alveolar pressure
1 icon, or coal dust, scar tissue on the lungs reduces

lung compliance and makes inspiration difficult.
(mm Hg)
0 As a result, individuals with fibrotic lung disease

tend to breathe shallowly, and thus must breathe
–1 more rapidly in order to obtain sufficient oxygen.
Lung elastance is a measure of the degree of re-
turn to resting volume after the lung is stretched.
When lung elastance is low, the lungs will not
Intrapleural pressure
–3
spring back to their original shape when the respi-
(mm Hg)
–4 ratory muscles relax. As a result, if lung elastance

is low, expiration must be active rather than pas-
–5 sive. In the disease emphysema, the springy elastin
fibers that are normally found in the lungs are de-
–6 stroyed. In individuals with emphysema the lung is
easier to inflate (it is more compliant), but its elas-
tance is low, so it will not spring back into shape as
Volume of air
500
moved (ml)
well as a healthy lung. Thus, individuals with em-

physema have difficulty on expiration, and must ex-
250 pend energy to breathe out even at rest.
0
0 1 2 3 4
Surfactants increase lung compliance
Time (sec) One important force that resists lung inflation (and
Figure 26 Pressure changes in a mammalian thus reduces lung compliance) is surface tension
lung during quiet breathing in the thin layer of fluid that lines the small air-
470
Respiratory Systems
ways and alveoli of the lungs. Surface tension re- airway diameter is small, airway resistance is
sults from hydrogen bonding between water mol- high, and the pressure gradient driving bulk flow
ecules, and provides a cohesive force that causes must be larger. Thus, airway resistance influences
two wet surfaces to stick together. Surface tension the size of the pressure gradient needed to move
can be altered by the addition of surfactants that air into or out of the lungs. In order to cause air to
disrupt these cohesive forces. Type II alveolar cells flow through high-resistance narrowed airways,
secrete lipoprotein surfactants that reduce the the lungs must develop a lower intra-alveolar
surface tension of the fluid layer lining the lungs, pressure, causing a larger gradient between at-
thus reducing the tendency of the walls of the mospheric pressure and intra-alveolar pressure,
small airways and alveoli to stick together. As a re- and providing a greater driving force for bulk flow.
sult, surfactants make the lung more compliant In order to attain low intra-alveolar pressure, the
and easier to stretch.1 Surfactant secretion from lungs must develop a large transpulmonary pres-
Type II cells is regulated so that stretching these sure gradient. Since muscular contractions and
cells (for example, during deep breathing) stimu- the resulting change in the volume of the thorax al-
lates surfactant secretion. ter the transpulmonary pressure, more energy
In humans, surfactant synthesis does not be- and thus more work is needed to inflate the lungs
gin until relatively late in embryonic development. when airway diameter is small.
As a result, babies that are delivered prematurely The nervous system, hormones, and paracrine
(more than eight weeks early) do not have suffi- chemical messengers can affect the diameter of the
cient surfactant in their lungs, greatly reducing the bronchioles. During bronchodilation airway diam-
compliance of the lungs. This low compliance eter increases, whereas during bronchoconstric-
makes it very difficult for premature babies to tion airway diameter decreases. Parasympathetic
breathe, potentially causing respiratory distress neurons innervate the smooth muscles surround-
syndrome. Amniocentesis can be used to deter- ing the bronchioles. Stimulation of these neurons
mine whether a baby is synthesizing sufficient causes bronchoconstriction. The paracrine chemi-
surfactant prior to birth. If birth cannot be de- cal messenger histamine also causes bronchocon-
layed, a physician may administer corticosteroid striction. Histamine is released in response to
drugs to the mother. These drugs cross the pla- tissue damage or as a result of allergic reactions.
centa and accelerate the development of the in- Because of this effect of histamine on the bronchi-
fant’s lungs. After birth, an infant with mild oles, severe allergic reactions can cause difficulties
respiratory distress syndrome may be treated with in breathing. Circulating epinephrine causes bron-
oxygen, or may need to be artificially ventilated. chodilation, acting primarily through ␤2 receptors
Premature babies are also often treated with arti- in the smooth muscle of the bronchioles. Similarly,
ficial surfactants that are sprayed into the lungs, high levels of CO2 in the alveoli cause bronchodila-
or administered via artificial ventilation tubes. tion. This negative feedback loop helps to keep
alveolar PCO2 within a set range.
Airway resistance affects the work

required to breathe Aspiration-based pulmonary systems have
Airway resistance, the force opposing bulk flow of substantial dead space
gas through the trachea, bronchi, and bronchioles, The total volume of air moved in one ventilatory
is the final determinant of the energy required for cycle is referred to as the tidal volume (VT). Some
breathing. The law of bulk flow and Poiseuille’s of the air that enters with each ventilatory cycle
equation tell us that airway diameter has an ex- does not participate in gas exchange, contributing
tremely large effect on airway resistance. When to the dead space (VD) of the system. The dead
1
space consists of two components: the anatomical
The importance of surfactants is often described in terms of
dead space and the alveolar dead space. The
the law of LaPlace for spheres as applied to the inflation of in-
dividual alveoli. But this represents a misconception of the anatomical dead space is the volume of the tra-
structure of the alveolus. Alveoli are not spherical, but rather chea and bronchi, which are not involved in gas
polygonal in shape and are interconnected by alveolar pores, exchange. The remainder of the physiological
and thus the law of LaPlace for spheres cannot apply. Instead,
surface tension along both flat and curved surfaces within the dead space, termed the alveolar dead space in
lungs contributes to resistance to lung inflation. mammals, consists of all the areas of the lungs that
471
Respiratory Systems
in principle could be involved in gas exchange, but Pulmonary function tests measure lung
for some reason are not exchanging gases during a function and volumes
particular ventilatory cycle. For example, in a
Pulmonary function tests allow clinicians and exper-
mammalian lung this could include the volume of
imenters to measure both lung volumes and lung
any alveoli that are not being perfused with blood.
function. An instrument called a spirometer can be
When an animal breathes out, some of the
used to measure the volumes of air inhaled and ex-
stale air leaving the lungs remains in the anatom-
haled under various conditions. When at rest, most
ical dead spaces, and is breathed in again at the
animals do not fully inflate or deflate their lungs
next inhalation. The total amount of fresh air that
with each breath. Thus, the tidal volume is usually
is involved in gas exchange during a respiratory
much smaller than the maximum possible amount
cycle is thus equal to the tidal volume minus the
of air that can be inhaled or exhaled. In a typical
dead space (VT ⫺ VD), and in mammals is symbol-
adult male human, the tidal volume at rest is ap-
ized as VA, or the alveolar ventilation volume. The
proximately 500 ml (lung volumes are typically
total effective ventilation of the lungs per unit time
about 20% less in females), whereas the total lung
is simply this quantity multiplied by the breathing
capacity is nearly 5800 ml (Figure 28). The maximal
frequency, or respiratory rate (f ). Thus, lung ven-
amount of air that can be inhaled over and above
tilation is equal to f (VT ⫺ VD). Since breathing fre-
the resting tidal volume is termed the inspiratory
quency is usually measured in breaths per minute,
reserve volume, and the tidal volume plus the inspi-
this is usually called the alveolar minute ventila-
. ratory reserve volume is the inspiratory capacity.
tion in mammals, and is symbolized as VA. The
The maximal amount of air that can be forcibly ex-
small dot over the V indicates that this is a rate
haled over and above the resting tidal volume is the
function. Increases in the size of the dead space
expiratory reserve volume. By summing the expira-
decrease alveolar ventilation at a given tidal vol-
tory reserve volume and the inspiratory capacity, we
ume. This effect is particularly important for
obtain the vital capacity, or the maximum amount
species with very long necks, such as giraffes and
of air that can be moved into or out of the respira-
some birds (Figure 27). These animals have ex-
tory system with one breath. Mammals are not able
tremely large tidal volumes in order to ensure ad-
to expel all the air out of their lungs, even with max-
equate ventilation of the respiratory surfaces.
imal exhalation. In fact, in humans approximately
1200 ml of air remains in the lungs even at the end
of a maximal exhalation. This residual volume oc-
curs because the lungs are held stretched against
the chest walls by the pleural sac. The total lung
capacity is the sum of the vital capacity and the
residual volume.
Ventilation-perfusion matching
is important for gas exchange
In order for gas exchange to occur efficiently, the
To ventilation of the respiratory surface must be
Trachea lungs matched to the perfusion of the respiratory surface
with blood. The ventilation perfusion ratio VA/Q
quantifies this relationship. In a normal human,
alveolar ventilation (VA) is usually around 4–5 l/min,
and cardiac output (Q) around 5 l/min, so that VA/Q
is close to 1 on average. The lungs have homeosta-
tic mechanisms to maintain ventilation-perfusion
matching at the level of the alveolus. If an alveolus
Figure 27 The respiratory system of a
whooping crane Some birds have an extremely long receives little or no fresh air, the PO2 in that alveolus
trachea, which greatly increases the dead space of the will be low. The low PO2 acts as a signal to the
respiratory system. smooth muscle surrounding the arterioles leading to
472
Respiratory Systems
Lung Volumes Lung Capacities
5700
End of IC =
maximum VT + IRV
inspiration
End of TLC =
normal VT + ERV +
inspiration IRV + RV
IRV
VT
2700
Volume (ml)
2200
End of ERV
normal VC =
expiration VT + IRV + FRC =
ERV ERV + RV
1200
End of
RV* maximum
expiration
0
Time
Normal lung volumes and capacities for a healthy 70-kg human male
Lung Volumes Lung Capacities

VT = Tidal volume = 500 ml IC = Inspiratory capacity = VT + IRV = 3500 ml
IRV = Inspiratory reserve volume = 3000 ml VC = Vital capacity = VT + IRV + ERV = 4500 ml
ERV = Expiratory reserve volume = 1000 ml FRC = Functional residual capacity = ERV + RV = 2200 ml
RV = Residual volume* = 1200 ml TLC = Total lung capacity = VT + ERV + IRV + RV = 5700 ml
*Cannot be measured by spirometry
Figure 28 Lung volumes and capacities Lung volumes and capacities can be
recorded on a spirometer. Inhalation causes the line to deflect upward, whereas exhalation
causes the line to deflect downward.
that alveolus.In systemic tissues low PO2 is a signal 12. What is the function of surfactants in the
for vasodilation, which increases oxygen delivery to mammalian respiratory system?
the tissues. In contrast, in the lungs, low PO2 causes 13. Explain why bronchoconstriction (for example,
vasoconstriction, reducing blood flow to areas that during an asthma attack) increases the work
required to breathe.
are poorly ventilated. This hypoxic pulmonary vaso-
constriction is the primary means by which the
lungs ensure appropriate ventilation-perfusion
matching. However, the mechanisms by which the
smooth muscle cells of the pulmonary arterioles Gas Transport to the Tissues
sense low PO2 and induce contraction are not yet
Animals such as sponges, cnidarians, and insects,
well understood.
which circulate the external fluid past almost
every cell in their bodies, can rely on diffusion to
transport gases between the external medium and
2 CO NC E P T C HE C K the tissues. But many animals transport gases us-
ing a circulatory system. Animals have exquisite
10. Outline the similarities and differences between
control of their circulatory systems, and can
the respiratory systems of insects and arachnids
(spiders and their relatives). regulate the transport of oxygen and
11. Compare and contrast the mechanisms of
carbon dioxide to and from the tissues by
ventilation in an air-breathing fish and an vasoconstricting or vasodilating the blood
amphibian. vessels, altering blood flow. In this section,
473
Respiratory Systems
we look at how animals use circulatory systems to Heme group

transport both oxygen and carbon dioxide.
α Subunit
β Subunit
Oxygen Transport
Oxygen can be transported from the respiratory sur-
face to the tissues dissolved in the circulatory fluid.
But because the solubility of oxygen in aqueous flu-
ids such as plasma is low, the amount of oxygen that
can dissolve in the plasma is relatively small. To
combat this limitation, the blood of many animals
contains specialized metalloproteins, which contain β Subunit
α Subunit
metal ions that reversibly bind oxygen. These met-
alloproteins greatly increase the amount of oxygen
(a) Hemoglobin molecule
that can be carried in the blood. For example, he-
moglobin (Hb), the oxygen carrier in vertebrate CH3 CH CH2
blood cells, increases the maximum amount of oxy-
gen that blood can carry—or the oxygen carrying
capacity—by as much as 50-fold. HC CH
At the respiratory surface much of the oxygen N
CH3 CH3
that diffuses into the blood binds to the metallopro-
tein oxygen carriers, thereby reducing blood PO2. N Fe N
By taking this oxygen out of solution, oxygen carri- –OOC CH CH2
CH2 CH2
ers help to maintain the PO2 gradient across the N
respiratory surface, improving oxygen extraction. HC CH
At the tissues, mitochondrial oxygen consumption
decreases the PO2 of the blood, causing oxygen to
–OOC
CH2 CH2 CH3
dissociate from the oxygen carrier. This oxygen
then diffuses down its PO2 gradient into the cells. (b) Heme group containing iron (Fe)
Figure 29 Structure of mammalian hemoglobin

All hemoglobins consist of one or more globin proteins
There are three main types
complexed to an iron-containing porphyrin ring. Most
of respiratory pigments vertebrate hemoglobins are tetramers, composed of four
The metalloprotein oxygen carriers are often re- globins and their heme groups. Mammalian hemoglobins are
composed of two alpha and two beta globin chains.
ferred to as respiratory pigments, because the
metal ions that they contain give them a color. In
animals, three major types of metalloproteins act
as respiratory pigments: hemoglobins, hemo- gests that these diverse molecules share a common
cyanins, and hemerythrins. evolutionary history.
Hemoglobins, the most common type of respi- In this chapter we focus on the globins found in
ratory pigment in animals, are found in a wide va- blood, either within blood cells or extracellularly,
riety of taxa including vertebrates, nematodes, but molecules related to the blood hemoglobins are
some annelids, some crustaceans, and some in- found in many tissues. These hemoglobins are also
sects. All hemoglobins consist of at least one mole- thought to play a role in oxygen transport and stor-
cule of a protein in the globin family noncovalently age. For example, a type of hemoglobin called
bound to a heme molecule, which consists of a por- myoglobin is found in muscles, where it helps to
phyrin ring containing ferrous iron at the center provide the oxygen needed for metabolism.
(Figure 29). The iron molecules in hemoglobin give A related protein called neuroglobin is found
vertebrate blood its reddish color. Globins are in neurons. Neuroglobin has been shown to
structurally diverse, but all share a characteristic protect neural tissue during periods
tertiary structure called the globin fold, which sug-
474
Respiratory Systems
of hypoxia (low oxygen). Recently, another protein increase in the viscosity of the hemolymph, making
closely related to myoglobin has been identified. it more difficult to pump around the body. Because
This protein, called cytoglobin, is found in many hemocyanins are colorless when deoxygenated and
tissues, with particularly high expression in the turn blue when oxygenated, the hemolymph of
cells of connective tissue. The function of cytoglo- these species appears blue.
bin is currently unknown. Hemerythrins are found in species from four
Active hemoglobin molecules can be made up invertebrate phyla (sipunculids, priapulids, bra-
of between one and several hundred globin mole- chiopods, and annelids). However, their distribu-
cules and their associated heme groups. Myoglo- tions within these phyla differ. They are found in
bin is monomeric, whereas the blood hemoglobins essentially all of the sipunculid and priapulid
of vertebrates are generally tetrameric, consisting worms, and many of the brachiopods, but in only
of four globin molecules. The hemoglobins of an- one family of marine annelids. This unusual phylo-
nelids such as earthworms (Lumbricus) contain genetic distribution is puzzling and may represent
nearly 150 globin molecules plus a number of a case of convergent evolution. Alternatively, pat-
linker proteins that do not contain heme. Hemo- terns such as this in which closely related genes are
globins can be found inside blood cells, as in the present in distantly related taxa may represent a
vertebrates, or extracellularly dissolved in the cir- case of horizontal gene transfer in which viruses
culatory fluid, as in many invertebrates. carry genes from one species into another.
A few families of marine annelids have unusual The hemerythrins do not contain heme. In-
respiratory pigments called chlorocruorins, also stead, iron is bound directly to the protein via the
known as the green hemoglobins because in dilute carboxylate side chains of a glutamate and an as-
solutions they are greenish in color. Some investi- partate, and the imidazole groups on five his-
gators consider the chlorocruorins to be a distinct tidines. Hemerythrins are generally trimeric or
class of respiratory pigment, but they share many octameric molecules in which each subunit con-
characteristics with the hemoglobins. Chloro- tains two iron ions. Most hemerythrins are found
cruorins are composed of a globin molecule com- inside circulating coelomic cells and in muscle
plexed to an iron porphyrin. The porphyrin ring in cells, and thus can be present at high concentra-
the chlorocruorins differs slightly from heme in tions without increasing the viscosity of the he-
that one of the CH⫽CH2 side chains is replaced molymph. Hemerythrins are colorless when
with a CHO side chain; however, the globin mol- deoxygenated but violet-pink when oxygenated.
ecule shares clear phylogenetic relatedness with As a result, the coelomic cells containing hemery-
other invertebrate globins, suggesting that thrins are sometimes called pink blood cells.
the chlorocruorins are simply a subclass of the The significance of the great variety of animal
hemoglobins. respiratory pigments is not well understood. The
Hemocyanins are found in both the arthro- respiratory pigments likely represent an example
pods and molluscs; however, the hemocyanins in of multiple independent solutions to the common
these two groups appear to have independent evo- problem of oxygen transport and storage.
lutionary origins. Among the molluscs, they are
found in some gastropods, some bivalves, and all
cephalopods. Among the arthropods, they are Respiratory pigments have characteristic
present in most crustaceans, arachnids, and cen- oxygen equilibrium curves
tipedes. Hemocyanins do not contain iron, but in- An oxygen equilibrium curve shows the relation-
stead contain copper, which is complexed directly ship between the partial pressure of oxygen in the
to the protein rather than being part of a heme plasma and the percentage of oxygenated respira-
group. Hemocyanins are very large multimeric tory pigment in a volume of blood (Figure 30a).
proteins consisting of up to 48 individual subunits When the partial pressure of oxygen in solution is
per molecule. They are usually dissolved in he- zero, no oxygen will be bound to the respiratory
molymph, often at high concentrations, rather pigment. As partial pressure increases, more and
than being located within blood cells. This extra- more pigment molecules will bind oxygen, until
cellular location poses a strong constraint on the the available molecules are fully bound to oxygen.
total concentration of hemocyanin because in- At this point, the blood is said to be saturated
creased hemocyanin concentration results in an with oxygen. An oxygen equilibrium curve is thus
475
Respiratory Systems
P50 gen, or hypoxia, triggers red blood cell release or

100 production. For example, in many vertebrates one
of the first responses to hypoxia is contraction of
Percent saturation
an organ called the spleen. One of the functions of

of hemoglobin
the spleen is to act as a storage site for red blood

50 cells. Splenic contraction pushes additional red
blood cells into the circulation, increasing the
hematocrit (Hct), a measure of the proportion of
blood volume that is occupied by red blood cells.
0
0 20 40 60 80 100 In addition, hypoxia stimulates the production of
PO2 (mm Hg) new red blood cells. Low PO2 stabilizes a protein
(a) Percentage of respiratory pigment oxygenated called HIF-1 (hypoxia inducible factor 1), causing
its concentration to increase. When HIF-1 levels
P50 are high, the protein acts as a transcription factor
20 and induces the expression of a number of genes
in a variety of tissues, including the gene coding
for erythropoietin, a hormone that induces the for-
100 ml of blood (vol%)
High hemoglobin content

Milliliters of oxygen/
mation of red blood cells. This increase in red

blood cell numbers, and thus in hematocrit and
10 hemoglobin concentration, increases the oxygen
Low hemoglobin content carrying capacity of the blood.
There is also evolutionary variation among an-
imals in the levels of respiratory pigment in blood.
For example, diving mammals have extremely high
0 levels of blood hemoglobin compared to terrestrial
0 20 40 60 80 100
PO2 (mm Hg)
mammals, which increases the oxygen carrying ca-
pacity of blood and allows it to act as an oxygen
(b) Oxygen content of blood
store during diving. In contrast, the Antarctic ice-
Figure 30 Oxygen equilibrium curves (a) The fish (family Channichthyidae) are unique among the
percentage of saturation of a respiratory pigment as a
vertebrates in that they do not have any hemoglo-
function of oxygen partial pressure. (b) The oxygen content of
blood as a function of partial pressure for blood with high and bin in the blood, and most icefish species have lost
low content of respiratory pigment. the gene coding for hemoglobin. As a result, the
blood oxygen carrying capacity of these species is
very low (approximately one-tenth that of the
very much like the hormone-binding closely related notothenioid fish). Icefish also lack
curves. myoglobin in their skeletal muscles, although some
We typically express oxygen equilibrium species express this protein in the heart. Because of
curves in terms of percent saturation, because this the cold, stable temperatures of the Antarctic Ocean
allows us to conveniently compare the properties (the mean temperature in McMurdo Sound is ap-
of the respiratory pigments in blood with different proximately ⫺1.9°C throughout the year), the meta-
amounts of pigment. However, we can also ex- bolic rate and thus the oxygen demand of these
press this relationship in terms of total oxygen fishes is relatively low. In addition, these low tem-
content of the blood. Figure 30b shows the total peratures increase the solubility of oxygen in water
oxygen content of blood that contains differing and plasma, increasing the oxygen concentration of
amounts of hemoglobin. As you can see, as the the blood. However, icefish also exhibit a number of
amount of hemoglobin increases, the total amount physiological adjustments that help to compensate
of oxygen that can be carried in the blood when for the lack of hemoglobin. These fish have unusu-
the hemoglobin is fully saturated also increases, ally large hearts and blood vessels, a large blood
thus increasing the carrying capacity of the blood. volume, and increased cardiac output compared to
Many animals regulate the amount of respira- their non-Antarctic relatives. Together, these circu-
tory pigment in the blood. For example, in many latory adjustments help to increase oxygen delivery
vertebrates exposure to low environmental oxy- in the absence of a respiratory pigment.
476
Respiratory Systems
The oxygen affinity of a respiratory pigment is The shapes of oxygen equilibrium

a measure of how readily the pigment binds oxy- curves differ
gen. We typically express the oxygen affinity of a
Oxygen equilibrium curves can be either hyper-
pigment using a measure termed the P50, which is
bolic or sigmoidal (Figure 31). For example, myo-
the oxygen partial pressure at which the pigment
globin exhibits a hyperbolic oxygen equilibrium
is 50% saturated. The P50 of a respiratory pigment
curve. Myoglobin is a monomeric respiratory pig-
is thus analogous to the Km of an enzyme. Note
ment containing a single heme molecule with one
that the P50, like Km, has an inverse relationship to
oxygen-binding site. Because each myoglobin mol-
affinity. Pigments that require relatively low par-
ecule binds oxygen independently of other myo-
tial pressures for oxygen to bind (i.e., have a low
globin molecules, the principles of mass action
P50) are said to have high affinity for oxygen,
predict that the equilibrium curve should be hy-
whereas pigments that require relatively high par-
perbolic in shape.
tial pressures for oxygen to bind (i.e., have a high
P50) are said to have low affinity.
The P50 of a respiratory pigment has important
implications for its ability to transport oxygen. For 100
Myoglobin
example, a terebellid polychaete worm Pista paci-
Percent saturation of hemoglobin

(human)
fica has three different types of hemoglobin, each 80
with a characteristic P50. It has a giant extracellu-
lar hemoglobin with a very low oxygen affinity that 60 Hemoglobin
circulates through its vascular system, a moderate- (human adult)
affinity hemoglobin that is located within circulat-
40
ing coelomic cells that travel through the
interstitial fluid, and a high-affinity myoglobin
20
within the cells of the body wall. These worms live
in burrows that can extend almost a meter down
in the anoxic (oxygen-free) sediments of mudflats. 0
0 20 40 60 80 100
At high tide, these worms extend their gills out PO (mm Hg)
2
into the well-oxygenated water above the mudflat
(a) Oxygen equilibrium curves
to obtain oxygen. Oxygen diffuses into the blood
vessels of the gills, raising the PO2 of the circulatory Salt
fluid. The low-affinity hemoglobin in this circula- bridges
Heme α1 α2 O2 α1 α2 O2
tion readily binds oxygen at the relatively high PO2
seen in the gills. As the blood leaves the gills, this Globin 4O2
low-affinity hemoglobin passes oxygen to the Hydrogen Hydrogen
bonds bonds
moderate-affinity hemoglobin in the coelomic cells
that circulate through the body cavity and carry oxy- 4O2
gen to the tissues. At the body wall, the moderate- β1 β2 O2 β1 β2 O2
affinity hemoglobin passes the oxygen to the Allosteric modifiers
high-affinity myoglobin in the muscle cells, pro- Tense state R state
viding oxygen to the tissues. Together, these three (b) A model for hemoglobin cooperativity
hemoglobins ensure efficient gas transport from Figure 31 Cooperativity in oxygen binding
the gills to the tissues of the worm. (a) Monomeric respiratory pigments, such as mammalian
Hemoglobin has extremely high affinity for myoglobin, do not bind oxygen cooperatively and have a
carbon monoxide, binding with carbon monoxide hyperbolic oxygen equilibrium curve. Multimeric respiratory
pigments, such as mammalian hemoglobin, often display
more than 200 times more readily than with oxy- cooperative binding. The result of this cooperative binding is a
gen. As a result, carbon monoxide can interfere sigmoidal oxygen equilibrium curve. (b) A model for
with hemoglobin oxygen binding. Thus, exposure mammalian hemoglobin cooperativity (after Weber and Fago,
to even relatively low levels of carbon monoxide 2004). Oxygenation causes tetrameric hemoglobins to
transition between the tense state that is stabilized by salt
can be fatal, because it decreases the oxygen car- bridges and has low oxygen affinity, and the relaxed state that
rying capacity of the blood, reducing oxygen sup- is stabilized only by hydrogen bonds and has high oxygen
ply to the tissues. affinity.
477
Respiratory Systems
In contrast, because of their tetrameric struc-

100
ture vertebrate hemoglobins exhibit a sigmoidal

oxygen equilibrium curve. These hemoglobins are pH 7.6
composed of two alpha and two beta subunits. 80
Each alpha subunit associates tightly with one of

the beta subunits, forming two dimers (␣1␤1 and 60 pH 7.4
␣2␤2) that associate with each other more loosely

(Figure 29a). When a hemoglobin molecule is fully 40 pH 7.2
deoxygenated, it adopts a rigid conformation
termed the tense, or T, state that is stabilized by hy- 20
drogen bonds, binding of allosteric effectors, and
salt bridges between the subunits (Figure 31b). In
contrast, fully oxygenated hemoglobin adopts a 0 20 40 60 80 100
loose conformation that is termed the relaxed, or PO2 (mm Hg)
R, state. In this conformation, interactions be-
Figure 32 The Bohr effect Decreases in pH or
tween the subunits are stabilized only by hydro- increases in CO2 cause a right shift of the oxygen equilibrium
gen bonds. In the T state, hemoglobin has a curve.
relatively low affinity for oxygen, but when an oxy-
gen molecule binds to one of the heme groups, the
hemoglobin begins a transition from the T to the R respiratory pigment at a specific site (in the verte-
state. Binding of oxygen to the iron atom causes brates, these protons bind at the C-terminal amino
the iron to alter its spin state and to move into the acids of the ␤ subunits, and the N-terminal amino
plane of the porphyrin ring of the heme group. acids of the ␣ subunits). Proton binding causes a
These movements are transmitted to the globin conformational change in the respiratory pigment
subunits, and weaken the salt bridges holding the protein that alters its oxygen affinity. Thus, pro-
molecule in the tense conformation. Oxygen affin- tons act as allosteric modulators of these respira-
ity increases progressively as each oxygen binds tory pigments.
and the molecule adopts an increasingly relaxed Carbon dioxide can cause the Bohr effect
conformation. The net effect of this cooperative through two separate mechanisms. As we discuss
binding (or cooperativity) is an oxygen equilib- in more detail later in the chapter, in blood CO2 re-
rium curve with a sigmoidal shape. acts to form a bicarbonate ion (HCO3⫺) and a pro-
Although most vertebrate hemoglobins con- ton (H⫹), and this proton can cause the Bohr effect
form to this model, the hemoglobins of the jaw- as described above. Alternatively, carbon dioxide
less fishes (lampreys and hagfish) have an can have a direct effect on the oxygen affinity of
entirely different mechanism. These hemoglo- respiratory pigments. CO2 binds to the amine
bins are monomers when they are oxygenated, group of the amino acids in the respiratory pig-
and form dimers, trimers, or tetramers when de- ments, forming carbaminohemoglobin, with a
oxygenated. This shift from a multimeric to a decreased oxygen affinity.
monomeric form also results in a sigmoidal oxy- The Bohr effect facilitates oxygen transport to
gen equilibrium curve. active tissues. At the respiratory surface, where
PCO2 is low and pH is high, the oxygen affinity of
the respiratory pigment will be high (the curve
Blood pH and PCO2 can affect oxygen affinity will be shifted to the left), facilitating oxygen
Changes in pH and PCO2 alter the shape of the oxy- binding. Metabolizing tissues produce CO2, so
gen equilibrium curve for the respiratory pig- PCO2 and [H⫹] in the blood increase at the tissues.
ments in many species, a phenomenon termed the This change in PCO2 and pH causes the Bohr effect,
Bohr effect or Bohr shift (Figure 32). In the Bohr decreasing the oxygen affinity of the respiratory
effect, a decrease in pH or increase in PCO2 reduces pigment, and shifting its oxygen equilibrium
the oxygen affinity of a respiratory pigment, shift- curve to the right. This facilitates oxygen release
ing the oxygen equilibrium curve to the right. Pro- from the respiratory pigment, helping to supply
tons (H⫹) cause the Bohr effect by binding to a the tissues with oxygen.
478
Respiratory Systems
The size of the Bohr effect differs among res- Temperature affects oxygen affinity
piratory pigments. For example, the hemoglo-
Increases in temperature can decrease the oxy-
bins of elasmobranch fishes usually have either
gen affinity of respiratory pigments such as he-
no Bohr effect or a very small one, whereas the
moglobin in many species, shifting the oxygen
hemoglobins of mammals and birds usually ex-
equilibrium curve to the right (Figure 34). This ef-
hibit modest Bohr effects, and the hemoglobins
fect may promote oxygen delivery during exer-
of many teleost fish have extremely large Bohr
cise. Exercising muscles generate heat, which can
effects.
increase the local temperature in the blood that
In some crustaceans, cephalopods, and many
perfuses the tissues. As temperature increases,
teleost fishes, increases in PCO2 and decreases in pH
P50 increases (oxygen affinity decreases), causing
cause not only a Bohr effect, but also a reduction in
oxygen to dissociate from hemoglobin, and deliv-
the oxygen carrying capacity of the respiratory pig-
ering oxygen to the tissue. This temperature ef-
ment (Figure 33), a phenomenon called the Root
fect works together with the Bohr effect to
effect (or Root shift). In addition to an increase in
maximize oxygen delivery. Similarly, the temper-
the P50 at low pH, the carrying capacity of a Root-
ature of the respiratory surface may decline dur-
effect hemoglobin decreases greatly, releasing oxy-
ing exercise if the temperature of the external
gen into solution. Thus, Root-effect hemoglobins
medium is low. This decrease in temperature in-
can act as proton-triggered oxygen pumps, greatly
creases hemoglobin oxygen affinity, which could
increasing the PCO2 of the plasma under low pH
promote oxygen uptake. However, even at normal
conditions. This mechanism is important in filling
temperatures, blood is typically almost com-
the swim bladder, an organ that some fish use for
pletely saturated with oxygen at the lungs, so this
buoyancy (see Box 2, Evolution and Diversity:
effect is likely to be minor.
Root-Effect Hemoglobins and Swim Bladders). The
Some arctic animals such as reindeer and
mechanisms involved in the Root effect have not
musk ox have hemoglobins that exhibit small or
been fully characterized, but site-directed muta-
no temperature effects. In these animals, which
genesis and other protein structure-function stud-
live at temperatures as low as ⫺40°C, the temper-
ies suggest that interactions among several amino
ature in peripheral tissues such as the feet can be
acids are involved, and that different amino acids
as much as 10°C lower than the core body temper-
may be important in different species.
ature. If their hemoglobin exhibited a typical in-
crease in oxygen affinity with decreasing
temperature, oxygen delivery to the tissues might
be greatly impaired.
100 Root
pH 8.0 effect
80
Organic modulators can affect oxygen
affinity
60 A variety of organic compounds can act as modu-
pH 7.0
lators of the oxygen affinity of respiratory pig-
40
ments. In most mammals the compound
2,3-bisphosphoglycerate, also called 2,3-diphos-
phoglycerate (2,3-DPG), acts as an allosteric regu-
20
lator of hemoglobin. 2,3-DPG is also the primary
allosteric modifier in reptiles (except crocodiles),
0 20 40 60 80 100 whereas in most birds inositol pentaphosphate
PO2 (mm Hg) plays this role. In contrast, in most fish (except the
cyclostomes), ATP or GTP modulates hemoglobin
Figure 33 Root effect The Root effect is seen only in oxygen affinity. Organic compounds including lac-
the hemoglobins of some teleost fish and a few species of
tate, urate, and dopamine modulate the arthropod
invertebrates. Decreases in pH cause an exaggerated right
shift of the oxygen equilibrium curve, and a decrease in the hemocyanins, with increases in these compounds
carrying capacity of the blood. increasing oxygen affinity.
479
Respiratory Systems

Root-Effect Hemoglobins and Swim Bladders
Fish tissues are somewhat more dense

than either freshwater or seawater, largely as a Swim bladder
result of the high density of the skeleton, so without (in physoclist)
some form of buoyancy compensation, fish tend to sink.
Many teleost fish use a gas-filled organ called a swim
bladder to maintain their vertical position in the water.
Swim bladders are located just above the gut, and below
the vertebral column and kidneys. The walls of the swim
bladder are largely impermeable to gas, since they are
Intestine
poorly vascularized and composed of a thick layer of
connective tissues. In some species the wall of the swim To heart
bladder is coated with a layer of guanine crystals, which
further decrease gas permeability. The gas content of
swim bladders varies among species, but in most From
heart Swim bladder
species O2 is the principal gas.
The buoyancy provided by a swim bladder depends
on the volume of this organ. Since swim bladders are Gas gland Oval
soft-walled and filled with gas, they change volume as To liver
pressure changes. Atmospheric pressure increases
with depth, as a result of the pressure of the overlying
water. In fact, pressure increases by approximately 1 at-
mosphere (atm) for every 10 meters beneath the sur-
Swim bladder wall
face. If a fish descends 10 m below the surface, the
volume of the swim bladder will be halved, and by 100 m Arterial blood
depth the swim bladder will be 1/10 its original volume.
Thus, in order to maintain neutral buoyancy, a fish must CO2 Hb•H
be able to add gas to its swim bladder as it descends Increasing PO
2
through the water column. CO2 O2
In some fish, such as eels and salmon, the swim CO2 CO2 H+ H+
bladder opens into the gut via the pneumatic duct.
Decreasing PO2
These physostome fish can fill the swim bladder by
HCO3– Hb•O2
gulping air, or empty the swim bladder by burping.
Venous
Thus, a physostome fish can fill its swim bladder only
blood
while at the surface where it has access to air. This Gas gland
arrangement poses substantial problems for physos-
tome fish such as salmon, which make extensive verti- Lumen of swim bladder
cal migrations in order to feed at different depths in the
water column. In order to be neutrally buoyant at depth,
a fish must fill its swim bladder with a great deal of air.
However, this large volume of air will make the fish pos- compressed in response to the increasing hydrostatic
itively buoyant at the surface, and it will tend to float up- pressure. Negative buoyancy is advantageous during
ward, making it very difficult for the animal to dive. descent, because it decreases the cost of swimming
Studies have shown that chum salmon, physostome downward, but disadvantageous during an ascent, be-
fish, do not gulp air into their swim bladder prior to a cause it increases the cost of swimming upward.
dive. As a result, a salmon becomes negatively buoyant The physoclist fish, such as perch, use an alternative
as it descends, because the swim bladder is gradually solution to filling and emptying the swim bladder. In
480
Respiratory Systems
these fish, the connection between the swim bladder The gas gland of physoclist fish is associated with a
and the gut is absent. Instead, gases move into or out of specialized capillary bed called a rete mirabile (“won-
the swim bladder from the blood. Thus, a physoclist fish derful net” in Latin), or rete. A rete is a bundle of capil-
can fill the swim bladder without returning to the sur- laries in which the capillaries are arranged with flow
face. Most of the swim bladder is impermeable to gases, through the arterial and venous vessels in countercur-
so movement of gas into and out of the swim bladder oc- rent. This countercurrent exchanger prevents the loss of
curs only at specialized structures termed the gas gland oxygen via the venous blood. The rete accomplishes this
and oval. The gas gland is involved in gas secretion into largely because of the movement of CO2 from venous to
the swim bladder, whereas the oval is involved in gas re- arterial blood, rather than by movement of oxygen. As
absorption from the swim bladder back into the blood. blood exits the gas gland, it has a high PO2 and very high
In order for oxygen to diffuse into the swim bladder CO2 content. This CO2 diffuses from the venous side of
from the blood, the blood PO2 in the gas gland must be the rete to the arterial side as it passes through the
greater than that in the swim bladder. To maintain this countercurrent exchanger. The increase in CO2 and the
high PO2, the tissues of the gas gland produce H⫹ ions and associated drop in pH on the arterial side contribute to
CO2. The resulting decrease in pH and increase in PCO2 the Root and Bohr effects, increasing the PO2 of the
cause both a Bohr effect and a Root effect. Because of the blood entering the gas gland. At the same time, the de-
Bohr effect, the oxygen affinity of hemoglobin decreases, crease in CO2 and the associated increase in pH on the
causing oxygen release from hemoglobin. Because of the venous side cause oxygen to bind to hemoglobin, de-
Root effect, the oxygen carrying capacity of hemoglobin creasing the PO2 of the blood. The longer the rete, the
decreases, causing oxygen release. The net result of greater the PO2 that can be achieved at the gas gland.
these two effects is that a substantial amount of oxygen Fish that live at great depths must be able to attain high
dissociates from hemoglobin and dissolves in the blood. PO2 in the gas gland to force oxygen into the swim blad-
This dissolved oxygen now contributes to the PO2 in the der. The length of the rete capillaries is correlated with
blood, increasing the blood PO2 within the gas gland. the maximum depth that this fish can attain. In some
The cells of the gas gland have very few mitochon- deep-sea fish, such as Bassozetus, the rete can be as
dria, and instead obtain most of their energy through long as 25 mm.
anaerobic glycolysis, causing the cell to become acidic. Physoclist fish empty their swim bladder at the oval.
The gas gland cells then secrete these protons into the Reabsorbing oxygen from the swim bladder is not as
blood, accounting for the blood acidosis. Because the physiologically challenging as secreting oxygen into the
gas gland cells have few mitochondria, most of the CO2 swim bladder, because oxygen can simply diffuse down
that they produce does not come from mitochondrial its partial pressure gradient from the swim bladder into
respiration. Instead, these cells activate a pathway the blood. In most species, the oval is equipped with a
called the pentose phosphate shunt, which produces muscular valve so that it can be opened and closed to
CO2 as a by-product. The gas gland also adds ions to the regulate the amount of gas removed from the swim
blood (largely lactate and bicarbonate, but possibly oth- bladder.
ers as well). These added ions cause a “salting-out” ef-
fect. Recall that the solubility of gases in solution
References
depends on the salt concentration of the fluid. When salt
q Pelster, B. 2004. pH regulation and swim bladder function in fish.
concentration increases, gas solubility decreases. From
Respiratory Physiology and Neurobiology 144: 179–190.
Henry’s law, we can see that for a fixed quantity of gas,
q Pelster, B., and D. J. Randall. 1998. The physiology of the Root ef-
if solubility decreases, partial pressure must increase.
fect. In Fish Respiration, S. F. Perry and B. L. Tufts, eds., 113–139.
Thus, this salting-out effect will increase PO2 and aid San Diego: Academic Press.
oxygen diffusion into the swim bladder. Other gases, in- q Tanaka, H., Y. Takagi, and Y. Naito. 2001. Swimming speeds and
cluding CO2 and N2, are subject to this effect, which may buoyancy compensation of migrating adult chum salmon
explain the relatively high levels of these gases in the Oncorhynchus keta revealed by speed/depth/acceleration data
swim bladders of some species. logger. Journal of Experimental Biology 204: 3895–3904.
481
Respiratory Systems
this chapter, a similar effect occurs in some mam-

100
mals in response to high-altitude hypoxia.
20°C
80
60 37°C 2 C O N C EP T CH E CK
14. What is the role of the metal ion that is found in
40 43°C most respiratory pigments?
15. What effect does changing the amount of
20
hemoglobin in the blood have on the P50 of a
blood sample, and why?
16. Why does the oxygen equilibrium curve of
0 20 40 60 80 100 mammalian hemoglobin have a sigmoidal
PO2 (mm Hg)
shape?
17. Compare and contrast the Root effect and the
Figure 34 Effects of temperature on oxygen Bohr effect.
equilibrium curves
In most mammals, the effect of increased 2,3-

Carbon Dioxide Transport
DPG is to increase the P50 (decrease the oxygen
affinity) of hemoglobin (Figure 35). Some 2,3-DPG Mitochondrial respiration produces carbon diox-
is present within red blood cells at all times, and ide that must be transported out of the body. As is
thus hemoglobin-oxygen binding is somewhat in- the case for oxygen, in very small animals, carbon
hibited even at rest. 2,3-DPG levels increase in re- dioxide can simply diffuse from the tissues to the
sponse to anemia, a condition in which external environment, but in larger animals, the
hemoglobin levels are low, causing reduced oxy- circulatory system transports carbon dioxide from
gen carrying capacity, which could reduce oxygen the tissues to the respiratory surface, where it dif-
delivery to the tissues. Increasing 2,3-DPG levels fuses into the external environment.
cause a modest right shift of the oxygen equilib- Carbon dioxide is much more soluble in body
rium curve. This change in P50 is not enough to fluids than is oxygen. However, very little of the CO2
harm oxygen loading at the lungs, but helps oxy- present in the blood of vertebrates is actually in the
gen unloading at tissues. As we discuss later in form of molecular CO2. Some of the CO2 binds to
proteins. For example, when CO2 binds to hemoglo-
bin, it forms carbaminohemoglobin. Carbaminohe-
moglobin is a significant means of CO2 transport in
100 No 2,3-DPG
mammals, but it may not be significant in other or-
ganisms (which have far less hemoglobin).

80 The majority of the CO2 is transported as bi-
carbonate (HCO3⫺). Carbon dioxide reacts sponta-
60 Normal 2,3-DPG neously in water according to the following
equation:
40 High 2,3-DPG
CO2 ⫹ H2O Δ H2CO3 Δ HCO3⫺ ⫹ H⫹
carbonic acid bicarbonate
20
However, the equilibrium constant of this equation
lies far to the left, and this spontaneous reaction
0 20 40 60 80 100 occurs slowly in aqueous solutions. In animals, an
PO2 (mm Hg) enzyme called carbonic anhydrase (CA) cat-
alyzes the formation of HCO3⫺. In contrast to the
Figure 35 Allosteric modulation of oxygen uncatalyzed reaction, the reaction catalyzed by
affinity of hemoglobin Effects of the organic
modulator 2,3-DPG on the oxygen equilibrium curve of carbonic anhydrase occurs extremely rapidly. Like
mammalian hemoglobin. the respiratory pigments, carbonic anhydrase is a
482
Respiratory Systems
metalloprotein, but in this case the enzyme con- tion depend on blood pH, and how well H⫹ ions
tains a zinc ion. Water binds to the zinc ion within are buffered. To understand this effect we need to
the protein, and is dissociated to form H⫹ and recall the principles of buffering and mass action
OH⫺. The enzyme then directs the transfer of the ratios from basic chemistry. We can write the equi-
OH⫺ ion to carbon dioxide, forming a bicarbonate librium constant for the reaction of CO2 and H2O as
ion in the following reaction:
3 HCO3⫺ 4 3H ⫹ 4
CO2 ⫹ H2O Δ HCO3⫺ ⫹ H⫹ K⫽
3CO2 4
In principle, the bicarbonate formed as a result of
carbonic anhydrase catalysis could further dissoci- Because K is a constant, from this equation we can
ate into carbonate (CO3⫺) and H⫹, but this reaction easily see that when [H⫹] is high, [HCO3⫺] must de-
is not physiologically significant in most animals. crease, if [CO2] stays constant. In essence, as pH de-
Together, molecular CO2, carbaminohemoglobin, creases (and H⫹ increases)—for example, as a
and HCO3⫺ make up the total CO2 content of the result of muscle anaerobic metabolism—the CO2-
blood. In mammals, approximately 70% of the bicarbonate reaction (CO2 ⫹ H2O Δ HCO3⫺ ⫹ H⫹)
blood CO2 content is in the form of HCO3⫺, whereas will be pushed to the left, decreasing the amount of
7% is present as dissolved CO2 in solution, and 23% HCO3⫺. In contrast, as pH increases (and H⫹ de-
is in the form of carbaminohemoglobin. creases) the reaction will be pushed to the right, in-
creasing the amount of HCO3⫺. The close
relationship between blood pH and carbon dioxide
The carbon dioxide equilibrium curve become even more obvious if we log transform this
quantifies carbon dioxide transport equation, yielding the Henderson-Hasselbalch
Carbon dioxide equilibrium curves show the rela- equation:
tionship between PCO2 and the total carbon dioxide 3 HCO3⫺ 4
pH ⫽ pK ⫹ log
3 CO2 4
content of the blood, and as such are analogous to
oxygen equilibrium curves (Figure 36). However,
blood does not become saturated with CO2; there is In general, blood is very well buffered. As HCO3⫺
a rapid increase in CO2 content at relatively low forms, the H⫹ ions are quickly bound to buffer
PCO2, and a continued but slower increase as PCO2 groups such as the terminal amino groups on pro-
rises. teins, and the imidazole side chains found on
The exact shape of the CO2 equilibrium curve amino acids such as histidine. This prevents H⫹
depends largely on the kinetics of HCO3⫺ forma- from accumulating and allows further HCO3⫺
tion in the blood. In turn, the kinetics of this reac- formation. The greater the buffering capacity of
the blood, the greater the capacity to form HCO3⫺.
For example, human blood is so highly buffered
Carbon dioxide content (ml/100 ml blood)
70
that 99.999% of the H⫹ formed by the carbonic an-
Deoxygenated hydrase reaction can be buffered. Mammalian he-
60 blood
moglobins have relatively high numbers of
50 histidines, and thus act as effective buffers. In con-
Oxygenated trast, many fish hemoglobins have few histidines
40 blood
on the surface of the molecule, and thus act as
30 poor buffers. Differences in the buffering capacity
of the blood contribute to differences in the shape
20
Dissolved CO2 of the CO2 equilibrium curve among species.
10
0
0 10 20 30 40 50 60 70
Blood oxygenation affects CO2 transport
PCO2 (mm Hg) Deoxygenated blood can carry more CO2 than can
oxygenated blood (Figure 36). In other words, the
Figure 36 Carbon dioxide equilibrium curve
CO2 equilibrium curve of deoxygenated blood is
(human blood) The carbon dioxide equilibrium curve of
most vertebrates differs for oxygenated and deoxygenated shifted to the left, a phenomenon known as the
blood, a phenomenon called the Haldane effect.
483
Respiratory Systems
Haldane effect. Oxygenated hemoglobin releases mation of HCO3⫺. The H⫹ formed by this reaction
H⫹ ions. This reduces pH (by increasing the concen- binds to hemoglobin. Bicarbonate does not readily
tration of H⫹ ions) and shifts the CO2-bicarbonate diffuse through membranes, but the HCO3⫺ ions
reaction to the left, reducing the amount of HCO3⫺ are moved out of the red blood cell by a chloride-
in the blood, and reducing the total amount of bicarbonate exchanger, also called band III. This
CO2 that can be carried. In contrast, deoxy- process of Cl⫺/HCO3⫺ exchange is known as the
genated hemoglobin tends to bind H⫹ ions, in- chloride shift. If this HCO3⫺ were not removed, it
creasing the pH and HCO3⫺, and increasing the would build up within the red blood cell and would
total amount of CO2 that can be carried. The sig- tend to reverse the carbonic anhydrase reaction.
nificance of the Haldane effect is that deoxygena- Within the red blood cell, band III and carbonic
tion of hemoglobin at the tissues promotes CO2 anhydrase are bound to each other, and another
uptake by the blood, whereas oxygenation of he- isoform of carbonic anhydrase is linked to band III
moglobin at the respiratory surface promotes CO2 on the extracellular face of the membrane. To-
unloading. gether, these proteins form a metabolon (a group
of enzymes that work together to perform a func-
tion and are spatially localized within the cell).
Vertebrate red blood cells play a role Metabolons allow pathways to function more rap-
in CO2 transport idly than would be possible if the substrates and
In vertebrates, carbonic anhydrase is present pri- products had to diffuse through the cell from one
marily within the red blood cells, and all of the re- enzyme to another.
actions discussed above occur within these cells At the respiratory surface, the PCO2 of the envi-
rather than in the plasma. However, most of the ronment is lower than that of blood, and CO2 dif-
bicarbonate is actually carried in the plasma. This fuses out of the plasma across the respiratory
phenomenon is easiest to understand by working surface. Because of this drop in plasma PCO2, CO2
through an example of carbon dioxide transport diffuses out of the red blood cell and into the
(Figure 37). At the tissues, CO2 is produced by aer- plasma. This decrease in [CO2] within the red
obic metabolism, and rapidly diffuses out of tis- blood cell shifts the CO2-bicarbonate reaction,
sues and into the red blood cells. Within the red causing the band III exchanger to move HCO3⫺
blood cell, carbonic anhydrase catalyzes the for- ions from the plasma into the red blood cells in ex-
Red blood cells Respiratory surface

Plasma Respiratory
medium
(air or water)
H2O
CO2 CA
CO2
CO2 CO2 Hb • H
Hb
Hb
Hb • CO2 HCO3– + H+ Hb • H Hb • CO2
CO2
Hb Hb
H+ + HCO3 – CO2
Cl– CA
Cl– H2O
Capillary wall
Red blood cells
Interstitial fluid
HCO3 –
Tissue cells Plasma
(a) Systemic tissues (b) Respiratory surface
Figure 37 Carbon dioxide transport in by the CA reaction are buffered by hemoglobin. (b) In the
vertebrate blood (a) Carbon dioxide diffuses from the lungs, CO2 diffuses into the alveoli, and the CA equilibrium
tissues into the red blood cell. Some binds to hemoglobin, shifts to favor the formation of CO2, reducing the amount of
forming carbaminohemoglobin (Hb ⭈ CO2). Carbonic HCO3⫺ within the red blood cell. HCO3⫺ enters the red blood
anhydrase (CA) within the red blood cell catalyzes formation cell in exchange for Cl⫺, and is converted to CO2, which then
of HCO3⫺. The HCO3⫺ is transported out of the red blood cell diffuses into the alveoli.
in exchange for Cl⫺ (the chloride shift). The H⫹ ions produced
484
Respiratory Systems
change for Cl⫺ (in a reverse chloride shift). The PCO2 PCO2
80
HCO3⫺ and H⫹ form carbonic acid and then CO2, 40 mm Hg 20 mm Hg
and the CO2 diffuses out of the red blood cell into
the plasma and then across the respiratory sur- 60
[HCO3–] (mM)
face. The location of carbonic anhydrase within PCO2
the red blood cell increases the total CO2 carrying 10 mm Hg
capacity of the blood by ensuring that the products 40
of the carbonic anhydrase reaction do not build up Blood
buffer line
within a single compartment. This forces the CO2-
20
bicarbonate equilibrium to the right, and in-
creases the amount of CO2 that is carried as PCO2 5
HCO3⫺. In many vertebrates, carbonic anhydrase 0
mm Hg
is also present on the endothelial cells lining tis- 7.0 7.2 7.4 7.6 7.8 8.0
sues such as the lungs. As a result, all of the bicar- pH
bonate does not necessarily have to travel via a Figure 38 A pH-bicarbonate plot Sometimes called
red blood cell to be converted to CO2. a Davenport diagram, a pH-bicarbonate plot with PCO2
isopleths can be used to visualize the relationships between
pH, HCO3⫺, and PCO2 in a buffered solution. Values shown are
The respiratory system can regulate for the European eel.
(Adapted from McKenzie, D.J. et al. 2003. Tolerance of chronic
blood pH hypercapnia by the European eel, Anguilla anguilla. Journal of
Experimental Biology 206: 1717–1726.)
Because most proteins have a relatively narrow
pH range in which they function effectively, most
animals closely regulate intracellular pH. Most an- plasma as HCO3⫺ is varied for a series constant val-
imals also regulate the pH of extracellular fluids ues of PCO2. A Davenport diagram also includes the
such as blood, because regulating extracellular pH blood buffer line, which is an empirically calculated
reduces the regulatory burden on individual cells. relationship showing the change in blood HCO3⫺
For example, in humans the normal pH of blood is when pH is titrated. The blood buffer line depends
approximately 7.4; a pH above 7.7 or below 6.8 on the composition of the plasma, and thus varies
can be fatal. Because of the tight linkage between among species. Under normal circumstances, an
CO2 and pH through the reaction catalyzed by car- animal has typical values of plasma pH, HCO3⫺, and
bonic anhydrase, which we have already dis- PCO2 that fall on the blood buffer line. For example,
cussed, respiratory systems play an important role for mammals PCO2 is typically 40 mm Hg, plasma pH
in the regulation of pH in extracellular fluids such is 7.4, and [HCO3⫺] is 24 mM.
as blood. Because the partial pressure of a gas, A pH-bicarbonate plot allows physiologists to
rather than its concentration, is the most physio- visualize what happens to the other parameters in
logically relevant parameter, we can rewrite the the system when any one parameter is varied. For
Henderson-Hasselbalch equation as follows: example, consider what happens when an animal
3HCO3⫺ 4
hyperventilates. Hyperventilation is defined as
pH ⫽ pK ⫹ log alveolar ventilation greater than is needed to re-
␣CO2 ⫻ PCO2 move the CO2 produced by metabolism. During hy-
where ␣CO2 is the solubility of carbon dioxide in perventilation plasma PCO2 will fall. As PCO2
the fluid, and PCO2 is the partial pressure of carbon declines, pH and HCO3⫺ values will shift along the
dioxide. blood buffer line, and pH will increase while HCO3⫺
Physiologists use a type of graph called a pH- decreases. In contrast, during hypoventilation,
bicarbonate plot (which is sometimes referred to alveolar ventilation is less than is needed to re-
as a Davenport diagram) to describe the interrela- move the CO2 produced by metabolism. In this
tionships between PCO2, HCO3⫺, and pH (Figure 38). case, plasma PCO2 will increase and pH and HCO3⫺
These diagrams consist of a graph of the relation- values will shift along the blood buffer line, with pH
ship between pH (plotted on the x-axis) and [HCO3⫺] decreasing and [HCO3⫺] increasing.
(plotted on the y-axis). Onto this graph are super- From a pH-bicarbonate plot it is very clear that
imposed a series of curved diagonal lines called changes in ventilation will result in changes in pH.
isopleths. Each isopleth represents the pH of the Respiratory acidosis occurs when ventilation is
485
Respiratory Systems
insufficient to remove all of the CO2 produced by 21. How can the respiratory system regulate
metabolism. This shifts the carbonic anhydrase blood pH?
reaction to the right, increasing [H⫹] and de-
creasing pH. In contrast, a respiratory alkalo-
sis occurs when ventilation is greater than is
needed to remove the CO2 produced by metabo- Regulation of Vertebrate
lism, causing a net loss of CO2, which shifts the Respiratory Systems
carbonic anhydrase reaction to the left, and in-
creases the pH. Like other physiological systems, respiratory sys-
Changes in metabolism can also directly affect tems are closely regulated in response to changes
extracellular pH. During intense exercise, muscles in both the internal and external environments.
produce H⫹ ions. This pH disturbance is often Vertebrate respiratory and circulatory systems
called a lactic acidosis, because intense exercise work together to regulate gas delivery and plasma
also produces lactate as a result of anaerobic glycol- pH by (1) regulating ventilation, (2) altering oxy-
ysis. Because the lactate itself is not the source of gen carrying capacity and affinity, and (3) altering
the protons, this decrease in pH is more properly perfusion.
referred to as a metabolic acidosis. Metabolic aci-
dosis can also occur because of excessive loss of
HCO3⫺ from the intestine during intense diarrhea, Regulation of Ventilation
or as a result of kidney failure. In contrast,
Ventilation is an automatic rhythmic process that
metabolic alkalosis can occur as a result of the
continues even during loss of consciousness.
loss of excess H⫹ from vomiting, or because of a loss
Rhythmically firing groups of neurons within the
of H⫹ from the kidneys as a result of kidney failure.
central nervous system, or central pattern gener-
Let’s examine what would happen during a meta-
ators, initiate ventilatory movements in animals.
bolic acidosis if PCO2 were held constant. The meta-
In the vertebrates, these central pattern genera-
bolic protons would react with HCO3⫺, decreasing
tors are located within the medulla of the brain.
[HCO3⫺]. If PCO2 is held constant, however, the rela-
All vertebrates that have been examined so far
tionship of pH to [HCO3⫺] cannot move off the PCO2
have a column of respiratory-related neurons run-
isopleth, and thus the values move off the blood
ning along each side of the medulla. In bony fish,
buffer line and pH falls. Of course, animals can ad-
the central pattern generator is located in the ros-
just their rate and depth of ventilation, which alters
tral (or anterior) part of the medulla near the neu-
PCO2. These changes can be used to correct pH im-
rons that innervate the buccal cavity. Lampreys,
balances. For example, metabolic acidosis causes
amphibians, and mammals, however, appear to
increased ventilation, inducing a respiratory alka-
have at least two pairs of pattern generators. In
losis and returning the pH to normal values. How-
mammals, these pattern generators are located in
ever, the respiratory system is responsible largely
the caudal medulla. Less is known about the loca-
for minute-to-minute regulation of blood pH, while
tion of the respiratory pattern generators in rep-
the excretory system plays the major role in long-
tiles and birds, but they are likely to be found in
term regulation. In the next section of this chapter,
locations similar to those in amphibians and
we examine some of the mechanisms by which an-
mammals.
imals regulate their ventilation, and thus gas ex-
Respiratory rhythm generation has been most
change and plasma pH.
extensively studied in mammals (Figure 39). The
precise mechanisms of respiratory rhythm gen-
eration are still not fully understood. In at least
2 CO N CEP T C HE C K some vertebrates, a small region of the caudal
18. List the forms in which CO2 is carried in the medulla called the pre-Bötzinger complex
blood of vertebrates. is essential for respiratory rhythm generation.
19. Using the Henderson-Hasselbalch equation, In addition, another neuronal complex, the
outline what happens to the pH of a poorly parafacial respiratory group or pre-I complex, is
buffered aqueous solution when [CO2] increases.
20. Why does blood oxygenation affect the CO2
equilibrium curve of blood?
486
Respiratory Systems
Chemosensory input influences ventilation

Chemosensory input helps to modulate the output
of the central pattern generators. Chemoreceptors
detect changes in CO2, H⫹, and O2 and send affer-
ent sensory information to the brain. Various re-
gions in the brain integrate this information and
provide input to the respiratory rhythm genera-
tors to modify the rate or depth of breathing.
Midbrain
These changes in breathing act by negative feed-
back to maintain blood PCO2 and PO2 within a nar-
row range.
Oxygen sensing is of primary importance in
Pons Pontine respiratory water-breathing vertebrates, whereas CO2 sensing
group (PRG)
is of primary importance in air-breathing verte-
Parafacial
respiratory group brates. Oxygen levels in water are low compared
(Pre- ) to those in air, and hypoxia, or lower than normal
Pre-Bötzinger PO2, is a common occurrence in aquatic environ-
complex ments. As a result, aquatic organisms must have
Medulla high ventilation in order to obtain sufficient CO2.
These levels of ventilation are usually more than
adequate to remove CO2, and blood CO2 content is
typically low. In contrast, oxygen is generally pres-
ent at high levels in air, and air-breathing organ-
Spinal isms do not need to ventilate at such high levels to
cord obtain oxygen. But as a result, less CO2 is removed,
and total CO2 content of the blood is typically
Figure 39 Location of the respiratory central higher in air breathers than in water breathers.
pattern generators in mammals
Water breathers have internal O2 chemorecep-
tors that monitor the PO2 of blood within the gills.
There are also O2 chemoreceptors on the surface of
coupled to the pre-Bötzinger complex. Neurons the body, particularly in the gill cavity and on the
in the parafacial respiratory group fire before surface of the gills, although the distribution of
those in the pre-Bötzinger complex and appear these receptors may vary among species. The O2
to play an important role in specifying the timing chemoreceptors send afferent signals to the
of the rhythm in the pre-Bötzinger complex. In medulla that modulate the output of the respiratory
addition, neurons in the ventral respiratory and cardiac rhythm generators. The efferent sig-
group, particularly in the Bötzinger complex, nals from these rhythm generators regulate ventila-
have also been implicated in respiratory rhythm tion volume and rate, cardiac output, and the
generation. perfusion pattern within the gills. Water breathers
Rhythm generators can work in a variety of also have CO2/pH chemoreceptors in the gills, al-
ways. Some combination of cells with intrinsic though these are thought to be primarily involved in
pacemaker properties and networks of groups of sensing the characteristics of the external medium.
neurons cause the rhythmic firing of neurons in Air-breathing vertebrates have internal
the respiratory rhythm generators, although the CO2/pH chemoreceptors that monitor either the
exact molecular mechanisms are not yet known. PCO2 or the pH of the blood. Because of the tight
These respiratory pattern generators send signals linkage between CO2 and [H⫹] through the car-
that are integrated by a variety of interneurons bonic anhydrase equilibrium, it is difficult to estab-
that ultimately send signals to the somatic motor lish with any certainty exactly which parameter
neurons that control the skeletal muscles involved these chemoreceptors are sensing, although recent
in breathing. evidence suggests that they sense intracellular pH.
There are two main clusters of internal CO2/pH
487
Respiratory Systems
chemoreceptors: central chemoreceptors, lo-

cated in the medulla of the brain, and peripheral Conscious
control CO2 pH O2
chemoreceptors, located in specific arteries.
The central chemoreceptors respond to pH
changes in the cerebrospinal fluid. Although the Higher Medullary Carotid and
blood-brain barrier is relatively impermeable to brain chemoreceptors aortic body
centers chemoreceptors
protons, CO2 readily diffuses into the cere-
brospinal fluid. Carbonic anhydrase within this
fluid catalyzes the formation of HCO3⫺ and H⫹, Limbic Afferent
which stimulates these chemoreceptors. Increases system Pons sensory
in CO2 (and thus H⫹) stimulate ventilation, whereas neurons
decreases in CO2 (and thus H⫹) reduce ventilation.

The peripheral chemoreceptors of mammals Central Pattern Generator
(Medulla oblongata—
sense both PO2 and PCO2 /pH. The carotid body Pre- + pre-Bötzinger complex)
chemoreceptors are located in the carotid artery
and monitor the composition of blood going to the
brain. The aortic body chemoreceptors, located Somatic motor
in the wall of the aorta, monitor the composition of neurons
the blood going to the body. These receptors fire Negative

feedback
only when plasma PO2 starts to fall below the level
Intercostal muscles
required to fully saturate hemoglobin, which in and diaphragm
most animals occurs only during pronounced hy-
poxia. As a result, the majority of respiratory reg-
ulation is accomplished by sensing CO2/pH, with Rate and depth
of ventilation
the central chemoreceptors playing the predomi-
nant role (Figure 40).
Figure 40 Reflex regulation of ventilation in
mammals
Other factors regulate breathing
A number of mechanosensory reflexes also influ- thus stimulates ventilation. These receptors are
ence breathing. For example, in mammals irritants particularly important in animals such as turtles in
such as inhaled particles can stimulate receptors in which the lungs fill, but do not stretch appreciably.
the airways of the lungs. These mechanoreceptors Breathing is also under the control of higher
send a signal to the central nervous system that brain centers in the hypothalamus and cerebrum.
causes the bronchi to constrict. This protective For example, we can voluntarily alter our breath-
bronchoconstriction prevents the inhalation of ing patterns. However, although we can temporar-
more particles. Another set of mechanoreceptors, ily override the respiratory centers, we cannot do
the slowly adapting pulmonary stretch receptors, so indefinitely. If you attempt to hold your breath,
detect the amount of tension in the walls of the air- eventually the drive to breathe becomes so in-
ways, including the trachea and bronchi. These tense, as a result of the chemoreceptor input into
stretch receptors trigger the Hering-Breuer infla- the medullary respiratory centers, that you are
tion reflex, which terminates inhalation. In adult forced to breathe.
humans, the Hering-Breuer reflex is difficult to
demonstrate except when tidal volumes are ex-
tremely large, and thus it is thought to protect the
lungs from being damaged by overinflation. How-
Environmental Hypoxia
ever, in human infants and in adults of other mam- Organisms regulate their respiratory systems in
malian species, the Hering-Breuer reflex may play response to changes in both their external and in-
a significant role in breath-by-breath regulation. ternal environments. Ventilation rate and breath-
Vertebrate lungs also contain receptors that are ing frequency typically increase in response to
sensitive to CO2 in the lungs or in the pulmonary cir- increases in metabolic demand, such as during
culation. Increasing CO2 inhibits the receptors, and exercise. Animals may also have to cope with
488
Respiratory Systems
changes in environmental oxygen and carbon ment. Some fish can reduce their metabolic rate
dioxide. In aquatic environments, for example, en- by reducing their activity level, moving to cooler
vironmental oxygen often varies from the water to reduce metabolic rate, or actively sup-
normoxic condition. During the day, when photo- pressing their metabolism to conserve energy (see
synthesis is maximal and plants are net oxygen Box 3, Evolution and Diversity: Hypoxic Metabolic
producers, enclosed bodies of water such as Suppression).
ponds, swamps, or tidepools can become
hyperoxic—supersaturated with oxygen. In con-
trast, at night when plants are net oxygen con-
Air breathers can experience high-altitude
sumers, these habitats can become extremely
hypoxia
hypoxic, and fish living in these areas can experi-
ence very low oxygen levels. Terrestrial animals Most air-breathing organisms only experience low
seldom experience hyperoxia, but may experience environmental oxygen in specific habitats, such as
hypoxia within burrows or at high altitudes. You when diving, within enclosed spaces such as bur-
may also come across the term hypoxemia— rows, or at high altitudes. When low-altitude-
lower than normal arterial blood oxygen content. adapted animals are brought to high altitudes,
Hypoxemia can be caused by environmental hy- they undergo a number of physiological changes,
poxia, inadequate ventilation, reduced blood he- some of which may be involved in acclimatizing to
moglobin content, and a variety of disease states. the environmental hypoxia, and some of which
The terms hypercapnia and hypocapnia de- may be pathological, if the animals are unable to
scribe higher or lower than normal PCO2 in either acclimatize. When a low-altitude-adapted mam-
the environment or the blood. Like hypoxia, envi- mal experiences high-altitude hypoxia, blood PO2
ronmental hypercapnia can occur within enclosed drops. Arterial chemoreceptors detect this decline
environments such as burrows. in blood PO2, and send a signal to the medulla to
increase the rate and depth of breathing, restoring
or partially restoring blood PO2. Because of the in-
Fish respond to hypoxia in many ways creased ventilation rate, more CO2 will be lost at
Many fish have external oxygen chemoreceptors the lungs, leading to hypocapnia, or lower than
that can detect environmental hypoxia, allowing normal blood PCO2. Recall that, in mammals, blood
fish to initiate behavioral or physiological re- PCO2 provides the primary drive to breathe. The
sponses to prevent hypoxemia from occurring, low blood PCO2 at altitude can cause difficulty with
for example by moving away from hypoxic water. breathing, particularly during sleep when the con-
If this initial strategy fails, environmental hy- scious drive to breathe is removed. Because of the
poxia causes an initial, usually transient, de- carbonic anhydrase equilibrium, hypocapnia also
crease in blood PO2. This decrease in blood PO2 leads to low [H⫹]. Thus, the ventilatory response to
stimulates the internal O2 chemoreceptors, caus- high altitude causes respiratory alkalosis. Over
ing an increase in ventilation. A fish that ram longer-term exposure to high altitude, this persis-
ventilates typically opens its mouth wider to in- tent respiratory alkalosis triggers the kidneys to
crease the flow of water over the gills, whereas a excrete HCO3⫺ in an attempt to homeostatically
fish that uses buccal-opercular pumping in- regulate blood pH.
creases the rate and depth of these movements. If High-altitude hypoxia also leads to increases
respiratory adjustments are insufficient to com- in red blood cell numbers. This effect of high alti-
pensate for environmental hypoxia, some types of tude is one reason competitive athletes may
fish initiate behavioral strategies such as aquatic choose to train at high altitudes or utilize a hypo-
surface respiration, in which they move to the baric chamber, which provides an artificial low-
surface of the water and ventilate their gills with pressure, low-PO2 environment. It is currently a
the thin layer of better-oxygenated water at the matter of some debate as to whether this increase
air-water interface. in red blood cell numbers (or polycythemia) actu-
Prolonged exposure to hypoxia causes an in- ally assists in acclimatization to altitude. Poly-
crease in red blood cell numbers, and thus hemo- cythemia results in an increase in hematocrit, the
globin concentration, increasing oxygen carrying proportion of the blood volume occupied by red
capacity and oxygen extraction from the environ- blood cells. High hematocrit causes increased
489
Respiratory Systems

Hypoxic Metabolic Suppression
In low-oxygen environments, animals vive adverse environmental conditions, including low

may be unable to obtain sufficient oxygen to temperature, low food availability, or desiccation, in addi-
meet the metabolic needs of their tissues. Many ani- tion to hypoxia. Although the nature of these conditions is
mals that can survive environmental hypoxia use a diverse, in each case animals need to reduce metabolic
strategy called hypoxic metabolic suppression (or hy- rate to preserve energy stores. Hibernation (a long pe-
pometabolism), in which they reduce their activity and riod of metabolic depression associated with cold tem-
metabolic needs in parallel with the reduced oxygen perature) and torpor (a shorter period of metabolic
supply. This reduction in metabolic rate reduces oxygen depression, often seen at night) are particularly interest-
demand and may allow an animal to survive for long pe- ing hypometabolic states because they occur under nor-
riods despite environmental hypoxia. For example, moxic conditions. As animals enter into hibernation or
some species of temperate zone turtles make use of hy- torpor they voluntarily reduce ventilation in parallel with
poxic metabolic suppression to survive long periods un- the reduction in metabolic rate. Thus, these animals ac-
derwater. Freshwater turtles, such as the painted turtle tively reduce both oxygen supply and demand in concert.
(Chrysemys picta) and the red-eared slider (Trachemys Many mammalian hibernators, such as ground squirrels,
scripta) are obligate air breathers, but can remain sub- exhibit a pattern of episodic breathing during hibernation
merged for long periods—for example, during winter in that includes long periods of apnea interspersed with
ice-covered ponds. Some species also bury themselves ventilatory bouts. The mechanisms that convert the reg-
in anoxic mud. The metabolic rate of a submerged tur- ularly spaced pattern of mammalian breathing to an
tle at low temperatures is less than 0.1% of the nor- episodic pattern during hibernation are not yet under-
moxic summer metabolic rate. Part of this metabolic stood, but presumably involve changes in the function of
rate depression is a result of the decrease in tempera- the respiratory pacemakers in the medulla.
ture, but a substantial component is the result of active
suppression of metabolism. References
The triggers that induce hypoxic metabolic suppres- q Boutilier, R. G., P. H. Donohoe, G. J. Tattersall, and T. G. West.
sion are not yet understood, but one cue may be tissue 1997. Hypometabolic homeostasis in overwintering aquatic am-
acidosis. When oxygen supply is not sufficient to meet phibians. Journal of Experimental Biology 200: 387–400.
the metabolic needs of the organism, such as during en- q Dupre, R. K., A. M. Romero, and S. C. Wood. 1988. Thermoregu-
vironmental hypoxia, ATP must be produced using lation and metabolism in hypoxic animals. In Oxygen Transfer
anaerobic pathways. In most animals this involves flux from Atmosphere to Tissues, N. C. Gonzalez and M. R. Fedde, eds.,
347–351. New York: Plenum Press.
through glycolysis, producing lactate as the metabolic
end product. High glycolytic flux that is not matched by q Gautier, H. 1996. Interactions among metabolic rate, hypoxia,
and control of breathing. Journal of Applied Physiology 81:
aerobic respiration results in a metabolic acidosis—an
521–527.
increase in the net hydrogen ion production by the cell. A
q Jackson, D. C. 2004. Acid-base balance during hypoxic hypome-
large metabolic acidosis can have dangerous conse-
tabolism: Selected vertebrate strategies. Respiratory Physiology
quences for an organism, because most enzymes are and Neurobiology 141: 273–283.
highly sensitive to the pH of the body. Initial exposure to
q Platzack, B., and J. W. Hicks, 2001. Reductions in systemic oxy-
hypoxia results in a modest tissue acidosis. This acidosis gen delivery induce a hypometabolic state in the turtle Trachemys
can then act as a cue to trigger a reduction in metabolic scripta. American Journal of Physiology 281: R1295–R1301.
rate, protecting the animal against further acidosis. q Tattersall, G. J., J. L. Blank, and S. C. Wood. 2002. Ventilatory and
Hypometabolic states are not unique to hypoxic envi- metabolic responses to hypoxia in the smallest simian primate,
ronments. Many organisms use hypometabolism to sur- the pygmy marmoset. Journal of Applied Physiology 92: 202–210.
blood viscosity, which could impair blood flow would, in principle, decrease the oxygen affinity of
through capillaries and interfere with gas ex- the blood, which might assist in oxygen unloading
change at the tissues. at the tissues. However, the respiratory alkalosis
In humans and many other lowland-adapted associated with hyperventilation generally cancels
animals, hypoxia also increases the levels of 2,3- out this effect, resulting in no net change in hemo-
DPG in the red blood cells. Increased 2,3-DPG globin oxygen affinity at altitude.
490
Respiratory Systems
Environmental hypoxia High altitude

also affects blood flow through
the lungs of lowland-adapted Negative feedback
Inspired PO2 – (cannot fully compensate
animals. The low alveolar PO2 when inspired PO2 very low)
caused by the low environmen-
tal PO2 causes the pulmonary Alveolar PO2
arterioles to vasoconstrict, re-
ducing perfusion of the lungs. Arterial PO2
This pathological response re-
duces oxygen uptake from the
atmosphere, and is dangerous Kidney synthesis Tissue O2 delivery Peripheral
because the generalized vaso- of erythropoietin chemoreceptor
– firing rate
constriction causes increased –
Reduces
blood pressure within the Hematocrit O2 loading
if change
lungs, which can lead to pul- is large Medullary central
monary edema, or accumula- pattern generator
tion of fluid in the lungs.
Pulmonary edema is particu- Improves Capillary
Red blood cell delivery if density Ventilation
larly dangerous because the 2,3-DPG change is
Myoglobin
accumulated fluid increases modest
the diffusion distance across the
Hb O2 Arterial PCO2
alveolar epithelium, reducing affinity
the efficiency of gas exchange.
High-altitude pulmonary edema Competing
effects Hb O2 Respiratory alkalosis
is one of the most severe forms affinity
of “mountain sickness” in hu-
mans, and is one of the most Figure 41 The response to high altitude in humans
dangerous consequences of ex-
posure to very high altitudes
(Figure 41).
A number of mammalian species, including been shown to be heritable in this population, and
some human populations, have colonized high- thus may be subject to ongoing natural selection.
altitude habitats. For example, populations of in- Individuals in high-altitude Ethiopian populations
digenous peoples in China, Nepal, Tibet, Ethiopia, exhibit yet another pattern. They are not barrel-
and Peru all inhabit altitudes that cause respira- chested, do not have elevated amounts of hemo-
tory problems for low-altitude-adapted human globin, and do not have high hemoglobin oxygen
populations. We are only just beginning to under- affinity, but they are able to maintain arterial oxy-
stand the physiological differences between indi- gen saturation at normal levels in the face of low
viduals in these populations and lowland human environmental oxygen. The physiological basis for
populations, but the data collected so far suggest this difference is still unknown.
that each of these populations uses a different A number of other mammals have colonized
strategy for coping with high altitude. For exam- high altitudes, including species such as llamas,
ple, the Quechua of Peru are typically barrel- chinchillas, guinea pigs, and deer mice. High-
chested, suggesting a higher than usual lung altitude-adapted populations of deer mice have re-
capacity, and have high hemoglobin levels. In con- duced levels of 2,3-DPG in their red blood cells
trast, Tibetan populations are not barrel-chested, compared to low-altitude populations, when both
and have moderately elevated hemoglobin levels. populations are reared at a common altitude. This
Individuals in Tibetan populations vary in arterial decrease in 2,3-DPG results in an increase in he-
hemoglobin oxygen saturation, and individuals moglobin oxygen affinity, allowing them to effi-
with higher oxygen saturation have higher off- ciently extract oxygen from the atmosphere at high
spring survival than individuals with low oxygen altitudes. Llamas, vicunas, chinchillas, and guinea
saturation. Differences in oxygen saturation have pigs also have unusually high hemoglobin oxygen
491
Respiratory Systems
affinity. In llamas and vicunas, this increase in lation and the resulting hypocapnia and alkalosis
affinity is the result of one or a few mutations in much better than mammals, allowing them to in-
the globin genes that eliminate the effects of 2,3- crease oxygen extraction at high altitude.
DPG, resulting in increased oxygen affinity.
The bar-headed geese (Anser indicus) de-
scribed at the beginning of this chapter have un- 2 C O N C EP T CH E CK
usually high hemoglobin oxygen affinity. There are
22. What is a central pattern generator?
only four amino acid differences between the ma-
23. Outline the mechanisms by which changes in
jor hemoglobin of bar-headed geese and the
blood PO2 affect ventilation.
closely related greylag geese that live in the low-
24. Why is it difficult to distinguish whether
lands. One of these mutations results in the loss of
chemosensory cells detect PCO2 or pH?
a hydrogen bond that normally stabilizes the T
25. What are some of the mechanisms by which fish
state of hemoglobin, causing the hemoglobin to as- respond to hypoxia?
sume a more relaxed conformation and causing
26. Why do humans typically become hypocapnic at
the increase in hemoglobin oxygen affinity. In ad- high altitudes?
dition, many birds are able to tolerate hyperventi-
Integrating Systems The Physiology of Diving

A variety of air-breathing vertebrates, including some Aerobic
mammals, birds, and reptiles, have adopted a fully or dive limit
15
partially aquatic mode of life. However, all of these ani-
mals remain dependent on air as a respiratory medium,
Blood lactate (mg/100 ml)
and must be able to actively hunt prey underwater while

relying on the oxygen stores that they carry with them as 10
they dive below the surface. The physiology of diving in
these animals provides an ideal example of the ways in
which the respiratory and circulatory systems are inte-
grated to allow animals to function in their environment. 5
Sperm whales are the champion divers among the
marine mammals, with recorded dives to a depth of
more than 2000 m and dive lengths of more than an
hour. In addition, stomach content analyses suggest 0
0 10 20 30 40 50 60
that sperm whales may dive as deep as 3000 m. The pin- Dive duration (min)
nipeds (seals and sea lions) are also excellent divers.
Among pinnipeds, the elephant seals hold the record for Figure 42 Lactate accumulation during
diving in Weddell seals The aerobic dive limit is
both the longest and deepest dives at almost 1600 m the dive time at which lactate begins to accumulate as a
and nearly 80 minutes. The emperor penguin can dive result of the switch to anaerobic metabolism.
down to 500 m, but its dives are typically relatively short,
averaging around 3 minutes. However, emperor pen-
guins have been known to dive for as long as 22 minutes. either surface to breathe or begin to use anaerobic
Green sea turtles can remain submerged for as long as metabolism—varies greatly among species. For exam-
five hours, although active dives typically average 5–10 ple, adult Weddell seals, which hunt underneath the
minutes. Antarctic ice sheets, have an aerobic dive limit of about
When an air-breathing vertebrate dives, it must rely 20 minutes, whereas California sea lions have an aero-
on stored oxygen to fuel aerobic metabolism. These on- bic dive limit of only about 5 minutes. In principle, two
board stores are typically sufficient for short dives, but physiological adjustments can alter the aerobic dive
cannot sustain metabolism during long dives, and limit: increasing oxygen stores and decreasing oxygen
anaerobic metabolism must be used (Figure 42). The demand. Marine mammals use both of these strategies
aerobic dive limit—the point at which an animal must to increase the length of their dives.
492
Respiratory Systems
A vertebrate can store oxygen in

Human Lungs
three places: in the blood (largely bound
to hemoglobin), bound to myoglobin in Blood
Leatherback turtle
muscle, and in the lungs. Total body oxy- Muscle
gen stores tend to be larger in diving Bottlenose dolphin
mammals than in terrestrial mammals,
although this relationship is most evident Northern fur seal
in very proficient divers (Figure 43). Diving
mammals often have high blood volumes Emperor penguin
and high oxygen carrying capacity, allow-
ing them to store more oxygen in the Weddell seal
blood than is typical for a terrestrial
Elephant seal
mammal. For example, a Weddell seal is
able to store almost five times as much 0 10 20 30 40 50 60 70 80 90 100
oxygen in blood as a human can. Recall Total oxygen (ml/kg)
from our discussion of the effects of high
Figure 43 Total body oxygen stores of diving mammals and humans
altitude that polycythemia increases (expressed per kg body mass)
blood viscosity, and can cause difficulties
with cardiac function. Some species of
seals avoid this problem by storing red blood cells in the A related condition called “the bends,” or decom-
spleen and releasing them during bouts of diving. The pression sickness, occurs when a diver ascends to the
blood cells are returned to the spleen for storage be- surface too quickly. At depth, nitrogen content of the
tween diving bouts. blood is high. As a diver ascends, this nitrogen will sim-
Diving animals typically also have high levels of ply diffuse back into the lungs, and can be exhaled.
muscle myoglobin. Weddell seals have over 50 mg of However, if a diver ascends too quickly the nitrogen will
myoglobin per gram of muscle, and ribbon seals can come out of solution while still in the blood, forming
have as much as 80 mg/g, whereas humans have about bubbles. This is similar to what happens when you open
5–10 mg of myoglobin per gram of muscle. Diving ani- a bottle of soda pop. Soda pop is bottled under a high
mals do not have unusually large lungs, and likely do not pressure of carbon dioxide. When you open the bottle,
make much use of their lungs as an oxygen store during the pressure drops abruptly, causing bubbles to form.
diving. In fact, some species including the Weddell seal Bubbles in the blood are not inevitably harmful. They
dive immediately after they exhale, and thus these ani- only cause problems if they become large, because
mals swim actively without fresh air in the lungs. large bubbles can lodge in small capillaries, blocking
As an animal descends through the water, the blood flow, or can press on nerve endings, or can be-
pressure of the surrounding water increases. The ele- come trapped in other enclosed spaces such as the
vated ambient pressure causes the lungs to decrease joints. Decompression sickness is associated with a va-
in volume. The decrease in volume increases the par- riety of symptoms, the most common of which are pain
tial pressure of the gases within the lungs. This effect in the joints and muscles, and neurological problems,
can be beneficial, because it tends to drive additional including headache and stroke. The risk of nitrogen nar-
oxygen into the circulation, but this benefit comes with cosis and the bends is higher in humans scuba diving
a substantial risk: the increased pressure can also than in free divers, but extreme human free divers, who
drive nitrogen gas into the circulation. This increase in can descend to depths of over 70 m, may experience
blood nitrogen content can lead to a condition called some of these effects. The effects of decompression
nitrogen narcosis. The symptoms of nitrogen narcosis sickness have been observed in the carcasses of
are similar to those of ingesting alcohol, progressing beached sperm whales that have ascended to the sur-
from an initial feeling of euphoria, through disorienta- face too rapidly after being startled by sonar signals.
tion, and finally to loss of consciousness. Nitrogen gas Many diving marine mammals avoid nitrogen nar-
is thought to act in a way similar to the anesthetic gas cosis and decompression sickness by allowing the
nitrous oxide, altering the activity of the nervous sys- lungs (or more properly, the alveoli) to collapse com-
tem by impairing the action of excitatory NMDA recep- pletely during diving. When the alveoli collapse, the air
tors, and enhancing the activity of the inhibitory opioid is pushed back into the conducting airways of the lungs,
receptors. which do not participate in gas exchange. Thus, blood
493
Respiratory Systems
nitrogen levels in diving seals increase very little, re- smooth muscles in the spleen contract, forcing stored red
gardless of dive depth. It is less clear how diving birds blood cells that are saturated with oxygen out into the cir-
avoid this problem, since the lungs themselves are culation. During a forced or long dive, heart rate also
rigid. This difference in lung anatomy may explain why slows, matching the reduced circulatory demand. The ex-
few birds dive deeply or for long periods. Laboratory extent of this diving bradycardia is dependent on dive dura-
periments with Adélie penguins suggest that nitrogen tion in voluntary dives, so that short dives involve little or
levels can increase into the danger zone during unusu- no bradycardia whereas long dives involve a profound
ally long or deep dives. bradycardia.
In addition to increasing oxygen stores, marine The cardiovascular dive response is not unique to
mammals also readjust oxygen demand during long diving mammals, but instead is a fundamental property
dives, presumably to conserve oxygen and increase their of all vertebrates. Most animals reduce metabolic rate
aerobic dive limit. In fact, experiments on freely diving and redistribute blood flow to essential tissues when
Weddell seals in nature suggest that the metabolic rate they are deprived of oxygen. However, the dive response
during diving is lower than during nondiving periods, de- is typically more profound in diving mammals than in
spite the fact that these animals hunt actively while div- terrestrial animals such as humans.
ing. Diving animals use a variety of biomechanical Finally, we must consider the effects of the CO2 that
strategies to reduce the costs of locomotion in water. is produced during a dive, and the resulting drop in
During forced dives in the laboratory, or when a freely div- blood pH. Diving animals appear to have unusually high
ing animal must stay underwater for a prolonged pe- buffering capacity in the blood, which blunts or prevents
riod—for example, to avoid a predator—the animal large swings in blood pH. In addition, diving mammals
invokes a series of physiological mechanisms that have have a greatly reduced ventilatory response to CO2. In
been collectively called the dive response. During the humans, the gradual buildup of CO2 and the resulting
dive response, arterioles leading to the skeletal muscles, decrease in blood pH during apnea act as a very strong
skin, kidneys, and gut constrict, shunting blood away stimulus to take a breath. If you have ever tried to swim
from the muscles and other nonessential organs, and to- a long distance underwater, you will have experienced
ward the heart and brain. The brain is entirely dependent this intense urge to breathe as a result of CO2 buildup.
on aerobic metabolism and cannot survive oxygen depri- Diving animals such as seals do not have nearly as
vation for very long, whereas other tissues can tolerate strong a response while submerged, which allows them
reduced oxygen supply by reducing metabolic rate and by to stay underwater longer without feeling the urge to
relying on anaerobic metabolism. At the same time, take a breath. 2
Summary
Respiratory Strategies k The relationship between ventilation and perfu-
k Respiratory systems consist of all the structures sion of the respiratory surface influences the ef-
animals use to obtain oxygen from the environ- ficiency of gas exchange.
ment, and to dispose of carbon dioxide.
k A countercurrent arrangement provides the
k Animals larger than a few millimeters in diam- most efficient exchange.
eter use a combination of diffusion and bulk
Ventilation and Gas Exchange
flow to transport gases between the environ-
k Animals living in air and water utilize differing
ment and the tissues.
respiratory strategies, because of the differences
k Animals use respiratory surfaces including the in the physical properties of these two media.
skin, gills, or lungs (or a combination of struc-
k Animals that breathe water must expend much
tures) for gas exchange.
more energy to obtain oxygen than do animals
k Animals with internal gills or lungs must move that breathe air.
the external fluid by bulk flow across the respi-
ratory surface, a process called ventilation.
494
Respiratory Systems
k Water-breathing animals use a variety of strate- k Blood pH, pCO2, temperature, and organic mod-
gies to ventilate their gills, involving the beating ulators can affect the shape of the oxygen equi-
of cilia or other structures, or muscular pumping librium curve.
to generate bulk flow of the external medium.
k The Bohr shift, which is a result of decreasing
k Sea cucumbers are unusual among water pH or increasing CO2, is a right shift of the
breathers in that they have tidally ventilated curve that results in unloading of oxygen at the
lungs. Animals that use air as a respiratory tissues.
medium employ either a tracheal system or
k Carbon dioxide can be carried in the blood as
lungs for gas exchange.
dissolved CO2, as HCO3⫺, or bound to proteins
k Air-breathing fish and amphibians gulp air us- such as hemoglobin.
ing a buccal pump.
k Blood CO2, HCO3⫺, and pH are interrelated via
k Reptiles, birds, and mammals ventilate their the carbonic anhydrase equilibrium reaction.
lungs using a suction pump. Blood oxygenation affects CO2 transport by al-
tering hemoglobin CO2 binding, and by altering
k Reptiles and mammals ventilate their lungs
blood pH.
tidally, but birds unidirectionally ventilate
their lungs. k Vertebrate red blood cells play an important
role in CO2 transport by separating the reac-
k Mammalian lungs consist of a series of conduct-
tants and products of the carbonic anhydrase
ing airways that lead to numerous thin-walled
equilibrium, greatly increasing the CO2 carrying
alveoli.
capacity of the blood.
k Mammals ventilate the alveoli by contracting
k Because of the carbonic anhydrase equilibrium,
the external intercostal muscles and dia-
the respiratory system can both cause pH dis-
phragm, which moves the rib cage and expands
turbances and regulate blood pH.
the chest cavity.
k We can visualize the relationships among pH,
k Under resting conditions, breathing out is usu-
HCO3⫺, and PCO2 using a pH-bicarbonate plot.
ally passive, as a result of the elastic recoil of the
lungs, although active expiration can occur dur- Regulation of Vertebrate Respiratory Systems
ing intense exercise. k In the vertebrates, central pattern generators in
the medulla initiate ventilation.
k The work required for ventilation depends on
lung compliance and resistance. k Chemosensory inputs influence the action of
these pattern generators, modulating the rate
Gas Transport to the Tissues
and depth of breathing.
k Oxygen is carried to the tissues either dis-
solved in blood or bound to a respiratory pig- k Mechanoreceptors and conscious control can
ment such as hemoglobin, hemerythrin, or also influence breathing.
hemocyanin.
k Environmental hypoxia and diving provide two
k Blood containing a respiratory pigment has a examples of the ways in which vertebrates reg-
characteristic oxygen equilibrium curve, but the ulate their respiratory systems in response to
shapes of these curves differ among types of environmental changes.
pigments and among species.
k Blood can vary in both oxygen affinity and car-
rying capacity.
495
Respiratory Systems
Review Questions
1. Why is diffusion an inefficient respiratory 5. Describe the changes in alveolar and in-
strategy for organisms that are more than a trapleural pressure during a single ventilatory
few millimeters thick? cycle in mammals.
2. Compare and contrast the lungs of birds, the 6. How does the Root effect help a physoclist fish
lungs of mammals, and the tracheal systems of to add oxygen to the swim bladder?
insects. 7. What is the significance of the red blood cell
3. Explain how countercurrent flow arrange- for CO2 transport in the vertebrates?
ments can lead to more efficient gas exchange 8. Outline how chemoreceptors influence ventila-
across a respiratory surface. tion in mammals.
4. Compare and contrast the force pumps and
aspiration pumps of tetrapod vertebrate respi-
ratory systems.
Synthesis Questions
1. Very few animals that use water as the respira- kaline tide, a large metabolic alkalosis in
tory medium have lungs. Instead, most water which blood pH increases. Outline the likely
breathers use gills for gas exchange. What func- response of the respiratory system to this in-
tional disadvantages do lungs have in water? creased oxygen demand and pH disturbance.
2. Lungless salamanders typically live in moist or 8. In fish, there is a positive correlation between
humid habitats, and can die if their skin dries whole animal metabolic rate and the surface
out. Explain why it is critical for the skin of area of the gill. What might explain this rela-
lungless salamanders to remain moist. tionship?
3. Some species of lungless salamander cannot 9. High-altitude-adapted mammals often do not
live in water as adults, and will drown if fully show as large a pulmonary vasoconstriction in
immersed. Why might this occur? response to low inspired PO2 (environmental
4. In an experiment to determine the role of the hypoxia) as do lowland-adapted mammals.
air sacs in the avian lung, physiologists tied off What advantages might this difference have at
an air sac so that gas from that air sac could high altitude?
no longer enter the lung. The experimenters 10. Hemoglobin is typically saturated with oxygen
then injected carbon monoxide into the sealed when the blood leaves the lungs. In a person
air sac. This manipulation did not decrease who is doing pull-ups, will hemoglobin release
the oxygen saturation of hemoglobin in arte- more of the bound oxygen in the quadriceps
rial blood. Explain why this was the case, and (leg muscles) or in the biceps (arm muscles)?
what this experiment demonstrates about the Describe at least two factors that could cause
nature of the air sacs in birds. a difference, if any, in oxygen release between
5. A woman gets a disease that makes her unable your biceps and quadriceps.
to produce surfactant in her lungs. If she has a 11. Imagine that you take hemoglobin molecules
normal tidal volume, what can you say about from both a sheep fetus and its mother. You
her intrapleural pressure during inspiration? mix equal amounts of these two hemoglobins
6. What effects might you expect in a mammal in an aqueous solution in the presence of oxy-
whose major hemoglobin is mutated such that gen, at a PO2 that is not sufficient to saturate all
it lacks a Bohr effect? the hemoglobin sites on the molecules you
have added. Given what you know about ma-
7. Metabolic rate can increase as much as 40-
ternal and fetal hemoglobins, where would
fold above resting values as a result of feeding
you expect to find most of this oxygen bound?
in some species of reptiles. In addition, during
How would this compare to the amount of oxy-
digestion, a large amount of H⫹ is secreted into
gen dissolved in your solution and not bound
the stomach, which results in the so-called al-
to hemoglobin? Why?
496
Respiratory Systems
12. Anxiety can cause a person to hyperventilate How (i.e., by what mechanism) might this af-
(rapid deep breathing). This can cause a vari- fect blood flow to the brain? Breathing into a
ety of symptoms, including dizziness and paper bag is often suggested as a treatment for
fainting. What changes would you expect in hyperventilation. Do you think this would
systemic arterial O2 and CO2 concentration work? Why or why not?
and pH during an episode of hyperventilation?
1. The graphs below represent the gas exchange long and 3 cm in diameter (the end of the hose
across two hypothetical respiratory surfaces is open to the air in the room). What changes
(a and b). One of these surfaces has concurrent would you expect in ventilation rate and tidal
flow, and one has countercurrent flow. volume compared to those measured in the
same subject breathing normally? (Explain
Medium Medium your answers.)
4. John, Jeff, and Harry are all breathing at dif-
PO2
PO2
ferent rates and depths. Using the data pro-

Blood Blood
vided below, who would have the highest PO2
in the blood leaving the lungs. Who would
Distance along Distance along have the lowest? (Show your work.)
respiratory surface respiratory surface Breathing Tidal
(a) (b) rate (breaths volume Dead
per (ml per space
(a) Which surface has concurrent flow, and minute) breath) (ml)
which surface has countercurrent flow? John 15 500 200
(b) Based on the data shown, which surface
Jeff 40 250 200
has the most efficient gas exchange?
(c) What might account for this observation? Harry 10 1000 200
2. If a mammal has a minute volume of 5200
ml/min, a breathing frequency of 13 breaths 5. Using the Hb-oxygen saturation curve in
per minute, a vital capacity of 4600 ml, and an Figure 30a, answer the following questions:
expiratory reserve volume of 1200 ml, what (a) If PO2 in the lungs is approximately 100
are the tidal volume and inspiratory reserve mm Hg, what is the percent saturation of
volume? Hb in the pulmonary capillaries?
(b) If PO2 in the tissues is approximately 5 mm
3. As part of a physiology experiment, a human Hg, what is the percent saturation of Hb in
subject is asked to breathe through a hose 1 m the systemic capillaries?
For Further Reading

See the Additional References section at the end Cameron, J. N. 1989. The respiratory physiology
of the chapter for more readings related to the of animals. New York: Oxford University Press.
topics in this chapter. Prange, H. D. 1996. Respiratory physiology:
Understanding gas exchange. New York:
Chapman and Hall.
Respiratory Strategies
These two advanced textbooks provide an The following engaging book provides a broad
excellent overview of respiratory physiology, overview of the impact of the physical properties
providing examples from a broad range of of air and water on a variety of processes in
animal taxa, with strong quantitative coverage of animals. It contains several sections that are
the material. relevant to understanding the functioning of
497
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respiratory systems. The treatment of diffusion is Giardina, B., D. Mosca, and M. C. De Rosa. 2004.
particularly good. The Bohr effect of haemoglobin in vertebrates:
Denny, M. W. 1993. Air and water: The biology An example of molecular adaptation to
and physics of life’s media. Princeton, NJ: different physiological requirements. Acta
Princeton University Press. Physiologica Scandinavica 182: 229–244.
Terwilliger, N. 1998. Functional adaptations of
Ventilation and Gas Exchange oxygen transport proteins. Journal of
The following papers address some of the factors Experimental Biology 201: 1085–1098.
involved in ventilation and the regulation of gas Weber, R. E., and A. Fago. 2004. Functional
exchange in insects. adaptation and its molecular basis in
Gibbs, A. G., F. Fukuzato, and L. M. Matzkin. vertebrate hemoglobins, neuroglobins and
2003. Evolution of water conservation cytoglobins. Respiratory Physiology and
mechanisms in Drosophila. Journal of Neurobiology 144: 141–159.
Experimental Biology 206: 1183–1192.
Regulation of Vertebrate Respiratory Systems
Lehman, F-O. 2001. Matching spiracle opening to
metabolic needs during flight in Drosophila. These reviews discuss the regulation of
Science 294: 1926–1929. vertebrate respiratory systems, with particular
focus on the differences between water breathers
Lighton, J. R. B. 1996. Discontinuous gas and air breathers.
exchange in insects. Annual Review of
Entomology 41: 309–324. Smatresk, N. J. 1990. Chemoreceptor modulation
of endogenous respiratory rhythms in
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W. J. Cooper, and W. K. Lee. 2003. Tracheal 259: R887–R897.
respiration in insects visualized with X-ray
synchrotron radiation. Science 299: 558–560. Smatresk, N. J. 1994. Respiratory control in the
transition from water to air breathing in
Johannes Piiper and Peter Scheid are two of the vertebrates. American Zoologist 34: 264–279.
leaders in the field of vertebrate respiratory Hypoxia
physiology. This chapter provides a concise
summary of the quantitative basis of gas This paper outlines the various mechanisms seen
exchange in a variety of vertebrates. in high-altitude-adapted human populations.
Scheid, P., and J. Piiper. 1997. Vertebrate Beall, C. M., M. J. Decker, G. M. Brittenham, I.
respiratory gas exchange. In Handbook of Kushner, A. Gebremedhin, and K. P. Strohl.
physiology: A critical, comprehensive 2002. An Ethiopian pattern of human
presentation of physiological knowledge and adaptation to high-altitude hypoxia.
concepts, W. H. Dantzler, ed. (Section 13: Proceedings of the National Academy of
Comparative Physiology), vol. 1, 309–356. Sciences, USA 99: 17215–17218.
Bethesda, MD: American Physiological Society.
This review outlines some of the mechanisms of
This readable article provides an excellent and hypoxia-induced metabolic suppression in
accessible introduction to vertebrate gas nonmammalian vertebrates.
exchange. Hicks, J. W., and T. Wang. 2004.
Truchot, J-P. 2001. Gas transfer in vertebrates. In Hypometabolism in reptiles: Behavioural and
Encyclopedia of life sciences. New York: Wiley. physiological mechanisms that reduce aerobic
demands. Respiratory Physiology and
Gas Transport to the Tissues Neurobiology 141: 261–271.
These papers review the structure and function Diving
of hemoglobins and other respiratory pigments.
These comprehensive reviews summarize the
Burmester, T. 2002. Origin and evolution of fundamental physiological mechanisms involved
arthropod hemocyanins and related proteins. in diving in the vertebrates.
Journal of Comparative Physiology B:
Biochemical, Systemic, and Environmental Butler, P. J. 2004. Metabolic regulation in diving
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Kooyman, G. L., and P. J. Ponganis. 1998. The Castellini, M. A., and J. M. Castellini. 2004.
physiological basis of diving to depth: Birds Defining the limits of diving biochemistry in
and mammals. Annual Review of Physiology marine mammals. Comparative Biochemistry
60: 19–32. and Physiology, Part B: Biochemistry and
Molecular Biology 139: 509–518.
The following review highlights some of the
pioneering work done by Peter Hochachka and
his students and colleagues on the physiology
and biochemistry of diving in pinnipeds.
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ventilation in tetrapods. Comparative Biochemistry and air and water. Comparative Biochemistry and Physiology
Physiology, Part A: Molecular and Integrative Physiology 79A: 275–282.
133: 269–288. Piiper, J., and P. Scheid. 1982. Models for comparative
Boutilier, R. G., ed. 1990. Vertebrate gas exchange: From functional analysis of gas exchange organs in vertebrates.
environment to cell. Vol. 6 of Advances in comparative Journal of Applied Physiology 53: 1321–1329.
and environmental physiology. Berlin: Springer-Verlag. Piiper, J., and P. Scheid. 1992. Gas exchange in vertebrates
Duncker, H-R. 2004. Vertebrate lungs: Structure, topography through lungs, gills, and skin. News in Physiological
and mechanics: A comparative perspective of the Sciences 7: 199–203.
progressive integration of respiratory system, locomotor Ridgway, S., and R. Howard. 1979. Dolphin lung collapse and
apparatus and ontogenetic development. Respiratory intramuscular circulation during diving: Evidence from
Physiology and Neurobiology 144: 111–124. nitrogen washout. Science 206: 1182–1183.
Farmer, C. G. 1999. Evolution of the vertebrate cardio- Sparling, C. E., and M. A. Fedak. 2004. Metabolic rates of
pulmonary system. Annual Review of Physiology 61: captive grey seals during voluntary diving. Journal of
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American alligator (Alligator mississippiensis). Journal of significance of respiratory structures on the legs of
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induced by exercise in the lizard Iguana iguana. Journal Taylor, E. W., D. Jordan, and J. H. Coote. 1999. Central
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Credits
410 Peter Arnold, Inc., John Cancalosi/Peter Arnold, Inc.
411 John Downer/Nature
Picture Library.
411 Stephen Dalton/Nature
Picture Library.
418 Tom McHugh, Photo Researchers, Inc.
431 Science Magazine, Reprinted with permission from
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438 blickwinkel/Alamy.
499
Ion and Water Balance
Somewhere around 700 million years ago (mya), the earli- early milestone was the formation of tissue layers. Next
est animal life forms arose. They were marine organisms, came the capacity to produce a specialized external tissue
much like the modern sponges. Like sponges, these pri- layer using cells that were interconnected in ways that lim-
mordial animals existed as a loose aggregation of cells, ited the passage of seawater into the body. The formation
bathed in seawater. Each cell of a marine sponge is bathed of this epithelial tissue provided barriers between the ex-
in seawater, but maintains an intracellular ion composition ternal world and internal fluids, resulting in the establish-
different from that of seawater, using ion pumps and active ment of an extracellular fluid that was separate from the
transport to create and maintain the electrochemical gra- external environment. Animals differ in their ability to con-
dients that drive transport and synthetic processes. trol the osmotic and ionic nature of this extracellular fluid.
Over the next 150 million years, evolution led to impor- Though sponges lack true tissues, other ancient ma-
tant changes in how animal tissues were organized. An rine invertebrates, such as flatworms (Platyhelminthes),
500
Crab.
Hagfish.
possess true tissues and can create an extracellular fluid acidic Amazonian waters (pH 3.5). Fish can be found in
that is physically separated from seawater. Yet in these waters of varying salinity, from the hypersaline salt
simple animals, the extracellular fluid contained within the marshes and inland seas, through the oscillating salinity
tissues is identical to seawater in its ionic and osmotic of the intertidal zone, to lakes and rivers that are nearly
properties. However, multiple lineages of animals have devoid of essential ions. A few species of fish even sur-
evolved mechanisms that provide much greater control vive out of the water. Some tropical catfish walk over land
over the properties of their extracellular fluids. The ability from one temporary pool to another. Other fish enter a
to control extracellular fluid composition allowed animals period of dormancy, such as the lungfish that bury them-
to invade brackish water, freshwater, and even land. selves underground in a mucus cocoon.
Major changes in osmoregulation and ionoregulation The ability to control internal osmolarity independent
occurred in the evolution of the chordates. Like many sim- of external conditions was essential for the success of the
ple marine invertebrates, the earliest chordates were ma- animal lineages that invaded land. The earliest of many
rine organisms that had little control over the nature of waves of terrestrial invaders were invertebrates. First the
their extracellular fluid composition. The extracellular ancient myriapods, then their arthropod predators, in-
fluid of the hagfish, a marine agnathan (jawless fish), is vaded land more than 420 mya. Later, around 400 mya,
similar to seawater, although it is somewhat reduced in the first amphibians ventured onto land. A terrestrial ex-
2⫹ 2⫹ 2⫺
the concentrations of Ca , Mg , and SO4 . Cartilaginous istence puts animals at risk for desiccation, and species
fish control the ion composition of the extracellular fluid, that successfully invaded land demonstrate evolutionary
but the osmolarity is close to that of seawater. Bony fish adaptations that reduce water loss. For one thing, they
regulate both the ionic and osmotic profile of their extra- need a body surface more resistant to desiccation. No
cellular fluids. This ability to control internal ionic and os- longer able to excrete metabolic wastes directly into the
motic properties was essential to the diversification of water, they also need an alternative way to dispose of ni-
bony fish, which now occupy almost every aquatic and trogenous waste.
semiaquatic niche on the planet, often tolerating inhos- Ion balance, water balance, nitrogen excretion, and pH
pitable ionic and osmotic conditions, environments with balances are interdependent processes that must be regu-
very high or low pH, extremes in salinity, and even periods lated (and evolve) in parallel to ensure homeostasis. The di-
of dehydration. For instance, cichlids live in the alkaline versity among modern animals reflects the many solutions
waters of Lake Magadi (pH 10) and tambaqui thrive in to problems encountered by animals in early evolution.2
501
Overview Each group of animals uses different combina-

tions of epithelial tissues to control ion and water
Normal animal function depends on the precise balance. For most animals, the kidney is central to
regulation of diverse physical relationships and ion and water balance. However, most animals
biochemical processes, which in turn are influ- also rely on extrarenal tissues, such as gills, skin,
enced by the chemical environment. The term and the digestive mucosa. These tissues regulate
environment may be interpreted in the broadest three homeostatic processes to ensure an appro-
sense. The environment for a whole animal is the priate chemical composition:
external world, for a cell it is the extracellular • Osmotic regulation is the control of tissue os-
fluid, and for intracellular enzymes, the cyto- motic pressure, which determines the driv-
plasm. Animals maintain a favorable profile of ing force for the movement of water across
solutes and solutions in their intracellular and ex- biological membranes. Animals and cells
tracellular body fluids largely by means of the ep- cannot actively pump water. Osmotic regula-
ithelial tissues that form the barrier with the tion requires the movement of solutes across
external environment (Figure 1). membranes, altering osmotic gradients.
• Ionic regulation is the control of the ionic
composition of body fluids. In this chapter
we focus on the ions that are important
solutes, and therefore relevant to the os-
moregulatory strategies.
• Nitrogen excretion is the pathway by which
animals excrete ammonia, the toxic ni-
trogenous end product of protein catabo-
lism. The process for expelling ammonia, or
metabolic alternatives such as urea and uric
acid, is linked to the control of osmotic and
ionic homeostasis. The tissues of the excre-
tory system are responsible for collecting
nitrogenous waste and expelling it into the
Water environment.
Mucus Diverse mechanisms ensure that the ionic and
Unstirred layer
osmotic properties of animals are maintained
Apical
membrane within acceptable limits. In simple invertebrates,
Basolateral the responsibilities for ionic and osmotic regula-
membrane tion reside primarily at the level of individual cells.
Interstitial fluid In more complex animals, specialized tissues carry
Endothelium the burden of maintaining the appropriate chemi-
Plasma cal composition and volume of the body fluids.
Blood cell
Figure 1 Tissues as osmotic and ionic barriers Ion and Water Balance
Epithelial tissues separate internal fluid compartments from
the external world. In the case of an aquatic animal, such as Recall what you’ve learned about the importance of
a mudpuppy, the external (apical) side of the epithelial cell water in biological systems. It is the solvent that is
layer interacts directly with the external water, though it can
secrete a protective layer
used to dissolve the ions and metabolites needed to
of mucus that also traps a layer of water underneath. sustain cells. Animals have diverse physiological sys-
Intercellular junctions connect epithelial cells together to
form a barrier between external and internal fluids. On the
internal (basolateral) side of the epithelium, cells are bathed
in interstitial fluid trapped between cells. The tissue is fed by
capillaries, with vascular endothelial cells separating
interstitial fluid from plasma.
502
tems that work together to ensure that ionic and gradients that result from disequilibrium of ions
osmotic conditions within the animal remain across the cell membrane are essential for normal
within acceptable limits. Changes in the concen- cellular function. Most animal cells act as perfect
tration of ions have the potential to affect the osmometers, swelling or shrinking as a result of
structure and function of macromolecules. Cellu- osmotic gradients across the cell membrane. Ani-
lar function can be affected by such disruptions in mals differ in (1) the sites of ion and water ex-
macromolecular function, but perhaps more im- change and (2) the nature of ionic and osmotic
portant, cells exposed to osmotic gradients can gradients between the extracellular fluids and the
shrink or swell. The changes in cell volume can environment. The main sites of ion and water ex-
damage cells directly, sometimes causing cell change are those in direct contact with the envi-
death. Even if cells survive the stress, the cell vol- ronment: the outer body covering, and the
ume changes damage multicellular tissues by dis- surfaces of the respiratory and digestive tracts.
rupting cell-to-cell interactions or by altering Most animals also have some specialized excre-
blood flow through the tissue. tory systems to regulate excretion of ions and wa-
Some aquatic animals minimize high costs of ter in support of the osmotic strategy. The ionic
ion and water balance by maintaining osmotic or and osmotic gradients differ for aquatic and ter-
ionic equilibrium with the external water. Most an- restrial animals. An aquatic animal is immersed in
imals maintain some degree of control over the a solution, and each external surface in contact
ionic and osmotic composition of their extracellular with the water could be a site of ion and water ex-
conditions, and thus must resist changes imposed change. For example, a freshwater vertebrate
by the external environment. Marine environments would tend to gain water and lose ions, whereas a
have high levels of ions, mostly Na⫹ and Cl⫺. Thus, marine vertebrate would tend to gain ions and
for many marine animals, their challenge is to ex- lose water. Most terrestrial animals live in a dehy-
pel ions against electrochemical gradients and ob- drating environment, losing water across the body
tain water against osmotic gradients. Freshwater surfaces, but few ions. The extent to which a par-
animals have the reverse problem: acquiring ions ticular ionic or osmotic gradient constitutes a
from ion-poor water and disposing of excess water. physiological burden depends on the ionoregula-
Terrestrial animals live under dehydrating condi- tory and osmoregulatory strategies of the animal.
tions, where water loss is the greatest threat and
most of the ions appear in the diet. The animals that
straddle multiple environments must have flexible Most aquatic animals regulate ion and
homeostatic mechanisms to cope with variable ion water balance to some degree
and water levels. Ionoregulatory and osmoregulatory strategies of
When considering how animals control ion aquatic animals can be distinguished by (1) the
and water balance, it is important to consider both differences between extracellular fluids and exter-
the behavior of individual cells struggling to main- nal conditions and (2) the extent to which extracel-
tain their own cell volume and the epithelial tis- lular fluids change when external conditions
sues working to ensure homeostasis of the whole change (Table 1). Conformers have internal condi-
animal. Each of these processes involves cell tions that are similar to the external conditions,
membrane transporters, including the channels even when the external conditions change.
that mediate facilitated diffusion, the exchangers Regulators defend a nearly constant internal state
working through secondary active transport, and that is distinct from the external conditions.
the pumps that move ions against concentration An ionoconformer exerts little control over
gradients at the expense of ATP. the solute profile within its extracellular space.
These animals usually live in seawater. Their ex-
tracellular fluids resemble seawater in terms of
the concentrations of the major cations (Na⫹, Ca2⫹,
Strategies for Ionic and Osmotic and Mg2⫹) and anions (Cl⫺ and SO42⫺). Ionocon-
Regulation formers include most simple invertebrates (such
All animals regulate the ionic profile of intracellu- as cnidarians), simple deuterostomes (such as as-
lar fluids in relation to the extracellular fluids that cidians), and the most ancient vertebrates (hag-
bathe cells within an animal. The electrochemical fish). Although hagfish are usually considered
503
Table 1 Osmoregulatory and ionoregulatory strategies of aquatic animals.
Plasma osmolarity Ionoregulator?

Animals in seawater (~1200 mOsM)
Most arthropods Isosmotic No
Molluscs (squid) Slightly hyperosmotic Yes
Agnathans (hagfish) Slightly hyperosmotic No
Agnathans (lamprey) Hyposmotic (~250 mOsm) Yes
Chondrichthians (shark) Slightly hyperosmotic Yes
Bony fish (tuna), amphibians (crab-eating frog), reptiles
(sea turtle), mammals (killer whale), birds (gull) Hyposmotic (~350 mOsM) Yes
Animals in freshwater (<10 mOsM)
Most arthropods (e.g., crayfish, insect larvae) Hyperosmotic (250–400 mOsM) Yes
Molluscs (freshwater clams) Slightly hyperosmotic (~50 mOsM) Yes
Agnathans (lamprey) Hyperosmotic (~270 mOsM) Yes
Chondrichthians (stingray) Hyperosmotic (~350 mOsM) Yes
Bony fish (goldfish) Hyperosmotic (~350 mOsM) Yes
Amphibians (leopard frog) Hyperosmotic (~250 mOsM) Yes
Reptiles (snapping turtle), mammals (river otter),
birds (mallard duck) Hyperosmotic (~350 mOsM) Yes
ionoconformers because their extracellular Na⫹ maintains internal osmolarity within a narrow
and Cl⫺ levels are near those of seawater, they are range regardless of the external environment. De-
in fact able to regulate Mg2⫹ and Ca2⫹ to levels be- pending on the conditions, the animal could have
low those seen in seawater. In contrast to ionocon- an osmolarity higher or lower than the surround-
formers, an ionoregulator controls the levels of ing water. Most marine vertebrates are osmoregu-
most of the ions in extracellular fluids, employing lators, defending an internal osmolarity that is
a combination of ion absorption and excretion much below that of the surrounding seawater.
strategies. Regulating the ionic profile of extracel- Freshwater vertebrates and invertebrates are os-
lular fluid compartments eases the burden of ionic moregulators, maintaining internal osmotic pres-
regulation placed on individual cells. sure well above that of the water. All otters, for
The internal osmolarity of an osmoconformer example, have a similar internal osmolarity
nears that of the external environment; if external whether in freshwater, like a river otter, or seawa-
osmotic conditions change, internal osmolarity ter, like a sea otter. These animals must retain the
changes in parallel. Marine invertebrates and vital ions and rid themselves of excessive ions,
primitive vertebrates are osmoconformers. Thus, a while also controlling the movement of water.
marine mollusc in full-strength seawater has an in- We also classify animals according to their abil-
ternal osmolarity of approximately 1200 mOsM, ity to tolerate changes in external osmolarity.
about three times more concentrated than human Stenohaline animals can tolerate only a narrow
blood. Marine chondrichthians are generally con- range of salt concentrations, whereas euryhaline
sidered osmoconformers; although their internal animals can tolerate widely variant osmolarities.
osmolarity is a bit greater than the surrounding There is no predetermined relationship between
seawater, it changes in parallel with external the strategy (osmoconforming versus osmoregulat-
changes. An osmoconformer may control the ing) and the degree of tolerance (euryhaline versus
profile of extracellular solutes, but the environ- stenohaline) (Figure 2). For example, intertidal
ment imposes the osmolarity. An osmoregulator molluscs are euryhaline osmoconformers whereas
504
1200 1 1 Euryhaline osmoconformer allows osmolarity to decrease

Stenohaline animal in parallel with water until death.
Euryhaline animal
Internal osmolarity (mOsm)
Starting osmolarity 2
2 Stenohaline osmoconformer dies after very modest
Death osmotic disruption.
3 Euryhaline osmoregulator defends a nearly constant

600 3 internal state but eventually succumbs.
4 4 Stenohaline osmoregulator can defend its internal

osmolarity over a narrow range of external osmolarities.
0
0 600 1200
External osmolarity (mOsm)
Figure 2 Osmoregulatory strategies and salinity tolerance Osmotic strategies

can be distinguished by three factors: (1) the osmotic gradients between the animal and the
water, (2) the degree to which internal osmolarity changes in relation to a changing external
osmolarity, and (3) the degree of tolerance of an osmotic challenge. The four osmotic strategies
depicted in this figure can be distinguished by following the internal osmolarity of four animals
living in full-strength seawater, then exposed to a decreasing osmolarity until death.
intertidal fish are euryhaline osmoregulators. The diet itself is a mixture of water and solutes
Closely related animals can also differ in their toler- in various chemical forms. Aquatic animals ingest
ance of osmotic stress. Consider, for example, the some liquid water while eating, and they must
decapod crustaceans, all of which are ionoregula- manage the resulting osmotic and ionic conse-
tors. Lobsters live in seawater, crayfish in freshwa- quences. Many aquatic animals expel the liquid
ter, and there are seawater and freshwater species before it enters the gastrointestinal tract. Filter-
of shrimp. In contrast to these stenohaline species, feeding whales, such as the baleen whale, gulp
the blue crab is exceptionally euryhaline. The blue large volumes of seawater laden with krill, and
crab osmoconforms at high salinities, but it os- then use the tongue to compress the meal against
moregulates if salinity decreases below a threshold. the baleen, expelling excess seawater. Many ma-
Osmotic strategies integrate the diverse physiologi- rine animals possess mechanisms that enable
cal systems to ensure that the internal ion and wa- them to expel excess salt, allowing them to drink
ter composition is suitable for the function of seawater to obtain water. For example, many ma-
macromolecules, cells, and tissues. rine reptiles and birds can drink seawater because
they possess specialized salt-secreting glands, dis-
cussed later in this chapter. Without a capacity to
The environment provides water in many rid its body of salt, an animal drinking seawater
forms will become progressively more dehydrated.
All animals require a source of water, though some Plant and animal tissues are important sources
animals have a harder time finding it than others. of dietary water for animals (see Table 2). This wa-
Freshwater osmoregulators have no problem ob- ter is preformed in the food, either trapped within
taining the water they need, and in fact must cope the solid food or as a liquid component of the meal.
with excessive water uptake. Marine osmoregula- An animal cannot absorb all of the dietary water,
tors must deal with the ion loads that accompany because it must retain some water to give the feces
the water they consume. Terrestrial animals con- the appropriate consistency for transit through the
sume much of their water in the diet, and generally gastrointestinal tract. Once ingested, many macro-
must find ways to minimize water loss. A few ani- molecules undergo hydrolysis as part of the diges-
mals have unusual physiological adaptations that tive process. Hydrolysis—literally “water
allow them to survive various degrees of water splitting”—consumes a water molecule to break a
deprivation, including dehydration (see Box 1, chemical bond. After this minor investment of wa-
Evolution and Diversity: Life Without Water). ter early in digestion, subsequent metabolic
505

Life Without Water
Water is essential to life, but some most abundant animals in the desert, find refuge in es-
species survive with precious little. These ani- tablished microclimates—under rocks or in burrows.
mals live in areas you would normally think of as dry The desert toad spends the hot daylight hours burrowed
(places like the hot deserts of Death Valley and the cold into the cooler soil. Burrowing animals may also modify
deserts of the Antarctic) as well as microclimates di- their microclimate. Even with physiological and
rectly underfoot, such as temporary ponds and moss anatomical specializations, all animals lose some mois-
patches. Some animals survive water deprivation using ture in their respiration. Thus, the subterranean bur-
adaptations to obtain, retain, or recover water to remain rows can become humid, providing refuges from both
hydrated, whereas others have adaptations to tolerate the heat and the dryness of the surface.
dehydration. Given the nature of the desert terrain, larger ani-
Many animals survive the desert by being better at mals, such as the camel, have little hope of finding
finding and storing water to remain hydrated. Of course, shade. Instead, physiological strategies help them cope
desert animals drink water when they find it, whether in with the direct sunlight. Just as waterproofing of the in-
standing pools found in oases, or as dew droplets form- tegument was an important adaptation in the earliest
ing on vegetation. One desert beetle can harvest water terrestrial invaders, the desert dwellers have evolved
directly from the air. It climbs to the top of sand hills in superior mechanisms to prevent water flux across the
the early morning and stands on its head. Water con- skin. Amphibians and reptiles that live in the desert
denses on its exoskeleton and falls in rivulets to its have skin with a thicker stratum corneum than do those
mouth. Preformed water is also trapped in solid food, that live in wetter habitats. Birds and mammals—both
such as succulent cactus. Water is also produced during homeotherms—face an additional risk of dehydration
the metabolic breakdown of dietary macromolecules. through cutaneous water loss. Generally, large mam-
Many desert animals, particularly insects, can sur- mals use sweating as a means of cooling under hot con-
vive radical changes in tissue water content between ditions. Although birds do not possess sweat glands,
dehydration and drinking bouts. Desert beetles swell cutaneous water loss contributes to cooling. However,
with water in the rainy season, increasing water content to many desert animals conserving water is more ur-
to about 70% of body mass. Over the course of the dry gent than cooling the body. They block evaporative cool-
season, they may lose as much as 60% of this water. ing, allowing their body temperature to rise. For
Most of this water is lost from the hemolymph; some example, the body temperatures of the oryx (a large an-
beetles can tolerate almost complete loss of he- telope) and the camel may exceed 40°C during the heat
molymph without obvious consequences (recall that the of the day. These animals do not shed the stored body
insect hemolymph has no role in delivery of oxygen). heat until the cool evening, when the body temperature
Most desert vertebrates cannot tolerate severe de- can fall below 35°C. Interestingly, the featherless neck
hydration, but the camel is one exception. When water of ostriches is actually much more permeable to water
is available, a 700-kg camel can consume as much as than is the skin of other birds. This suggests that evap-
100 kg of water in as little as 10 minutes. Similarly, a orative cooling is more important to the ostrich than is
camel gorges when food is available, storing excess en- water conservation.
ergy in its hump as fat. When deprived of food and wa- Other physiological processes, such as ventilation, di-
ter, the camel draws on water stores and degrades the gestion, and excretion, lead to water loss. Desert animals
fat in the hump. Eventually, the hump shrinks in size, often have unusual adaptations that reduce this inciden-
slumping over to one side as the fat is oxidized to pro- tal loss of water. Some desert mammals, such as the
duce energy and metabolic water. Despite the produc- kangaroo rat, minimize respiratory water loss by passing
tion of metabolic water, camels undergo severe the expired air over a region of the nose equipped with a
dehydration. In contrast to camels, most desert verte- countercurrent heat exchanger. The dik-dik, an African
brates maintain tissue water content within a narrow antelope that lives in semiarid scrubland, possesses an
range using physiological mechanisms that maximize enlarged nose that acts as a cooling chamber. Moisture
water conservation. condenses out of the expired air before it escapes
An important element of desert survival is avoiding through the nostril. The kangaroo rat is also able to ex-
the sun’s heat, by either finding or altering a microcli- tract most of the water from its urine and feces prior to
mate. During the day, many reptiles and insects, the excretion. Desert birds and mammals limit excretory wa-
506
ter loss by producing a very concentrated urine. The urine til body water content reaches 50%; then metabolic rate
of a dik-dik, for example, is 12 times more concentrated declines as more body water is lost. In the final stages,
than its plasma. The camel also reduces the degree of when body water levels are below 1%, no evidence of life
dehydration by blocking urination, retaining urea within can be detected. Metabolism essentially stops, as indi-
the tissues until water becomes available. cated by measurement of metabolic fuel levels, gas ex-
In contrast to the animals that resist dehydration, change, and heat production.
some animals survive water stress by tolerating dehy- Central to the survival of most species that tolerate
dration, in some cases losing all free water, a state anhydrobiosis is accumulation of protective agents, par-
known as anhydrobiosis. In contrast to the exotic ani- ticularly carbohydrates and proteins. For example, when
mals living in distant lands, many of the desiccation tol- a nematode experiences some desiccation, it produces
erant animals live underfoot. Many invertebrates, such large amounts of the disaccharide trehalose, which ac-
as rotifers and tardigrades, live and breed in wet moss, cumulates to levels as high as 15% of its dry mass. Tre-
but enter a dormant state when the moss desiccates. halose replaces the water molecules in the hydration
Unlike their cousins, bivalves and cephalopods, the pul- shell of proteins and other macromolecules, and forms
monate snails are terrestrial and use a simple lung to a coating around proteins, lipids, and other macromole-
breathe air, which puts them at risk for dehydration. Be- cules that stabilizes macromolecular structure. In many
cause of this vulnerability, most pulmonate snails are species, the ability to survive dehydration correlates with
confined to humid, tropical environments where there is trehalose levels, suggesting that trehalose may be re-
little risk of desiccation. A few pulmonate snails have quired for survival. Recent studies have gone one step
exceptional desiccation tolerance. The snail Helix with- further, to test whether trehalose alone is sufficient to
stands dry conditions for months by entering a period of endow cells with desiccation tolerance. Researchers
dormancy (estivation) in which it lowers metabolic rate bathed mammalian platelets in trehalose, allowing them
precipitously and seals off its shell, retarding water to take up the sugar. The cells were then frozen slowly
loss. In some cases, the snail may lose almost 50% of its and dehydrated in this frozen state, reducing water con-
body water with prolonged exposure, but because dry tent to about 5% of mass. When the freeze-dried platelets
mass also decreases proportionately, the percentage of were thawed, they remained viable. Transgenic mam-
tissue water is fairly constant. malian cells have also been constructed to test the hy-
Even more tolerant of desiccation are the nematodes pothesis that trehalose alone can endow desiccation
that live in the Antarctic. These worms must survive cold tolerance. When mouse cells were transfected with two
stress as well as osmotic stress. The cold, dry air can de- bacterial genes for the enzyme trehalose synthase, they
hydrate an animal, but these nematodes also experience produced very high levels of trehalose (about 100 mM).
hyperosmotic stress when melting water dissolves salts, Unfortunately, these cells could not survive the desicca-
elevating osmolarity as much as fivefold. During dehy- tion process. These studies suggest that trehalose is nec-
dration, the water content of the nematode’s tissues may essary for desiccation, but that other factors may be
decrease to 2–10% of body mass. Like the snails, nema- required to endow an animal with desiccation tolerance.
todes survive this extreme dehydration in a dormant, hy-
pometabolic state that may last for decades. References
The champion of desiccation tolerance is the brine q Crowe, L. M. 2002. Lessons from nature: The role of sugars in an-
shrimp, Artemia. The encysted embryos, often called hydrobiosis. Comparative Biochemistry and Physiology—Part A:
Molecular and Integrative Physiology 131: 505–513.
eggs, are sold as “sea monkeys,” with promises that the
desiccated animals can be reanimated with the addition q Tunnacliffe, A., A. Garcia de Castro, and M. Manzanera. 2001. An-
hydrobiotic engineering of bacterial and mammalian cells: Is in-
of water. If protected from the damaging effects of oxy-
tracellular trehalose sufficient? Cryobiology 43: 124–132.
gen, dehydrated brine shrimp eggs can survive hun-
q Wharton, D. A. 2003. The environmental physiology of Antarctic
dreds of years in this dehydrated state. Once the eggs
terrestrial nematodes. Journal of Comparative Physiology 173B:
hatch, the larvae lose their desiccation tolerance. Brine 621–628.
shrimp inhabit waters that experience periodic dehy-
q Wolkers, W. F., F. Tablin, and J. H. Crowe. 2002. From anhydrobio-
dration. When water appears, the Artemia eggs hatch sis to freeze-drying of eukaryotic cells. Comparative Biochemistry
and larvae mature quickly to initiate a rapid round of re- and Physiology—Part A: Molecular and Integrative Physiology 131:
production. Artemia retains a normal metabolic rate un- 535–543.
507
Table 2 Water and solute content of food.
Water content Perturbing solute

Nutrient (% of wet weight)
Km (mM)
Animal and plant fluids
Sap and nectar 90–100% Compatible solute
Blood 95%
Milk (most mammals) 87%
Milk (marine mammals) 40% Concentration (mM)
(a) Perturbing and compatible solutes
Fruits and vegetation 80–95%
Plant and animal tissues
Urea
Muscle and animal tissues 50–70%
Seeds and grains <10%
Km (mM)
Urea + TMAO
processes generate water as a result of oxidative TMAO

phosphorylation; this water is known as metabolic
water. Each of the major macromolecules pro-
duces about the same amount of metabolic water,
expressed per unit of metabolic energy. Based on Concentration (mM)
the same 100 kcal of metabolizable energy, carbo- (b) Counteracting solutes
hydrate produces 15 ml of water; protein, 10.5 ml
Figure 3 Perturbing, compatible, and
of water; and fat, 11.1 ml. For an average human, counteracting solutes Each type of solute exerts
about 10% of daily water requirements come from characteristic effects on macromolecular structure and
metabolic water production, 60% from drinking, function, such as enzyme kinetics (Vmax or Km). (a) A
and 30% from water trapped in solid foods. As dis- perturbing solute is shown to increase the Km value of a
hypothetical enzyme, whereas a compatible solute at the
cussed in the previous feature (Box 1), many desert same concentration has no effect on Km. (b) Each
animals drink no fluids, and instead obtain their counteracting solute has perturbing effects when present
water entirely from solid foods and metabolic alone, but when both are present, the effects are offset. Urea
water. is shown to increase Km and TMAO decreases Km, but the
combination of the two has no effect.
Solutes can be classified as perturbing, amino acids (e.g., arginine). Compatible solutes
compatible, or counteracting have little effect on macromolecular function and
Recall what you’ve learned about the chemistry of can accumulate to high concentration without dele-
solutes and solvents in biological systems. The to- terious effects on cellular processes. The most com-
tal concentration of solutes imparts an osmolarity mon compatible solutes in body fluids are polyols
and determines the osmotic gradient across bio- (trehalose, glycerol, and glucose) and uncharged
logical membranes, and thereby the direction and amino acids, including several of the ␣-amino acids
magnitude of water movement. In addition to (alanine, glycine, serine, and proline) as well as
these general osmotic effects of solutes, there are other amino acids (␤-alanine and taurine).
solute-specific effects. Three classes of solutes are Counteracting solutes are deleterious when used
distinguished by their effects on the structure and on their own, but can be employed in combina-
function of macromolecules, such as enzymes (Fig- tions where the deleterious effects of one solute
ure 3). Perturbing solutes disrupt macromolecular counteract the deleterious effects of the other.
function at normal concentrations found within the For example, urea disrupts hydrophobic interac-
animal. These include the inorganic ions found in tions and methylamines strengthen hydrophobic
body fluids, primarily Na⫹, K⫹, Cl⫺, and SO42⫺, as interactions. A combination of urea and
well as some organic solutes, such as charged methylamines allows the effects of one
508
solute to negate the effects of the other solute. Osmoconformer Osmoregulator

The most common methylamines employed by
animals are trimethylamine oxide (TMAO), be- Ionoconformer Ionoregulator
taine, and sarcosine. 1200
Various
Figure 4 summarizes the solute composition of
1000 Urea
Osmolarity (mOsM)
selected animals to illustrate the relative impor-
Amino acids
tance of the various solutes in different species and 800
Methylamines
cellular compartments. The extracellular space of 600 Cl–
most animals is dominated by Na⫹ and Cl⫺. Marine Other cations
400
ionoconformers possess extracellular concentra- Na+
tions of these ions, as well as Mg2⫹ and Ca2⫹, close 200
to seawater levels. In osmoconforming ionoregula-
0
tors (molluscs, sharks), elevations in organic com-
er
h
ria
fis
nc
lv
fis
at
va
ag
da
ra
patible and counteracting solutes allow inorganic
aw
ny
bi
ob
H
ni
Bo
Se
e
C
sm
in
ion levels to decline. The most abundant inorganic
ar
a
El
M
ions in extracellular fluid of osmoregulators are
also Na⫹ and Cl⫺, although the levels are generally Figure 4 Organic and inorganic solutes in
extracellular fluid of animals Seawater is mainly Na⫹
about one-third the strength of seawater. The cyto-
and Cl⫺, with lower levels of other ions such as K⫹, Mg2⫹, and Ca2⫹.
plasm of most animals is dominated by the same Ionoconformers have high levels of Na⫹ and Cl⫺, whereas the levels
ions; the major cation is K⫹ and the major anions of these ions are lower in ionoregulators. Osmoconformers have the
are SO42⫺, acetate, and Cl⫺. Organic solutes occur same osmolarity as seawater but maintain an inorganic ion profile
much like that of an osmoregulator. The remainder of the osmolarity
in all animals but are most abundant in marine os-
is due to organic solutes, such as urea, amino acids, and
moconformers. Cartilaginous fish rely on the coun- methylamines.
teracting solutes: urea and various methylamines
such as TMAO, sarcosine, and betaine. Inverte-
brates possess high concentrations of compatible
solutes, mainly amino acids such as cell volume. Animal cells change in cell volume in
␤-alanine, taurine, and proline. These organic response to the osmotic gradients across the
solutes confer more than half the osmolarity in ma- plasma membrane. Changes in cell volume are
rine osmoconformers. When osmolarity changes, problematic for several reasons. Severely hypo-
the concentrations of organic solutes often change tonic conditions can cause a cell to explode, trig-
disproportionately, allowing ionic solutes to re- gering a local immune response that can disrupt
main relatively constant. neighboring cells. Swollen cells can disrupt tissue
structure or occlude blood vessels. When water
movement changes cell volume, it also affects the
Cells transport solutes in and out of the intracellular concentration of metabolites and en-
extracellular fluid to control cell volume zymes within cells, disrupting metabolic regula-
Cells control their volume by transporting solutes tion. A cell volume change can also deform the
across the plasma membrane, causing changes in cytoskeleton and plasma membrane, altering the
osmotic pressure that induce the movement of wa- function of receptors and transporters.
ter. Although some cells directly interface with the A change in cell volume can arise in response
external environment, most cells within the body to environmental osmotic stress, but it may also
are surrounded by extracellular fluid held within arise as part of signaling pathways. For example,
the confines of the animal. The interstitial fluid— some hormones induce a change in cell volume
the extracellular fluid found in the narrow regions that is a critical component of the signaling path-
between cells—possesses a chemical composition way. Thus, a volume change can be induced in a
distinct from plasma or lymph because it is a small cell to compensate for osmotic imbalance, or in an
volume directly affected by cellular transport unstressed cell as part of a signaling pathway.
processes. Cells induce a regulatory volume increase (RVI) by
Animals regulate the composition of the extra- importing ions, causing an influx of water. A regu-
cellular fluid to provide cells with an external so- latory volume decrease (RVD) occurs when cells
lution that allows them to maintain an appropriate expel ions, causing an efflux of water.
509
The RVD is best understood in the context of

recovery from swelling, but the same principles Cl– channel
are thought to apply when normal cells are in- K+ channel
Na+ channel
duced to shrink as part of a signaling pathway. Cl– channel
Na+-K+-2CI–
Many combinations of transporters can be used cotransporter K+-Cl– cotransporter
+
to undergo a RVD; the most common mechanism Na+/Ca2 exchanger
Na+/H+
is by activation of K⫹ channels. With an outward
+
2
Ca ATPase
exchanger
K⫹ gradient, K⫹ leaks out of the cell, causing the Na+/K+ATPase
polarized membrane to hyperpolarize until it
reaches the K⫹ equilibrium potential (EK). At the To swell cells To shrink cells
same time, Cl⫺ channels open to allow Cl⫺ to
move out of the cell in response to the hyperpo-
larizing effects of K⫹ movements. The combina- Cl–
K+
tion of K⫹ and Cl⫺ movements reduces the total Cl–
Na+
solute content of the cell, creating an osmotic gra-
dient that drives water out of the cell. Another
pathway of RVD involves an electroneutral K⫹-
Cl⫺ cotransporter, which pumps K⫹ and Cl⫺ out of
the cell. This transporter achieves much the
same effect as the combination of K⫹ channel and K+
Cl⫺ channel activation. A third pathway uses the
Cl–
Na⫹/Ca2⫹ exchanger, operating in a direction that
expels Na⫹ and imports Ca2⫹. The Ca2⫹ is then K+
exported from the cell via the Ca2⫹ ATPase. Fi- Na+
nally, some cells use their Na⫹/K⫹ ATPase to reg-
2Cl–
ulate cell volume. This active transporter exports
three Na⫹ for two K⫹, thereby reducing intracel- Na+
+
lular osmolarity. Ca2
Cells induce a RVI to recover from cell shrink-
age or to induce swelling by transporting solutes
into the cell. Most commonly, cells activate a Na⫹-
K⫹-2Cl⫺ cotransporter (NKCC), bringing these
solutes into the cell to drive osmotic swelling. Cells Na+
can also induce swelling by opening Na⫹ channels. H+
Na⫹ rushes into the cell in response to its electro- 3 Na+
chemical gradient, both depolarizing the mem- 2 K+
brane and causing an osmotic gradient that

induces the influx of water. Most cells complement Figure 5 Regulatory volume increases and
the effects of Na⫹ channels with other transporters, decreases Cells actively change cell volume by moving
ions in or out of the cell. Each of the cells depicts a
such as the Na⫹/H⫹ exchanger, which imports Na⫹ combination of transporters commonly used to transfer
and exports H⫹. Since the pool of H⫹ is largely as- ions into the cell (causing a volume increase) or out
sociated with buffers, this exchange leads to a net of the cell (causing cell shrinking).
increase in cellular solutes, tending to increase cell
volume. For most cells a myriad of transporters are ious transporters are stimulated at least in part by
available to alter solute distributions and cell vol- mechanosensing pathways, whereby volume
ume. Figure 5 summarizes how various trans- changes alter the shape of the cytoskeleton and
porters can be used in combination to induce net plasma membrane, changing the activity of mem-
ion movements that result in volume changes. Al- brane transporters. Alternately, protein-modifying
though the mechanisms involved in compensatory enzymes, such as protein kinases, can modify the
changes are well understood, the exact trigger for structure of the transporters to increase their per-
activation remains unclear. It is likely that the var- meability (channels) or pumping (carriers).
510
epithelial tissues, both internal and external.

2 CO NC E P T C HE C K Some animals reduce this permeability by control-
1. Distinguish between perturbing, compatible, and ling the number of aquaporin proteins in the
counteracting solutes plasma membrane. Recall that each aquaporin
2. What is the difference between osmolarity and permits more than a billion water molecules to
tonicity? pass through each second. An epithelial cell with
3. Are terrestrial animals osmoregulators, aquaporins may be 100-fold more permeable to
osmoconformers, or neither? water than a cell without aquaporins. The aqua-
porin levels in the plasma membrane depend on
the expression of aquaporin genes and on path-
ways of intracellular traffic that control the inter-
The Role of Epithelial Tissues
change of aquaporins between storage vesicles
Animals change the profile of the extracellular and the plasma membrane.
fluid by importing or exporting ions and water Some animals reduce water loss by covering
across those epithelial tissues that interface with external surfaces with a thick layer of hydrophobic
the external environment. This includes the exter- molecules. Mucus—an extracellular secretion of
nal surfaces, such as skin and gills, as well as the mucopolysaccharides, lipids, and proteins—is an
internalized “external” surfaces, such as the lu- example of such a hydrophobic barrier. Mucus lay-
mens of the excretory system and digestive sys- ers on the surface of the lung and gastrointestinal
tem. These epithelial tissues form the boundary tract reduce water loss across these epithelia.
between the animal and the environment, and Many semiaquatic animals, such as frogs, use mu-
usually have other physiological responsibilities, cus to prevent water loss and keep the skin hy-
such as respiration and digestion. However, the drated. The thick mucus layer of a hibernating
properties that make a tissue good at gas ex- lungfish dries to form a water-impermeable co-
change or nutrient absorption—high surface area coon that prevents the animal from dehydrating
and high permeability—make it more vulnerable during the many months of estivation. Surface mu-
to ion and water movements. An epithelial tissue cus also reduces osmoregulatory costs by trapping
has properties that reflect a balance between its a layer of water between the animal and the envi-
different physiological roles. Every animal relies ronment. This layer of water is a microcompart-
on suites of tissues to control osmotic and ion bal- ment that acts as an osmotic and ionic buffer zone.
ance. Ions and water can exchange across each of Land animals use more elaborate adaptations
the body surfaces in contact with the external en- in epithelial structure to prevent water loss across
vironment, including the respiratory surface, di- the skin. The keratinocytes of the skin of terres-
gestive tract, and body surface. Whether these trial amphibians and amniotes secrete proteins
surfaces are barriers to movement, sites of uptake, and modified lipids to form a dense, hydrophobic
or sites of excretion depends upon the nature of extracellular matrix. The amniotes, but not the
the environment (ionic and osmotic gradients) and amphibians, possess an additional layer on top of
the physiology of the animal (ionic and osmotic the keratinocytes. This layer, called the stratum
strategies). In addition to these epithelial tissues corneum, is composed of keratinocytes that have
where ion and water flux can occur, many animals differentiated to form another type of cell—a
have additional epithelial tissues with a primary corneocyte. During the differentiation process, the
role in ion and water regulation: kidneys and their cells produce thick bundles of the protein keratin,
equivalents in the invertebrates. In the following an intermediate filament of the cytoskeleton.
sections we discuss the function of several of these These bundles are, in turn, interconnected by other
epithelial tissues, but we reserve our discussion of proteins, such as keratohyalin. The cell then pro-
the kidney for later in the chapter. duces a complex layer of proteins, called the
cornified envelope, which eventually replaces the
corneocyte plasma membrane. During cornifica-
The integument is an osmotic barrier tion, the corneocyte undergoes programmed cell
Animals reduce the flux of water across the body death, and what remains is the keratin network
surface by limiting the water permeability of the surrounded by the cornified envelope. Extracellular
511
matrix proteins connect these cellular remnants to terproof integument. The insect cuticle is a com-
stacks of lipid molecules called the lamellar mem- plex network of hydrophobic molecules that cov-
brane. Once formed, this mixture of proteins and ers all of the external surfaces of insects, including
lipids undergoes a series of enzymatic and chemi- the surfaces of the trachea and gut. The main
cal processes that modify it into the stratum structural component of the cuticle is the polysac-
corneum (Figure 6). Although the tissue is dead, it charide chitin. It is synthesized within the cells of
remains responsive to physical changes, trigger- the epidermis and then transported to the extra-
ing the underlying keratinocytes to secrete pro- cellular space, where it is chemically modified,
teins, lipids, and signaling factors. crystallized, and combined with other proteins
The diversity in the properties of vertebrate and polysaccharides to obtain the appropriate
skin is due mainly to the way the stratum corneum physical properties. The mature cuticle has very
is constructed. The scales of reptiles and birds are low permeability to water, and is rigid enough to
composed of interconnected patches of stratum act as an external skeleton for the animal.
corneum (largely keratin). Mammalian skin is also
keratinized, although only a few mammals retain
the ancestral “scales,” such as the covering on a
rodent’s tail or an armadillo’s shell. Modifications
of the keratinized stratum corneum provide ter-
restrial vertebrates with other structures, such as
the scutes on the underbelly of snakes that are
used in locomotion and the protective spines of the
desert lizards. However, all tetrapods depend on
their keratinized stratum corneum to minimize
desiccation (Figure 7).
The other major group of terrestrial animals,
the arthropods, possesses a different type of wa-
Stratum corneum Corneocyte Keratinocyte
(a) Armadillo
Epidermis
Basement
membrane
Blood
vessel
Figure 6 Stratum corneum structure The

stratum corneum is the thickened external layer of modified
epithelium found in mammals. Keratinocytes differentiate (b) Horny skin iguana
into corneocytes, producing a waterproof layer composed of
a complex network of intracellular and extracellular Figure 7 Diversity in the stratum corneum of
proteins, augmented by lipids. vertebrate tetrapods
512
The integuments of both tetrapods and terres- External environment

trial insects possess an additional layer of lipid
that reduces evaporative water loss. The cells of
the epidermis secrete these lipids, which then Transporters
Apical
form a continuous coat that acts as a sealant. Birds membrane
and mammals possess a thin layer of glycolipid Mitochondrion
that covers the stratum corneum and fills gaps be- Cell-cell junction
tween cells. The exoskeleton of insects also has a (tight junction)
surface coating of long chain fatty acids and wax
esters. In fact, this thin lipid layer gives the insect
exoskeleton its resistance to water movement. The Transporters
Basolateral
ability of the lipid layers to limit water movement membrane
depends on the interaction between the lipid mol- Basement
ecules, creating a hydrophobic barrier that ex- membrane
cludes water. The lipid layer is held together by Blood vessel
hydrogen bonds, and an increase in temperature
weakens such bonds. Consequently, the lipid layer Figure 8 General features of epithelia The
loses its integrity at higher temperature, greatly typical epithelial tissue displays four main features: (1) an
asymmetrical distribution of membrane proteins; (2) tight
enhancing evaporative water loss. intercellular connections that govern paracellular movement;
Collectively, the properties of the integument, (3) a multiplicity of cell types; and (4) a high density of
established by the cells of the epidermis, control mitochondria.
the magnitude of water loss. Although we have fo-
cused on the outer body covering, the same strict their movement in the lipid bilayer. In part,
processes occur across another epithelial tissue: the proteins are collected together in chemically
the respiratory surface. The magnitude of respira- distinct regions of the membrane, such as lipid
tory water loss depends on structural features, de- rafts. Once in membranes, they are anchored in
scribed for the outer integument, as well as other position by attachment to the cytoskeleton.
factors. For example, an air-breathing animal Second, epithelial cells are interconnected by
with a high metabolic rate will have higher venti- protein linkages that convert the collection of cells
lation rates and therefore greater respiratory wa- to an impermeable sheet of tissue. Tight junctions
ter loss than an animal with a lower metabolic are formed when membrane proteins of one cell
rate. Many animals, especially desert animals we connect to a specific protein in an adjacent cell.
discuss in a later feature, possess anatomical The interaction between adjacent cells limits the
adaptations that reduce respiratory water loss. movement of solutes and water around cells.
These intercellular connections also create a kind
of protein belt around the circumference of the ep-
Epithelial tissues share four specialized ithelial cell, restricting the free movement of mem-
properties that affect ion movements brane proteins between apical and basolateral
The properties of epithelial tissues depend on both membrane regions to maintain the cellular topog-
the transport properties of individual epithelial raphy.
cells, and the way cells are interconnected to form Third, epithelial tissues consist of many types
the tissue. The diverse epithelial tissues, from frog of cells. This diversity is most extreme in the diges-
skin to insect Malpighian tubule, share four gen- tive system. However, even relatively simple tis-
eral features (Figure 8). sues, such as the fish gill, are composed of several
First, epithelial cell function depends on the cell types, each with important roles, such as pro-
asymmetric distribution of transporters within the viding specific transport capabilities or structural
cell. The apical cell membrane, exposed to the out- support.
side world, has a different profile of proteins than Fourth, ion transport demands a great deal of
the basolateral cell membrane, which faces in- energy. Most epithelial cells with a major role in
ward. This cellular topography arises because transport possess abundant mitochondria to pro-
cells insert proteins in the correct location and reduce ATP. In some cases, mitochondria are in close
513
proximity to the regions of the plasma membrane across the apical membrane into the external en-
that conduct the transport processes. In other vironment (either the open water or the lumen of
cases, motor proteins and the cytoskeleton ac- an organ that communicates with the external en-
tively transport mitochondria to these regions vironment). Conversely, the movement of solutes
when the metabolic demands increase. The ener- (or water) between adjacent cells is paracellular
getic costs of ion transport may account for almost transport. For example, molecules diffuse from
half of the metabolic rate of the tissue. the blood, through the extracellular fluid, and into
the narrow confines of the interstitial fluid be-
tween adjacent cells. From here, the molecules
Solutes move across epithelial tissues by pass through the tight junctions that connect ep-
paracellular and transcellular transport ithelial cells into sheets. The neighboring cells can
Although epithelial tissues transport some solutes secrete molecules into the interstitial space to con-
for their own purposes, most transport processes trol its nature in ways that create gradients that
serve to transfer solutes from one side of the tissue drive paracellular movements. Although the tight
to the other. Epithelial tissues use two main routes junction can prevent large molecules from cross-
of transport across the cell (Figure 9). ing, small molecules (water, ions) can cross
Transcellular transport is the movement of through the protein connections. Tissues that per-
solutes (or water) through epithelial cells. For ex- mit paracellular transport are frequently called
ample, solutes can diffuse from the extracellular leaky epithelia. Tissues that conduct minimal
fluid that bathes the cells, and move across the ba- paracellular transport are called tight epithelia.
solateral membrane, through the cytoplasm, and Epithelial tissues possess suites of trans-
porters, including the following transporters fre-
quently implicated in ion and water balance.
Though many of these transporters have acquired
common names, typically as a result of how they
Carrier Channel
were first discovered, we use the more descriptive
Solute names throughout this chapter to better demon-
Tight strate their function.
junction
• ATPases are central to ion movements. The
Na⫹/K⫹ ATPase, or sodium pump, is a pri-
Water mary active transporter that uses the en-
Aquaporin ergy of ATP hydrolysis to export three Na⫹
in exchange for importing two K⫹. Some tis-
sues use a H⫹ ATPase to pump protons to
(a) Transcellular transport change pH, a driving force for other trans-
port processes. Ca2⫹ ATPases re-establish
Ca2⫹ gradients across cellular membranes.
Solute
• Various ion channels (Cl⫺, K⫹, and Na⫹) can
(small) open or close in response to mechanical,
electrical, or chemical signals to permit spe-
cific ions to flow down electrochemical gra-
dients. The Cl⫺ channel most commonly
Water implicated in transfer of Cl⫺ across the api-
cal membrane of cells is better known as
the cystic fibrosis transmembrane conduc-
(b) Paracellular transport tance regulator, or CFTR.
Figure 9 Transcellular and paracellular • Electroneutral cotransporters carry both
transport (a) Tight epithelia can transfer solutes across anions and cations in the same direction in
the cell using transporters on the apical and basolateral
plasma membrane. (b) In leaky epithelia, small solutes can
response to the electrochemical gradient.
also move between cells, passing through the tight junctions There are Na⫹-K⫹-2Cl⫺ cotransporters
that interconnect cells. (NKCC) and K⫹-Cl⫺ cotransporters.
514
• Various electroneutral exchangers are re-

versible transporters driven by electro-
chemical gradients, including the pH
Mucus
gradients. Some transporters are cation an- cell
tiporters, such as Na⫹/H⫹ exchangers (com-
monly abbreviated as NHE) and NH4⫹/H⫹
exchangers. Other transporters are anion Pavement
antiporters, such as the Cl⫺/HCO3⫺ ex- cells
changer (commonly known as band 3 as a
result of its electrophoretic mobility in red
blood cell preparations).
Chloride
cell
Fish gills transport ions into and out of

the water
(a) Gill surface (SEM)
Like most transport epithelia, fish gills have sev-
eral types of cells involved in control of ion and
water balance. Perhaps the best-studied system is
that of the rainbow trout (Figure 10). Mucus-se-
Pavement
creting cells are scattered over the surface of the cell
gill. There are chloride cells, which are large
cells with abundant mitochondria. Much of the
surface is covered by smaller, flattened cells collec- Chloride
cell
tively called pavement cells. Some pavement cells,
like chloride cells, have numerous mitochondria,
whereas others possess fewer mitochondria. It is
thought that most of the ion regulation in the gill
is mediated by the two types of cells that are rich
in mitochondria. These two cell types can be dis-
tinguished using histochemical methods that em-
ploy a glycoprotein (peanut lectin agglutin or
PNA) that binds carbohydrates on chloride cells
that are absent from pavement cells. Thus, chlo-
ride cells are often called PNA⫹ cells, and pave-
ment cells are PNA⫺ cells. In rainbow trout, and
perhaps freshwater fish in general, these two
types of mitochondria-rich cells mediate different
transport processes.
(b) Chloride cell (TEM)
The direction of transport of ions and water
depends on the salinity of the water (Figure 11a). Figure 10 Cells of the fish gill The fish gill is an
The gill of a freshwater fish must take up Na⫹, important site of ion exchange in both freshwater and
seawater species. It has multiple cell types, including mucus
Ca2⫹, and other ions from the water, frequently
cells, chloride cells, and pavement cells. SEM, TEM: scanning
against steep electrochemical gradients. The PNA⫺ or transmission electron micrograph.
cells take up Na⫹ through an apical Na⫹ channel. (Images courtesy of Steve Perry, University of Ottawa)
Although there is an unfavorable gradient for Na⫹
uptake, these cells create a favorable electrochem- capes through basolateral Cl⫺ channels. In both
ical gradient using a H⫹ ATPase that acidifies the transport schemes, production of HCO3⫺ and H⫹ by
water in the boundary layer. Once inside the cell, carbonic anhydrase is essential, providing ions
Na⫹ is exported to the extracellular fluid by the ba- that can be used as counterions or to change pH.
solateral Na⫹/K⫹ ATPase or a Na⫹/HCO3⫺ ex- In contrast to freshwater fish, marine fish must
changer. PNA⫹ cells import Cl⫺ into the cell using avoid excessive ion uptake and limit water loss.
an apical Cl⫺/HCO3⫺ exchanger, which then es- The gill is central to ion balance, and chloride cells
515
PNA– cell the outside). Na⫹ is thought to escape through

Na+ Na+
paracellular channels, driven by the transepithe-
K+ lial membrane potential. This arrangement of
Na+
Na+ transporters is common in other ion-pumping ep-
HCO3
– H+ ithelial cells that expel Cl⫺ from cells, such as the
– – shark rectal gland we discuss later in this chapter.
HCO3 HCO3 H+ H+
CI– As you can see, the responsibilities of the ion-
CA
pumping cells of the fish gill change depending on
CO2 CO2
the external conditions. Some fish species are dia-
dromous, migrating between seawater and fresh-
Pavement cell water. Catadromous fish, such as eels, migrate to
seawater to breed. In contrast, anadromous fish,
Ca+ PNA+ cell such as salmon, migrate from seawater to freshwa-
+
Ca2
Ca+ ter to reproduce. Young salmon grow in freshwater,
Na+
then migrate to the sea. Prior to migration, the gills
Na+ of these fish undergo a dramatic cellular reorgani-
zation as the ion-pumping properties of the gill cells
K+
– CI– prepare for the new environment (Figure 12). Inter-
H+ HCO3
CA
estingly, the remodeling process, called
CO2 CO2 smoltification, occurs before exposure to seawater.
It is mediated largely by growth hormone, insulin-
(a) Freshwater trout gill like growth factor 1, cortisol, and to a lesser extent
thyroid hormone. Smoltification also leads to the
Na+ remodeling of other tissues involved in ion and wa-
K + ter balance, including the gastrointestinal tract and
Na+
probably the kidney. As a consequence of the cellu-
K+ lar changes, there is very little ionic and osmotic
CI–
2CI– disturbance when the salmon enter seawater.
K+
Na+ Digestive epithelia mediate ion and water

Pavement cell transfers
Every time an animal consumes food or water, the
(b) Marine fish gill digestive tract, with its high surface area, becomes
Figure 11 Ion transport processes in gills of a site of exchange of solutes and water. The diet
freshwater and marine fish Gills possess ion- may be a vital source of water but it may also cre-
pumping cells that cause the net uptake of Na⫹ and Cl⫺ in ate an osmotic burden. Many insects, for example,
freshwater and the net export of Na⫹ and Cl⫺ in seawater.
(a) The freshwater gill possesses two types of ion-pumping
feed on diets rich in water, such as sap, nectar, or
cells. Acid-secreting cells (PNA⫺) import Na⫹ from the water. blood. Consider the osmotic challenge faced by
Base-secreting cells (PNA⫹) import Cl⫺ and Ca2⫹. (b) Gill Rhodnius, a blood-sucking bug that consumes
epithelial cells of marine fish export Cl⫺ and Na⫹. more than 12 times its body mass in a single blood
(Source: Adapted from Perry and Gilmour, 2006)
meal. Blood-sucking insects must remove the water
from the blood meal in order to process the remain-
in particular are critical for excreting ions (Figure ing energy-rich macromolecules. Facing similar
11b). The combined actions of the Na⫹/K⫹ challenges, a female mosquito begins to urinate
ATPase and the Na⫹-K⫹-2Cl⫺ cotransporter bring shortly after commencing feeding, allowing her to
K⫹ and Cl⫺ (and some Na⫹) into the cell from the compress the solids of the blood meal in the gut.
blood. The Cl⫺ channels in the apical membrane Scientists debate the relative importance of
allow Cl⫺ to escape into the seawater, and basolat- transcellular and paracellular transport in water
eral K⫹ channels allow K⫹ to return to the blood. transport across the gut, but it is likely that both
The movement of Cl⫺ and other ions creates a processes are important. Transcellular transport is
transepithelial membrane potential (negative on driven by osmotic gradients and facilitated by
516
aquaporins in both basolateral and

apical membranes of the epithelium.
Paracellular transport occurs when
the internal and external fluids are Pre-smolt (parr) Smolt
nearly isosmotic. Ions, mainly Na⫹
(a) Smoltification
and Cl⫺, are secreted into the inter-
stitial space to create an osmotic gra-
dient that drives movement of water
across the tight junctions. Once in
the interstitial fluid, water makes its
way into the blood.
Reptiles and birds possess

salt glands
Since freshwater has a very low
solute concentration, it creates an
inward osmotic pressure that helps
drive water uptake. However, ani-
mals that drink seawater face two
challenges. First, water molecules
25 μm
must be selectively transported
across the gut against the osmotic
gradient. It is likely that transcellu- Parr Pre-smolt Smolt Post-smolt
lar transport across tight epithelia (b) Changes in gill Na+/K+ ATPase
is important in these animals. Sec-
ond, the animals must be able to ex-
pel the salt that accompanies the
seawater consumed in the diet.
Many reptiles and birds possess a
salt gland that aids in ion and water
balance by excreting hyperosmotic
solutions of Na⫹ and Cl⫺. Whether liv- 65 μm
ing in the ocean or the desert, species
with salt glands can cope without ac-
cess to freshwater, deriving water NKCC Na+/K+ ATPase NKCC Na+/K+ ATPase
from drinking hypertonic seawater or
exclusively from food. Seawater Freshwater
In birds, the salt gland is found in (c) Seawater versus freshwater
a depression at the base of the beak,
Figure 12 Smoltification and ion regulation Salmon undergo complex
and its secretions drain through a physiological changes when they move from rivers and streams into the ocean, where
canal that runs along the beak and they grow and reach reproductive maturity. In addition to a color change (a), salmon
opens at the nostrils. The nasal salt remodel their epithelial tissues to make them better able to expel ions. Gills,
gland secretion can be as much as intestines, and skin increase the activities of ion-pumping machinery. (b, c) The
fluorescent images of a salmon gill show the relative abundance of important
three times more concentrated than
transporters. The levels of the Na⫹/K⫹ ATPase (red) increase during smoltification (b).
the plasma. Thus, if a bird drinks The levels of Na⫹-K⫹-2Cl⫺ cotransporter (NKCC) and the Na⫹/K⫹ ATPase also differ
30 ml of seawater, it can excrete all of manyfold in freshwater- versus seawater-acclimated fish (c).
the salt in 10 ml of salt gland secre- (Image courtesy of Ryan Pellis and Steve McCormick, Contes Anadromous Fish Laboratory)
tion, gaining 20 ml of pure water. The
salt glands are able to do this by us-
ing metabolic energy to create a
countercurrent multiplier.
517
The salt gland is composed of a series of secre- the tubule cells and the blood. The basolateral mem-
tory tubules, surrounded by peritubular fluid and brane and apical membrane work in conjunction to
a capillary network. The tubule has a closed end produce a hyperosmotic secretion. The basolateral
and an elongated tube that empties into a collect- membrane of the epithelial cells brings ions into the
ing duct. Fluids flow from the closed end of the cell using the suites of transporters involved in a
tubule to the open end. A capillary network is regulatory volume increase. Conversely, the apical
arranged in parallel to the tubule, though direc- membrane possesses the transporters that are in-
tion of blood flow is the opposite direction to that volved in regulatory volume decreases. Although
of the lumen fluids (Figure 13). This countercur- the exact mechanisms remain unclear, the Na⫹/K⫹
rent arrangement of flows is central to the ability ATPase, NKCC, K⫹ channels, and Cl⫺ channels have
of the salt gland to produce a concentrated secre- all been implicated in the formation of the hyperos-
tion. The countercurrent multiplier works like motic secretion. The net result of these activities is
this. As blood flows toward the closed end of the the import of Na⫹ and Cl⫺ from the plasma and their
tubule, salts escape into the interstitial fluid and secretion into the lumen of the tubule. Like other ep-
are taken up by the tubule cells and transferred to ithelial tissues involved in ion transport, the cells of
the lumen. As a result, the blood becomes progres- the secretory tubule have a high content of mito-
sively more dilute. The interstitial fluid that bathes chondria, which produce the ATP needed to pump
the tubule cells is in equilibrium with the blood ions and establish the gradients used by secondary
passing over the tubule: low osmolarity near the active transport. The ion-secreting machinery of the
closed end and high osmolarity near the opening. salt glands is similar in many respects to the trans-
Thus, the tubule cells near the closed end of the porters used by other salt-secreting epithelia dis-
tubule are exposed to a dilute interstitial fluid and cussed earlier in this chapter, such as the fish gill.
create a dilute lumen fluid. As lumen fluids flow
from the closed end to the open end, the surround-
ing interstitial fluids are increasingly concen-
Elasmobranch rectal glands excrete Na⫹
trated, and the transcellular transport of salts
and Cl⫺, while retaining urea
across the tubule cells causes the lumen fluids to Like seabirds, elasmobranchs have an accessory
become more concentrated. excretory organ that aids in salt excretion. The
The epithelial cells that line the secretory tubule rectal gland is composed of many tubules sur-
extract salts from the interstitial fluid found between rounded by capillaries. Each tubule is composed of
Blood vessel
flow Interstitial
Blood
space
Lumen of
secretory
tubule
Epithelial
cells
(a) (b)
Figure 13 Salt glands of birds and reptiles (b) The hypersaline excretions form in secretory tubules
Some birds and reptiles that live in seawater or the desert that are arranged into lobes that drain into collecting
are able to excrete Na⫹ and Cl⫺ from specialized salt glands. ducts. Blood vessels juxtaposed to the secretory tubules flow
(a) The glands are located near the eye, but drain into ducts countercurrent to the flow of fluid through the tubule.
that empty near the nostril. Salt can precipitate and (Photo courtesy of Robert H. Rothman, Rochester Institute of
accumulate on the head, as shown in this marine iguana. Technology)
518
a single type of epithelial cell. Like other transport Blood Rectal gland
epithelial cells, the cells of the rectal gland tubule lumen
have abundant mitochondria and basolateral in-
vaginations, much like microvilli, that increase the Rectal gland cell
surface area for ion exchange with the blood. The
tubules are able to transfer NaCl from the blood to
the tubule lumen. Though the osmolarity of the VIP CI–
tubule secretions is similar to that of the plasma, G protein CI–

ATP
the secretions have a much higher concentration
Adenylate
of NaCl because urea is retained in the blood. Two cyclase
separate mechanisms are responsible for transep- cAMP
K+
ithelial movement of Na⫹ and Cl⫺. Tubular epithe-
lial cells actively transport Cl⫺ from the blood via Na+
transcellular transport, whereas Na⫹ moves be- K+
Cl– channel
2CI– PKA
tween the tubular epithelial cells, from the blood
to the tubule lumen via paracellular transport. 3Na+ CI–
2K+
The transport processes carried out by the tu-
bular epithelium function much like those of chlo-
ride cells of the teleost gill and the salt gland of
birds, using a combination of basolateral NKCC,
Na⫹/K⫹ ATPase, K⫹ channels, and apical Cl⫺ chan-
nels. A model for describing the secretion of Cl⫺ is Figure 14 Chloride transport in the
shown in Figure 14. The main source of entry of elasmobranch rectal gland The excretion of salt
in the shark rectal gland is driven by the secretion of Cl⫺.
Cl⫺ into the epithelial cells is via the NKCC. The in- Chloride is imported into the cell from the plasma through
ward movements of Na⫹ and K⫹ are reversed by the Na⫹-K⫹-2Cl⫺ cotransporter and escapes through Cl⫺
the action of the basolateral K⫹ channels and the channels. The entire process is sensitive to hormones such
exchange of Na⫹ for K⫹ via the Na⫹/K⫹ ATPase. as vasoactive intestinal peptide (VIP), which elevate cAMP
levels, activating protein kinase A (PKA).
Once Cl⫺ enters the cytoplasm of the epithelial cell,
(Source: Adapted from Silva et al., 1997)
it can escape across the apical plasma membrane
through Cl⫺ channels. The rectal gland is also the crease Cl⫺ conductance. Though the changes in Cl⫺
site of Na⫹ excretion, which moves between cells activity probably drive this process, the activity of
from the interstitial fluid to the lumen of the NKCC is also regulated during stimulation of salt se-
tubule. This paracellular transport is driven by the cretion. The efflux of Cl⫺ causes a regulatory de-
transepithelial electrochemical potential. crease in cell volume and cytoplasmic Cl⫺ levels.
Salt secretion by the rectal gland occurs in The changes in cell volume trigger phosphorylation
pulses after a shark has incurred a salt load, either of NKCC, which is normally inactive in the basolat-
through drinking or eating salt-laden food. The os- eral membrane. Although the exact protein kinases
motic perturbation triggers release of hormones that phosphorylate NKCC are not yet established,
that stimulate rectal gland secretion. The osmotic PKA is not involved. These protein kinases, what-
and blood volume changes stimulate the release of ever their nature, may also be activated through
atrial natriuretic peptide from the heart. We discuss hormonal or neuroendocrine factors.
this hormone in more detail later in this chapter,
but in sharks atrial natriuretic hormone triggers
the release of the neuroendocrine hormone vasoac-
tive intestinal peptide (VIP). When VIP binds to its 2 C O NC E P T C H E CK
G-protein linked receptor, it activates adenylate cy-
4. Name two tissues specialized to produce
clase, increasing cAMP synthesis, which activates concentrated salt solutions.
protein kinase A (PKA). The main target of PKA in
5. What are the four main features of a transport
this process is the apical Cl⫺ channel itself; phos- epithelium?
phorylation opens the channel. PKA may also affect 6. Distinguish between transcellular and
intracellular traffic, causing movement of more Cl⫺ paracellular transport.
channels to the apical membrane to further in-
519
Nitrogen Excretion Table 3 Nitrogen excretion strategies.

The ammonia produced during amino acid break- Nitrogen excretion
down is a toxic solute that must be excreted, either strategy Animal group
as ammonia, urea, or uric acid (Figure 15). Ani-
Ammonioteles Simple invertebrates
mals use a variety of strategies to excrete these ni- (cnidarians, nematodes)
trogenous wastes, and these strategies have
important implications for ion and water balance. Aquatic molluscs
An animal that excretes most of its nitrogen in the Agnathans,
form of ammonia is called an ammoniotele. Be- chondrichthians, bony
fish, larval amphibians
cause ammonia is very toxic, it cannot be stored in
the body and must be excreted as a dilute solution, Uricoteles Terrestrial molluscs
resulting in water loss. Alternative strategies in- (snails, slugs), terrestrial
arthropods
volve energy-dependent production of nitroge-
nous wastes that can be stored at higher levels, Reptiles, birds
and excreted with less water loss. The two most Ureoteles Some larval bony fish,
common alternatives to ammoniotelism are estivating lungfish
ureotelism and uricotelism. A ureotele excretes All mammals
urea, and a uricotele excretes uric acid. Although
animals excrete most of their nitrogenous waste in
one form, almost every species has the capacity to Ammonia is produced in amino acid
produce each of these molecules. For example, hu- metabolism
mans are ureoteles, but they also produce and ex-
Ammonia is at the heart of amino acid metabolism.
crete some ammonia and uric acid.
It is used in the synthesis of amino acids by reac-
Each group of animals relies predominantly on
tions that add ammonia to a carbon skeleton to cre-
a particular strategy (Table 3). Among the verte-
ate an amino acid that can be used in biosynthesis
brates, there are ureoteles (mammals), uricoteles
of proteins. When proteins are degraded, the amino
(birds and reptiles), and ammonioteles (amphib-
acids are broken down to produce carbon skeletons
ians and fish). However, there are many exceptions
that can be used for energy metabolism. The am-
to these generalizations. There are exceptional
monia that is liberated is toxic and must be either
species; for example, a few species of bony fish are
excreted or metabolized into a less toxic form.
ureoteles. There are also developmental transi-
The removal and processing of ammonia from
tions; for instance, most amphibians excrete am-
amino acids is complex because of the unique
monia as larva but urea as adults. Other transitions
structural features of each amino acid. A few
in nitrogenous excretion strategies are triggered
amino acids (asparagine, glutamine, glutamate,
by environmental conditions; dehydration causes
histidine, serine) can be deaminated, with ammo-
some lungfish to convert from ammoniotelism to
nia cleaved from the carbon backbone and re-
ureotelism. Since the enzymes necessary for am-
leased. For most amino acids, aminotransferases
monia, urea, and uric acid synthesis exist in most
transfer their amino group to 2-oxoglutarate, pro-
animals, we can assume that the atypical species
ducing glutamate, which can then be deaminated
or developmental changes arise through variation
by the enzyme glutamate dehydrogenase (Figure
in the control of expression of genes, rather than
16). In many animals, ammonia produced by glu-
convergent evolution of novel capabilities.
tamate dehydrogenase or other deaminating en-
O zymes is repackaged into a form that is less toxic.
C O Many animal tissues use the enzyme glutamine
HN C N synthase to transfer ammonia to glutamate, form-
N H4+ H2 N C N H2
C C C O ing glutamine. This amino acid can then be trans-
O N N ported to other tissues, where it can be
H H
deaminated by the enzyme glutaminase, releasing
Ammonium Uric acid Urea ammonia and glutamate. This complex cycle of
Figure 15 Structures of the nitrogenous end ammonia release, glutamine synthesis, and gluta-
products mine deamination costs the animal metabolic en-
520
α-amino acid α-keto acid Ammonia can cross biological membranes as

both NH3 and NH4⫹, although by different mecha-
Aminotransferases nisms. NH3 can passively diffuse through mem-
branes at a moderate rate. Recently it has been
shown that, like water movement, some NH3
2-Oxoglutarate Glutamate crosses membranes via specific gas channels.
Though animals have an NH4⫹/H⫹ exchanger,
NAD+
GDH NH4⫹ can also replace K⫹ in some transporters,
NADH such as NKCC and Na⫹/K⫹ ATPase, or replace H⫹
in the Na⫹/H⫹ exchanger.
NH4+ Ammonioteles export the ammonia produced
ATP
ADP + Pi in these reactions across diverse epithelial tissues.
GS In general, the uncharged form, NH3, crosses
membranes, whereas the charged form, NH4⫹, re-
Glutamine Glutamate quires specific transporters. Ammoniotelism is
most common in animals that live in water. Fresh-
Glutaminase water fish are typically ammonioteles, excreting
most of their nitrogen waste as NH3. Marine fish
can also excrete NH3, but in these species NH4⫹ ex-
NH4+ cretion across the gills is also important. Some air-
breathing fish are able to excrete some ammonia
Figure 16 Glutamine metabolism and
ammoniogenesis NH4⫹ from most amino acids is through volatilization of NH3. Most terrestrial ani-
transferred to glutamate through various aminotransferases. mals release at least some NH3 across the skin and
The glutamate can then be oxidatively deaminated by lung, even if ammoniotelism is not their primary
glutamate dehydrogenase (GDH). NH4⫹ can also be used by mode of excretion of nitrogenous wastes.
glutamine synthase (GS) to produce glutamine, a convenient
molecule to transport ammonia between tissues. Glutamine
Ammoniotelism has one main advantage; lit-
can then be deaminated by glutaminase. tle additional energy is required to metabolize
this nitrogenous waste into a form ready for ex-
cretion. However, ammonia excretion is not prac-
ergy in the form of ATP. However, it gives an tical for terrestrial animals because it requires
animal greater control over the rate and location large volumes of water and constant urination to
of ammonia production, which is particularly im- ensure that ammonia levels remain within a tol-
portant in animals that further metabolize ammo- erable range.
nia into less toxic nitrogenous compounds bound
for excretion.
Birds, reptiles, and insects excrete uric acid
The terrestrial invasion by animals necessitated
Ammonia can be excreted across epithelial an excretory strategy that permitted nitrogen ex-
tissues cretion with little need for water. The earliest evo-
Metabolic enzymes produce a combination of NH3 lutionary solution to this problem was uricotelism.
and NH4⫹, but the relative concentrations of the Unlike ammonia, uric acid can accumulate in body
different forms of ammonia in fluids depend on fluids with few toxic effects. Uricotelism spares
many factors. Since NH3 is a gas, its concentration water, because uric acid is excreted as anhydrous,
in biological fluids depends on how much dis- white crystals. However, uric acid synthesis does
solves into water, which in turn depends on the require metabolic energy.
partial pressure of the gas (PNH3), its solubility in Uric acid is produced by most animals as part
water, and the temperature. Once dissolved, some of an energy-dependent pathway for nucleotide
NH3 becomes protonated to form NH4⫹. The bal- synthesis (Figure 17). Networks of aminotrans-
ance between these two forms depends on pH. ferases transfer nitrogen from various amino
Since the pKa value for NH4⫹ is approximately 9, at acids to the three amino acids that act as sub-
a physiological pH most of the ammonia occurs in strates for IMP synthesis: glutamine, glycine, and
the ionized (NH4⫹) form. aspartate. IMP synthesis requires 5 ATP, but an
521
PRPP cleotide metabolism. Its fate varies among species.

2 Glutamine (2N) Of course, in uricoteles (birds, reptiles, and in-
Glycine (N) sects), uric acid from nucleotide metabolism inter-
7 enzymes
Aspartate (N) mingles with that produced in nitrogen excretion.
5 ATP However, primates also excrete some uric acid. In
other animals, uric acid is further metabolized,
GTP ATP
IMP then excreted as allantoin (in nonprimate mam-
mals), allantoate (in bony fish), urea (in amphib-
2 enzymes 2 enzymes
ians and cartilaginous fish), or ammonia (in
marine invertebrates).
AMP GMP Multiple, unrelated lineages of animals—
vertebrates and invertebrates—share the feature of
uricotelism. This striking example of convergent
4 enzymes 3 enzymes evolution is possible only because the pathway of
Xanthine uric acid synthesis is available to all animals as part
of intermediary metabolism. The inherent flexibility
Excretion of these pathways is evident in the animals that can
Uric acid switch between uricotelism and ammoniotelism, de-
pending on conditions. The amphibious Indian ap-
Excretion ple snail can switch modes depending on the
Allantoin
environment, living as an ammoniotele while in wa-
ter and a uricotele when on land.
Excretion
Allantoic acid
Urea is produced in the ornithine-urea cycle
Excretion
Urea Long after the first invertebrate and vertebrate
uricoteles appeared on the scene, another form of
Figure 17 Uric acid metabolism A complex
reaction network uses high-energy phosphate compounds to nitrogen excretion—ureotelism—arose in the ter-
use amino acids as substrates to produce various nucleotides, restrial lineages. Urea is the main excretory prod-
and then break those nucleotides down for excretion. This uct of mammals, as well as selected species in
pathway is also an important route of nitrogenous waste other taxa. Urea is produced in some species in
production. Amino acid nitrogen is transferred to uric acid,
which, depending on the animal, may be excreted or further
the breakdown of uric acid or arginine, but ureo-
metabolized to produce other nitrogenous wastes. PRPP: teles produce urea by another pathway, the
5-phosphoribosyl-1-pyrophosphate. ornithine-urea cycle (Figure 18).
The prelude to urea production is the transfer of
additional high-energy phosphate is required for amino groups from the diverse amino acids to the
the conversion of IMP to either AMP or GMP. Both form that can be used by the enzyme carbamoyl
AMP and GMP are broken down to form xanthine. phosphate synthase (CPS). One isoform of CPS (CPS
AMP is metabolized to adenosine, inosine, hypox- II) is involved in pyrimidine nucleotide synthesis and
anthine, and then xanthine, whereas GMP is me- uses glutamine as a substrate. However, ureotelic
tabolized to guanosine, guanine, and then animals possess other CPS isoforms (CPS I and CPS
xanthine. Some terrestrial arthropods (for exam- III) that are specialized for urea synthesis. The evo-
ple, spiders and scorpions) excrete guanine as a lutionary origins of the urea cycle are intimately
nitrogenous waste product. The xanthine that is linked to the evolution of the CPS genes (see Box 2,
produced in these reactions is oxidized to form Genetics and Genomics: Evolution of the Urea Cy-
uric acid. Depending on the species, uric acid may cle). The two CPS forms involved in urea synthesis
be further metabolized to allantoin, allantoic acid, differ in the N-donor; CPS I uses NH4⫹ whereas CPS
or urea, any of which may be excreted as a ni- III uses glutamine. Once carbamoyl phosphate is
trogenous waste. produced, it enters the ornithine-urea cycle.
Even those animals that use other pathways In addition to the five enzymes of the ornithine-
for disposing of nitrogenous wastes also produce urea cycle, urea synthesis requires two transporters
some uric acid as a normal end product of nu- to shuttle substrates across the mitochondrial mem-
522
Mitochondria Cytoplasm
Glutamine
Glutaminase
PPi Aspartate
Glutamate ATP AMP
Glutamate dehydrogenase
Argininosuccinate
synthetase
2-Oxoglutarate
NH4+ Citrulline Citrulline
2 ATP
CPS I Ornithine
Argininosuccinate
HCO3– transcarbamylase
Urea
Carbamoyl phosphate Ornithine Ornithine Argininosuccinate

lyase
2 ATP Fumarate
CPS III
Arginase
HCO3– Arginine
Glutamine
Figure 18 Ornithine-urea cycle Amino nitrogen in the form of either glutamine or

NH4⫹ is used to produce carbamoyl phosphate, which enters the ornithine-urea cycle.
brane: the ornithine/citrulline transporter and the of the ornithine-urea cycle. Glucagon and glucocor-
aspartate/glutamate transporter. The division of the ticoids stimulate the expression of ornithine-urea
pathway between the cytoplasm and mitochondria cycle enzymes, whereas insulin inhibits expression
allows greater control over the fate of metabolites. of these genes. Second, animals regulate CPS activ-
There is also evidence that metabolites are chan- ity through the allosteric regulator N-acetyl gluta-
neled from one enzyme to the next to avoid the loss mate. When amino acid levels are high, an elevation
of metabolites to other pathways. Arginine, for ex- in glutamate levels increases the activity of the en-
ample, is used in multiple other pathways and must zyme N-acetyl glutamate synthetase.
be constrained within the ornithine-urea cycle for
efficient urea production.
Urea is made in the liver and released into the
Each nitrogenous waste strategy has
blood, where its fate depends on the species. In
inherent costs
mammals, urea is collected by the kidney and ex- Excretory strategies have been an important ele-
creted in the urine. In other animals, urea may be ment of many ecophysiological studies. The costs
excreted via other routes, such as the fish gill. and benefits are clear and can readily be under-
Urea is carried across the plasma membrane by stood in terms of the environmental and ecological
facilitated diffusion on specific urea transporters. constraints on the animal: available water, dietary
These transporters govern how fast urea crosses strategies, and metabolic cost.
membranes in different cell types and regions of Each excretory strategy has implications for
the kidney. Active transporters for urea may exist water balance, but not all animals within a taxo-
in tissues such as shark gills, although much less nomic group have the same needs for water conser-
is known about such carriers. vation. For example, all birds share the reptilian
The rate of urea production is matched to the trait of uricotelism, which offers the greatest bene-
rate of protein metabolism, which is high in animals fits in terms of water conservation. However, not all
that (1) eat protein-rich diets or (2) degrade body birds live in a water-poor environment. Humming-
protein during starvation. The rate of urea synthesis birds, for instance, eat a diet that is very low in pro-
is regulated by enzyme quantity and allosteric regu- tein and high in water content. They produce very
lation. First, animals use hormones to regulate the little nitrogenous waste during digestion. Thus,
rate of expression of genes that encode the enzymes hummingbirds and other nectar feeders can expend
523

Evolution of the Urea Cycle
All animals possess the genes that en- tion near the catalytic site of an NH4⫹-dependent CPS I
code the enzymes required to produce urea, but can endow the mutated enzyme with the ability to use
only selected groups produce a functional ornithine- glutamine (a property of both CPS II and CPS III). In the
urea cycle. The evolutionary processes that enabled next few years, when more genomic analyses are avail-
these animals to produce high levels of urea must have able from primitive fish, the exact evolutionary history of
affected multiple genes. Some changes were mutations CPS genes will become clearer.
that altered the structure of enzymes, imparting novel A second challenge in the evolution of the ornithine-
catalytic properties. Other mutations altered the target- urea cycle was securing the mutations necessary to en-
ing sequence of proteins, causing a distinct pattern of sure that each enzyme is targeted to the appropriate
enzyme subcellular localization. By looking at the prop- subcellular compartment. The urea cycle of terrestrial
erties of existing animals, we can understand some of animals spans two compartments, which allows spe-
the evolutionary steps needed for the formation of the cialized functions to be isolated from competing path-
ornithine-urea cycle. ways. The enzymes of the pathway must also be
One of the central enzymes in the ornithine-urea cy- expressed in the appropriate intracellular compart-
cle is carbamoyl phosphate synthetase (CPS). All ani- ment. For example, CPS II is found in the cytoplasm with
mals have CPS II, but this enzyme is not useful in urea the other enzymes of nucleotide metabolism. Con-
synthesis for two reasons. First, it has a very low affin- versely, both CPS I and CPS III are mitochondrial en-
ity for NH4⫹, relying on glutamine as a nitrogen donor. zymes, allowing the cell to segregate nucleotide
Second, its catalytic activity, though adequate to meet metabolism from urea synthesis. With the mutations
the demands of nucleotide degradation, is insufficient to that created the allosteric site on CPS, the cell must
match the needs of NH4⫹ detoxification arising from have a way of ensuring the regulator (N-acetyl gluta-
amino acid oxidation. Two distinct solutions to the first mate) could gain access to CPS. In nonureogenic or-
problem have arisen in animals in the form of two addi- ganisms, N-acetyl glutamate is an intermediate in
tional CPS isoforms with more useful kinetics and sen- arginine biosynthesis, a pathway that is largely cyto-
sitivity to the allosteric regulator N-acetyl glutamate. plasmic. Thus, the gene encoding the N-acetyl gluta-
One isoform, CPS I, is found in mammals and some mate synthetase also needed mutations that changed
lungfish. It has a much greater affinity for NH4⫹ than its targeting information. In ureogenic animals,
does CPS II. The other isoform, CPS III, is found in chon- N-acetyl glutamate synthetase is located in the mito-
drichthians and ureogenic bony fish. It uses glutamine chondria, where it produces the most important al-
as a substrate (like CPS II) but has an activity that is losteric regulator of mitochondrial CPS.
much more sensitive to the allosteric regulator N-acetyl
References
glutamate. Interestingly, some species, including the
q Mommsen, T. P., and P. J. Walsh. 1989. Evolution of urea synthe-
coelacanth and some lungfish, possess both CPS III and
sis in vertebrates: The piscine connection. Science 243: 72–75.
CPS I. Although CPS II is likely the ancestral form of the
q Saeed-Kothe, A., and S. G. Powers-Lee. 2003. Gain of glutami-
enzyme, it is not yet clear which of the derived forms nase function in mutants of the ammonia-specific frog car-
came first, CPS I or CPS III. Such phylogenetic analyses bamoyl phosphate synthase. Journal of Biological Chemistry 278:
have relied on kinetic properties to help define evolution- 26722–26726.
ary relationships. However, major differences in kinetic q Walsh, P. J. 1997. Evolution and regulation of urea synthesis and
properties can arise from subtle genetic differences. Mu- ureotely in (batrachoidid) fishes. Annual Reviews in Physiology 59:
tational analyses have shown that a single genetic muta- 299–323.
the water necessary to make greater use of ammonia, since it does not need to be further metabo-
nia excretion. However, even these birds are not lized after protein metabolism. Both urea and uric
truly ammoniotelic—most of their nitrogenous acid have metabolic costs associated with their
waste is still excreted in the form of uric acid. synthesis, and we can estimate these costs by
The other cost of excretory strategy is the comparing Figures 17 and 18.
metabolic cost of producing the excretory product The costs of urea synthesis depend on the ni-
itself. The cheapest nitrogenous waste is ammo- trogen source used to make carbamoyl phosphate.
524
If glutamine is the nitrogen donor, then 1 mol of The gulf toadfish, Opsanus beta, also can convert
urea costs 4 mol of ATP (1 mol of ATP to make glu- to ureotelism, typically when it moves to crowded
tamine, 2 mol of ATP for carbamoyl phosphate conditions. The urea is stored in the blood and re-
synthesis, and 1 mol of ATP for argininosuccinate leased once or twice daily in short pulses across
synthesis). The pyrophosphate produced in argini- the gill following the insertion of urea transporters
nosuccinate synthesis is normally hydrolyzed, into the gill epithelia. It remains unclear why
wasting an additional high-energy phosphate. ureotelism is advantageous in this species. It may
Thus, the costs of urea synthesis are most often es- serve to reduce the risk of local fouling of water
timated as 5 mol of ATP per mol of urea. In com- where animals are closely associated together. Al-
parison to urea, uric acid costs more to produce ternatively, since many animals use ammonia as a
(7 ATP) but it also has more nitrogen (4N). Thus, cue to detect prey, urea production may confuse
uric acid (7 ATP; 1.75 ATP/N) is slightly more eco- predators. Urea production is more common in
nomical than urea (5 ATP; 2.5 ATP/N). However, the early developmental stages of many ammo-
uric acid pellets include numerous proteins; since niotelic species, including rainbow trout. It is
these proteins are lost in the excreta, they repre- likely that all fish are capable of synthesizing urea,
sent an indirect cost of uricotelism. but the species that produce urea as adults likely
do so by retaining this embryonic capacity.
The mode of nitrogen excretion can change

with development or environmental Cartilaginous fish produce urea as an
conditions osmolyte
The reasons for the occurrence of ureotelism in Most species that produce a lot of urea do it mainly
species other than mammals are not always clear, to excrete nitrogenous wastes. However, some
although it usually coincides with an atypical envi- species produce urea but retain it as an osmolyte.
ronmental situation or life history strategy. Let’s For example, the urea concentration in the plasma
consider some examples. of the crab-eating frog (Rana cancrivora) in-
Urea production by most teleost fish is nor- creases more than 20-fold when the frog is ex-
mally quite low and an insignificant contribution posed to high salinity. Since the rates of urea
to nitrogen excretion. Some fish species live most excretion do not change, it is likely that urea is
of their life as ureoteles. For example, the Lake serving an important role as an osmolyte.
Magadi tilapia lives in water with a pH so high that Urea is an important osmolyte in cartilaginous
the gill cannot excrete NH3. In most fish, NH3 dif- fish, where it can account for almost half of the tis-
fusion across the gills is accelerated when external sue osmolarity. At the high concentrations seen in
protons ionize NH3 to form NH4⫹. At a high exter- shark blood, urea could disrupt macromolecular
nal pH, well above the pKa value for NH3, this re- structures. However, its effects are counteracted by
action is very slow, reducing the rate of NH3 methylamines, such as TMAO, betaine, and sarco-
diffusion. These fish have an active ornithine-urea sine, which are also accumulated at high concentra-
cycle in the liver, but surprisingly, the muscle also tions. By relying on counteracting solutes, sharks
plays an important role in urea synthesis in these can maintain the concentration of inorganic ions
fish. Urea is excreted across the gills as the pri- (perturbing solutes) at low levels. Although most
mary form of nitrogenous waste. cartilaginous fish are stenohaline, several species
Other fish species may adopt a ureotelic strat- can tolerate some degree of diluted seawater. When
egy, depending on external conditions. Lungfish a euryhaline shark moves from seawater to dilute
are normally ammonioteles, excreting ammonia seawater, it excretes urea as well as some ions.
into the surrounding water. However, when water More than 40 species of elasmobranchs can survive
levels decrease, the African lungfish (Protopterus) in freshwater. Species such as bull sharks may
burrows into the mud and forms a mucus cocoon. travel from the sea into freshwater lakes, such as
Since the animal cannot excrete ammonia, other Lake Nicaragua, surviving for years before return-
pathways must be used for nitrogen excretion. ing to the sea to breed. In freshwater, these sharks
Once exposed to the air, the lungfish rapidly in- lose some of their osmolytes—about 50% of urea
duces the expression of urea cycle enzymes and and 20% of Na⫹ and Cl⫺—yet maintain an osmolar-
glutamine synthase, and converts to ureotelism. ity well above that of other freshwater fish. The
525
Amazonian stingray remains in freshwater all its adequate water excretion can result in high
life, maintaining an osmolarity near that of teleost blood pressure and edema.
fish by excreting urea as it is produced. 3. Blood pressure. By controlling blood volume,
the kidney acts over the long term to regulate
blood pressure. It acts in concert with shorter-
2 CO N CEP T C HE C K term cardiovascular effectors, such as cardiac
7. What are the costs and benefits of using contractile properties and peripheral resistance
ammonia, urea and uric acid as nitrogenous of the vasculature. The volume of the extracel-
wastes? lular fluid is under the control of the kidney,
8. What substrates are required to produce a through hormones and nerves that integrate
molecule of urea? cardiovascular conditions with the output of the
central cardiovascular control center. Low
blood pressure (hypotension) compromises the
delivery of fuels to tissues with high energy de-
The Kidney mands, such as the brain and locomotor mus-
cle. High blood pressure (hypertension) can
Most animals maintain ion and water balance us- compromise the integrity of the microvascula-
ing some form of internal organ derived during the ture in vital tissues, putting the animal at risk
development of the embryonic digestive system. for a myocardial infarction, stroke, or em-
Multiple types of cells combine to produce a tube- bolism. Many antihypertensive agents are di-
like structure, or tubule, through which excretory uretics, enhancing the production of urine to
solutions pass from the animal to the external en- reduce blood volume.
vironment. Animals differ in the way the tubule
4. pH balance. The kidney augments the respira-
fluid is produced and how it is modified prior to
tory system in the control of the pH of body
excretion. In some animals, a few simple tubules
fluids. The kidney regulates the pH of the ex-
are sufficient to produce the excretory products.
tracellular fluid by retaining or excreting H⫹ or
More complex animals, such as vertebrates, com-
HCO3⫺. Many of the metabolic and transport
bine tubules to form the kidney, which has six
pathways of ammonia metabolism also in-
roles in homeostasis.
volve acid or base production. The production
1. Ion balance. Sodium levels are an important of urea leads to the consumption of bicarbon-
determinant of extracellular fluid osmolarity. ate, which also has consequences for whole
Animals exhibit fluid imbalances if blood body pH regulation.
[Na⫹] is too high (hypernatremia) or too low 5. Excretion. The kidney plays an important role in
(hyponatremia). Potassium balance is impor- the excretion of nitrogenous wastes as well as
tant because changes in [K⫹] can alter resting other water-soluble toxins. Excess water-soluble
membrane potential, which affects the function vitamins, for example, are excreted in the urine.
of excitable tissues such as muscles and neu-
6. Hormone production. The kidney has an im-
rons. If blood [K⫹] is too high (hyper-kalemia), portant role in the synthesis and release of
excitable tissues can undergo spontaneous de- hormones, such as renin, which controls
polarization, causing cardiac arrhythmias and blood pressure, and erythropoietin, which
muscle twitches. Low [K⫹], or hypokalemia, regulates red blood cell synthesis.
can cause muscle weakness. The kidney also
controls the loss of ions that have important We begin our discussion of the kidney by ex-
roles as micronutrients, including Ca2⫹, iron, ploring the structure and function of the mam-
and trace metals. malian kidney, focusing on its role in the
2. Osmotic balance. The kidneys determine the regulation of water and ion balance. Our under-
volume of urine produced, and thereby control standing of animal kidney function benefits from
water balance. Dehydration results from inad- the many studies that examine the role of the kid-
equate consumption of water, or consumption ney in human diseases, such as hypertension.
of chemicals known as diuretics, which in- Later in this section we examine the specific prop-
crease water loss in the urine. Conversely, in- erties of kidneys from other species.
526
Kidney Structure
and Function Renal cortex
Renal pyramid
The typical mammalian kidney (Fig- Renal medulla
ure 19) is crescent shaped with two
layers: an outer cortex and an inner Renal papilla
medulla. The medulla is composed Renal pelvis
of a number of parallel cone-shaped
segments called renal pyramids. Renal artery
The inner narrow region of each

Renal vein
pyramid is called the papilla. Once
the urine is formed, it passes into a Minor calyx
cavity called the minor calyx. Multi-
ple minor calyces drain into the
major calyx, which in turn empties
into the ureters that drain the kid- Major calyx Ureter
ney. The ureters empty into the

urinary bladder where urine is
Ureters
stored. Eventually, the urine is ex-
pelled from the bladder through a
single urethra, a process with the el-
egant name micturition. Kidneys
must process tremendous volumes
Urinary bladder
of blood. Even though kidneys make
up less than 1% of the entire body
mass, the blood flow through the
kidneys is much greater than that to
muscles during heavy exercise. In
humans, the kidney may process
Urethra
4 liters of blood per kilogram each
minute but exercising muscle re-
ceives only about 0.5 l/kg per minute. Figure 19 Mammalian kidney The kidney is composed of two layers, the
Numerous hormones and neuro- cortex and medulla. As urine is produced, it is collected by the minor calyces, which
transmitters ensure that urine com- join together to form the major calyx. The urine passes through the ureter into the
position and release are matched to urinary bladder for storage, eventually leaving the animal through the urethra.
the physiological needs of the animal.
These regulatory factors affect the four processes in- twisted ball of capillaries that delivers fluids to the
volved in urine formation: filtration, reabsorption, tubule. In a typical kidney, some nephrons exist
secretion, and excretion. within the cortex (cortical nephrons), and others
span both the cortex and medulla (juxtamedullary
nephrons) (Figure 20).
The nephron is the functional unit of the The tubule is composed of epithelial cells with
kidney characteristic transport properties that allow
Kidney function depends on the interplay between them to reclaim specific solutes and expel others.
the renal epithelium and the cardiovascular system. Bowman’s capsule is the mouth of the tubule, a
The functional unit of the kidney is the nephron. cuplike expansion that surrounds the glomerulus.
Each nephron is composed of two elements: the re- The fluids that leave the glomerulus enter Bow-
nal tubule and the associated vasculature. A renal man’s capsule and move down the lumen through
tubule is a tube constructed from a single layer of successive specialized regions of the tubule: prox-
epithelial cells, though the nature of the cells differs imal tubule, loop of Henle, and distal tubule. The
along the length of the structure. The main element fluids from multiple tubules then drain into a col-
of the nephron vasculature is the glomerulus, a lecting duct, several of which fuse together to form
527
beds that wrap around the tubules.

In juxtamedullary nephrons, the ef-
ferent arterioles diverge into the vasa
recta, long, straight vessels that run
Bowman’s capsule
along the loop of Henle. A small pro-
portion of the blood entering the kid-
Renal ney is directed deep into the medulla,
Bowman’s Proximal cortex
capsule tubule
without passing through a glomeru-
lus. Changes in the blood pressure in
Proximal these renal vessels alter the renal in-
tubule
Distal terstitial hydrostatic pressure, which
tubule Distal
tubule
is in dynamic equilibrium with the
hydrostatic pressure of the capillaries
surrounding the medullary capillar-
ies. The blood from these capillary
beds then drains into the venous sys-
tem, carrying away recovered solutes
Loop of
Collecting Henle and water from the interstitial fluid
duct
Renal that surrounds the tubule.1
medulla Nephron function depends on
the processing of a blood filtrate as it
passes through the renal tubule. The
primary urine produced by filtration
Collecting Loop of is transformed through reabsorption
duct Henle and secretion to become the final
urine, processes that depend upon
(a) Cortical nephron (b) Juxtamedullary nephron
cellular specializations.
Figure 20 Nephron structure Two types of nephrons are distinguished by
their location within the kidney. Though the glomerulus is in the cortex, tubules can
penetrate the medulla to different degrees. (a) Cortical nephrons are located
predominantly in the outer cortex. (b) Juxtamedullary nephrons are mainly in the Filtration occurs at the
inner medulla. glomerulus
The wall of a glomerular capillary is a complex bi-
papillary ducts, which in turn empty into the mi-
ological filter that retains the blood cells and large
nor calyx.
macromolecules but permits liquid components of
The vasculature of the nephron is central to
blood to escape into the lumen of the Bowman’s
nephron function, delivering the fluids that be-
capsule (Figure 22). The glomerular capillaries are
come the primary urine and governing the nature
fenestrated, with pores that allow low-molecular-
of the interstitial fluids that surround the tubule
weight molecules to escape the blood. A special-
(Figure 21). Blood enters the kidney from the re-
ized type of epithelial cell called a podocyte covers
nal artery, which branches into smaller vessels
the outer surface of the capillary. The podocytes
that give rise to the glomerulus. After the filtered
have foot processes, which are cytoplasmic
blood leaves the glomerulus, it passes into an ef-
extensions that help form the filtration structure.
ferent arteriole. This arrangement is unlike a
The podocyte attaches to the basement
conventional capillary bed where the venous sys-
membrane, a filamentous extracellular
tem is immediately downstream of the capillar-
matrix produced by the capillary cells. The gap
ies. The efferent arteriole generates enough
between the foot processes, about 14 nm
smooth muscle contraction to maintain a degree
wide, is a filtration slit. The fibrous basement
of vasoconstriction, causing a higher degree of
resistance than could a venule. The blood passes
1
The definition of a nephron differs among researchers. In con-
through the efferent arteriole into one of two
trast to the most restrictive definition—the glomerulus and
types of capillary beds. In cortical nephrons, the tubule—some researchers include the collecting duct and the
efferent arterioles flow into peritubular capillary vasa recta as part of a nephron.
528
final urine. The remodeling of the primary urine oc-

Efferent arteriole Glomerulus Afferent arteriole curs as it passes through successive regions of the
tubule, each with specialized transport capacities.
Recall that the tubule wall is composed of a single
layer of epithelial cells. Like most epithelial cells,
Peritubular
the apical membranes (facing the lumen) and baso-
capillaries lateral membranes (facing the interstitium) have
specialized profiles of transporters. Also, the cells of
the epithelium may be interconnected in ways that
Cortex form a tight epithelium or a leaky epithelium. Be-
fore discussing the roles of each region of the
Medulla tubule, let’s first consider the general features of tu-
bular transport.
Recovery of substances from the lumen of the
Vasa tubule requires a combination of favorable electro-
recta
chemical gradients and transport capacities. Some
substances in the primary urine are reclaimed by
transepithelial transport, moving from the lumen,
across the single layer of epithelial cells, into the
interstitial fluid (peritubular fluid) and ultimately
back into the blood. Some hydrophobic solutes
cross the tubular epithelium by passive transport;
Figure 21 Blood vessels of the nephron. Blood as water is removed from the primary urine, con-
delivered to the kidney by the renal artery passes through
smaller arteries and reaches an afferent arteriole that centration gradients are created that can drive
services one nephron. The arteriole diverges into the hydrophobic solutes back to the blood. Larger mol-
glomerulus, a network of capillaries within the Bowman’s ecules in the filtrate, such as small proteins, can be
capsule. After leaving the glomerulus, blood enters an recovered by transcytosis: endocytosis into the ep-
efferent arteriole. The efferent arterioles that drain cortical
nephrons empty into peritubular capillaries. The efferent
ithelial cell and exocytosis into the interstitial fluid.
arterioles that drain juxtaglomerular nephrons flow into the Most molecules, however, are reabsorbed through
vasa recta. a combination of facilitated diffusion and active
transport, both primary and secondary.
membrane spans the filtration slits to act as the bi- Consider how cells reabsorb glucose against its
ological filter of the glomerulus, excluding blood concentration gradient, driven by a larger, more fa-
cells and large proteins, and passing water, ions, vorable Na⫹ electrochemical gradient (Figure 23).
and low-molecular-weight molecules. The concentrations of Na⫹ and glucose in the pri-
The mesangial cells, similar to smooth mus- mary urine are not different from that of the blood,
cle cells, wrap around the capillaries of the so the challenge is how to recover these solutes in
glomerulus. Contraction of the mesangial cells re- the absence of favorable concentration gradients.
stricts blood flow to specific vessels within the cap- The major driving force underlying the transport is
illary network, regulating blood pressure within the Na⫹/K⫹ ATPase found in the basolateral mem-
the glomerulus to control filtration. brane. By pumping Na⫹ out of the cell into the in-
terstitial fluid, the nephron cells create a favorable
inward Na⫹ electrochemical gradient on the apical
The primary urine is modified by side that can be used to drive both Na⫹ uptake and
reabsorption and secretion Na⫹-coupled glucose uptake. Na⫹ can cross into the
As fluid passes into the lumen of the tubule, a fil- tubule cells by a Na⫹ channel, Na⫹/H⫹ exchanger,
trate is formed. The filtrate, or primary urine, is es- or by suites of other carriers that couple the import
sentially isosmotic to blood (about 300 mOsM). As of organic molecules and Na⫹. One such trans-
the fluid passes through the tubule, about 99% of porter is the Na⫹-glucose cotransporter, which
the volume is recovered. For example, an average- allows the cell to import glucose from the
sized human produces about 7.5 liters of primary lumen. Concentrating glucose inside the cell
urine each hour, but generates only about 75 ml of creates a favorable outward chemical gradient
529
Bowman’s
capsule
Blood flow
Proximal
Efferent tubule
arteriole
Endothelial Foot process

cell of podocyte
Afferent Basement
arteriole membrane
Endothelial
Blood flow cell of capillary
(a) Glomerulus
Podocyte Blood
vessel
Capillaries lumen
Foot
processes
Mesangial cell Podocyte

(b) Glomerular capillaries (c) Glomerular capillaries (d) Glomerular filter
(cross-section)
Figure 22 Glomerulus (a) The glomerulus is a external surface by podocytes. (c) The podocytes issue
network of capillaries that empty much of the fluid from the several foot processes that form filtration slits. (d) The
blood into the Bowman’s capsule of the nephron. (b) Mesangial podocytes interact with the basement membrane to create
cells between the capillaries help control blood flow through a filter that retains blood cells and large proteins in the
the glomerulus. The individual capillaries are composed of plasma while permitting the passage of fluids through
loosely connected endothelial cells and are covered on the filtration slits.
Apical Proximal tubule Basolateral Capillary

membrane epithelial cell membrane endothelial cell for glucose; glucose permease allows
glucose to cross into the peritubular
Tubular interstitial fluid via facilitated diffu-
fluid sion. Each of these transport
Glucose processes requires energy, either in
Na+ Na+
the form of ATP used by the primary
Glucose
Na+
active transporters (for example,
Na+ K+ Na⫹/K⫹ ATPase), or in the form of elec-
H+ trochemical gradients used by second-
Cl– ary active transporters (for example,
the Na⫹-glucose cotransporter).
Peritubular space
The ability to reabsorb solutes
such as glucose is limited by trans-
Figure 23 Reabsorption of glucose and Na⫹ Suites of specific port capacity. Like many active
transporters remove solutes from the lumen in the process of reabsorption. Glucose, transporters, the kinetics of the
and other organic molecules, may be reabsorbed using a Na⫹-linked cotransporter. transport machinery can become
Once in the cytoplasm, the glucose can be exported across the basolateral membrane
saturated at high substrate levels
by a facilitated diffusion using glucose permease. Na⫹ can also be reabsorbed by
other transporters, such as the Na⫹/H⫹ exchangers shown here. Na⫹ is exported from (Figure 24). This capacity for solute
the cytoplasm to the peritubular fluid by Na⫹/K⫹ ATPase. recovery is known as the
530
into the tubule lumen. The most important secretory

products are K⫹, NH4⫹, and H⫹. Many water-soluble
waste products are also secreted into the tubule, in-
Filtrate
cluding pharmaceuticals and water-soluble vitamins.
Glucose flux (mmol/min)
Like other active transport processes, secretion de-

pends on transport proteins and requires energy.
Reabsorption The various regions of the tubule mediate
different transport processes, as summarized in
Figure 25.
Urine
Renal Cellular properties differ among regions

threshold
of the tubule
The transformation of the primary urine to the fi-
Plasma [glucose] (mmol) nal urine involves a series of specialized regions of
Figure 24 Renal threshold Reabsorption depends the tubule that depend upon cellular specializa-
on the activity of specific transporters that have a finite tions. Though the tubule wall is a single layer of
maximal capacity. Solutes move from the plasma to the epithelial cells connected together by tight junc-
tubule fluid when the blood passes through the glomerulus. If
a solute is present at a low concentration in the plasma (and
tions, cell morphology and function differ consid-
hence the tubule fluid), all of the solute can be recovered erably among regions of the tubule.
during reabsorption. As the concentration of solute increases The proximal tubule can be a simple, straight
in the plasma, it becomes more difficult to recover all of the tube or take a path with many convolutions; for this
solute from the tubule fluid. When the plasma concentration
reason it is sometimes called the proximal convo-
is so high that the tubule cannot reabsorb all of the solute,
some appears in the urine. At still higher concentrations, the luted tubule. The cells of the proximal tubule are
solute concentration in the urine increases dramatically. tall cuboidal epithelial cells, with abundant mito-
chondria and microvilli. As with other epithelial tis-
renal threshold. If the amount of substance to be sues, these features are common in cells that carry
recovered is in excess of the capacity of the trans- out energy-dependent solute transport processes.
port machinery, some of the substance will escape The proximal tubule then gives way to the loop
in the urine. In type 1 diabetes, the levels of glucose of Henle. There is considerable variation in the na-
can be very high in the blood. When the blood is fil- ture of the loop of Henle among species, and even
tered by the glomerulus, the primary urine also has among nephrons of a single animal. In general,
a very high glucose con-
centration. Despite the ac- Proximal tubule Tubular fluid Distal tubule Collecting
tive glucose transporters, duct
the kidney cannot reab-
sorb all of the glucose, and
+
some is lost in the urine Na+ H+ H+ Ca2 Na+
Cl– NH4 + K+ Na + K+
(glucosuria). K+ Toxins Cl– Cl–
The other way the Ca2
+
Drugs H2O Ca2
+
HCO3 – HCO3–
primary urine is modified
H2O H 2O Na + H+
is through secretion. Se- Glucose Urea
Cl–
cretion is similar to reab- Amino acids H2O
K+
sorption in that it uses Vitamins Mg2
+
Urea Ca2
+
transporters found in the K+
Choline NH +
cells that line the lumen. 4 H+
NH4+
However, the process Descending Ascending
limb limb
works in the opposite
direction, transferring Loop of Henle
solutes from the blood,
through the peritubular Figure 25 Solute and water transport in each region of the nephron Each
fluid, and across the cells region of the nephron has specific transporters that can reabsorb or secrete molecules.
531
the loop of Henle is divided into a descending limb, The differences in cell type and morphology
a loop, and an ascending limb. The first part of the along the tubule and collecting duct are summa-
descending limb of the loop of Henle is composed rized in Figure 26.
of cuboidal epithelial cells, much like the proximal
tubule. These are gradually replaced with the flat-
ter squamous epithelial cells. The difference in
The proximal tubule reabsorbs salts and
the height of the cuboidal and squamous cells cre-
organic metabolites
ates a difference in width of the wall, and these The proximal tubule is specialized for transport,
regions of the tubule are often distinguished as and it is the region where most solute and water
thick descending limb and thin descending limb. reabsorption occurs (Figure 27). Many solutes are
Further along the tubule, the ascending limb of transported from the lumen into proximal tubule
the loop of Henle becomes thicker as cuboidal ep- epithelial cells via Na⫹ cotransporters including
ithelial cells predominate. As with the descending organic molecules (glucose, lactate, amino acids,
limb, the ascending limb may be subdivided as water-soluble vitamins) and inorganic ions (phos-
thin ascending limb and thick ascending limb. phate). These processes are also important in con-
These distinctions are made because the differ- tributing to reabsorption of Na⫹. The organic
ences in cell shape coincide with distinctions in molecules can escape the cell into the interstitial
transport properties. fluid via facilitated diffusion, whereas Na⫹ is
Following the loop of Henle is the distal tubule, pumped across the basolateral membrane via the
which can be simple and straight or long and con- Na⫹/K⫹ ATPase. The transepithelial electrochemi-
voluted. In contrast to the proximal tubule, most of cal gradient also drives the paracellular transport
the epithelial cells of the distal tubule have simple of Cl⫺ from the lumen to the interstitial fluid. As a
membranes with few microvilli. This type of cell, result of the net movement of ions and solutes
known as a principal cell, also dominates the cell from the lumen to the peritubular interstitial fluid,
profile of the collecting duct. The less common in- a decrease in osmolarity creates a favorable os-
tercalated cells are cuboidal epithelial cells with motic gradient for the movement of water.
abundant microvilli. Not surprisingly, the functions Transepithelial water movement occurs mainly
of principal cells and intercalated cells differ as through transcellular transport, mediated by
much as their structures. aquaporins, although some paracellular move-
Principal Intercalated
cell cell
Basolamina
Nucleus
Microvilli
Lumen
Collecting duct
Lumen
Lumen Lumen
Proximal tubule Descending limb Ascending limb
Figure 26 Cell type and morphology in the tubule and collecting duct The
wall of the tubule is composed of a single layer of epithelial cells that differ in morphology.
532
Lumen Peritubular
countered by the primary urine is the descending
X fluid limb of the loop of Henle. This region of the tubule
X is specialized to transport water, but it is not a ma-
Na+
Na+ jor site of transport for solutes. As with the proxi-
K+ mal tubule, aquaporins allow water to move
H2O H2O H 2O across epithelial cells in relation to the osmotic dif-
OC ference from the lumen to the interstitial fluid.
OA OA
OC
Critical to the water recovery strategy is an os-
Drugs motic gradient that exists within the medulla (Fig-
Drugs
ure 28). At the transition between the proximal
Cl–
tubule and descending loop of Henle, the osmolar-
ity of the interstitial fluid is similar to that of the
Figure 27 Transport in proximal tubule cells
OA: organic anion. OC: organic cation. blood—about 300 mOsM. As the descending loop
of Henle goes deeper into the medulla, the osmo-
larity of the interstitial fluid increases, drawing
ment of water may also occur. Transgenic mice water from the primary urine across the epithelial
lacking the gene for aquaporin-1 have a dimin- cells. With loss of water, but not solutes, the osmo-
ished ability to recover tubular fluids and create larity of the primary urine increases, reaching a
hyposmotic urine. maximum at the loop region of the loop of Henle.
Through these interdependent transport Once the tubule turns and moves back toward
processes, the proximal tubule is able to reabsorb the cortex, the epithelial cell transport capacity
almost all organic solutes, most of the phosphate, changes. Instead of expressing aquaporin genes,
and 60–75% of the Na⫹, Cl⫺, and water that appear these epithelial cells express solute transporters.
in the primary urine.
The proximal tubule is also the
site of secretion of organic anions, or-
ganic cations, and water-soluble tox-
ins, including pharmaceutical agents.
These molecules are imported into
the proximal tubule cells through
Proximal tubule Distal tubule
suites of transporters in the basolat-
eral membrane, then exported into Tubular fluid
Cortex
the lumen through apical trans-
porters: organic cation transporters 300
(OCT), ATP-dependent multidrug re- 300 Collecting
sistance transporters (MDR and 400 duct
MRP), and organic anion transport- 500

ing polypeptide transporters (OATP).
600
Osmotic gradient
700
The loop of Henle mediates 800
sequential uptake of water, Medulla
900 Descending Ascending
then salt limb limb
1000
When the primary urine has passed 1100
through the proximal tubule, the
1200
volume has diminished and most of
1300
the valuable solutes have been
recovered. The remainder of the 1400
tubule is responsible for recovering Loop of Henle
the balance of the solutes and water,
Figure 28 Osmotic gradients in the interstitial fluid of the medulla
dependent on the physiological state The loop of Henle passes through osmotic gradients in the medulla. The osmolarity is
of the animal. The next region en- lowest near the border of the cortex, and increases deeper into the kidney.
533
As the tubule passes through the medulla, the in- of uptake of solutes and water. Hormones pro-
terstitial osmolarity decreases. Since the epithelial duced by the adrenal gland (mineralocorticoids),
cells can only transport solutes, the transepithelial hypothalamic-pituitary axis (vasopressin), and
gradients drive movements of solutes from the pri- parathyroid (parathyroid hormone) act on distal
mary urine to the interstitial fluid. As a result of tubule epithelial cells to alter levels and activities
various transporters in the apical and basolateral of transport proteins.
membranes, there is a net movement of Na⫹ and Though the proximal tubule reabsorbs most of
Cl⫺ from the primary urine to the interstitial fluid. the Na⫹ and Cl⫺ appearing in the primary urine,
On the apical membrane, the NKCC transporter the distal tubule reabsorbs most of the remaining
mediates uptake of Na⫹, K⫹, and Cl⫺ into the cell. Na⫹ and Cl⫺. An apical Na⫹-Cl⫺ cotransporter car-
The basolateral membrane transports Na⫹ and Cl⫺ ries the ions into the cell; Na⫹ is then exported
into the interstitial fluid: Na⫹ via the Na⫹/K⫹ from the distal tubule epithelial cells via the
ATPase, and Cl⫺ via Cl⫺ channels and a K⫹-Cl⫺ co- Na⫹/K⫹ ATPase, and Cl⫺ escapes through Cl⫺
transporter. An apical K⫹ channel allows K⫹ im- channels.
ported via NKCC to escape back to the lumen. As with the Na⫹ and Cl⫺, the proximal tubule
The transport processes in the ascending is the main site of reabsorption of Ca2⫹ and Mg2⫹,
limb and descending limb are summarized in but the distal tubule is the segment where hor-
Figure 29. mones exert their effects on absorption of the re-
mainder. Ca2⫹ enters the distal tubule epithelial
cells through Ca2⫹ channels, and exits into the in-
The distal tubule mediates K⫹ secretion, terstitial fluid via a Na⫹/Ca2⫹ exchanger and, to a
NaCl reabsorption, and hormone-sensitive lesser extent, a Ca2⫹ ATPase.
water recovery The distal tubule is an important site for recov-
After fluids leave the loop of Henle, they enter ery of water, under conditions where water recov-
the distal tubule. This region of the tubule is an ery is required. Under normal circumstances, the
important site for hormone-mediated regulation distal tubule cells have low expression of aqua-
porin genes. When an animal is dehydrated, hor-
mones such as vasopressin lead to increased
Lumen Peritubular
fluid expression of aquaporin genes, allowing water re-
covery from the tubule lumen.
The distal tubule is also the main site of secre-
H 2O H 2O H2O tion of K⫹ into the tubule. As the primary urine
moves through the proximal tubule and loop of
Henle, about 90% of K⫹ is reabsorbed. In the dis-
tal tubule, the epithelial cells are able to secrete
K⫹. It is brought into the epithelial cell from the in-
terstitial fluid via Na⫹/K⫹ ATPase, and moves into
(a) Thin descending limb
the lumen through either a K⫹-Cl⫺ cotransporter
or K⫹ channel.
Lumen Peritubular The transport processes in the distal tubule
fluid
are summarized in Figure 30.
Na+
Na+
K+ K+ The collecting duct regulates ion
2CI–
CI– and water flux
K+
K+ The collecting ducts traverse the layers of the kid-
CI– ney, connecting the distal tubules of cortical and
juxtamedullary nephrons. As they move deeper
into the kidney, the profile of cells changes, en-
abling specialized transport functions in different
(b) Thick ascending limb
segments. The principal cells secrete K⫹ and reab-
Figure 29 Transport in the loop of Henle sorb Na⫹, similar to those found in the distal
534
Lumen Peritubular
and collecting ducts. Some segments also possess
fluid proton pumps, such as the H⫹ ATPase and H⫹/K⫹
K+ Na+ ATPase of the distal tubule and collecting duct.
Na+ K+ Overall, proton excretion by the collecting duct
CI– CI– plays the greatest role in regulation of acid extru-
Ca2+ Na+ sion by the tubule.
Ca2
+
Movements of bicarbonate (HCO3⫺) also affect
Ca2
+
acid-base balance. Many regions have Cl⫺/HCO3⫺
H2O H2O H2O exchangers that allow cells to recover Cl⫺, while
alkalinizing the primary urine. The proximal
tubule and ascending limb of the loop of Henle are
the main sites of HCO3⫺ reabsorption. The tubule
epithelial cells that secrete protons derive those
Figure 30 Transport in the distal tubule
protons through the actions of carbonic anhydrase
(CO2 → HCO3⫺ ⫹ H⫹). Protons are exported across
tubule. The intercalated cells are able to secrete the apical membrane into the lumen, whereas
H⫹ or HCO3⫺, depending on the acid-base status of HCO3⫺ can be exported into the blood via a baso-
the animal. H⫹ secretion is coupled to K⫹ import lateral Cl⫺/HCO3⫺ exchanger. The net effect is acid-
through a H⫹/K⫹ ATPase. ification of the urine and alkalinization of the
As with the distal tubule, the collecting ducts are interstitial fluid.
important targets of regulatory changes in ion and Ammonia production, reabsorption, and se-
water movements, including hormone-responsive cretion affect pH balance. The proximal tubule is
pathways. Thus, the collecting ducts can be impor- an important site of ammonia production, largely
tant sites of K⫹ secretion or reabsorption, depend- from glutamine. Metabolism of glutamine occurs
ing on the nature of the primary urine and systemic via glutaminase (producing glutamate), glutamate
K⫹ homeostasis. When K⫹ excretion is needed, se- dehydrogenase (producing 2-oxoglutarate), and
cretion by principal cells is stimulated, but when K⫹ TCA cycle enzymes (producing oxaloacetate).
recovery is needed, reabsorptive pathways in inter- Whether the resulting oxaloacetate is completely
calated cells are stimulated. oxidized in the TCA cycle or used as a gluco-
neogenic substrate, each glutamine generates two
HCO3⫺ and two NH4⫹. These reactions have an in-
Nephrons also contribute to acid-base fluence on acid-base balance because the NH4⫹ (an
balance acid) is excreted and HCO3⫺ can titrate H⫹. Ammo-
In the previous discussion, we focused on the role nia produced by the proximal tubule is secreted
of the nephron in ion and water balance, but the into the lumen, reabsorbed in the ascending limb
kidney also has an important role in regulation of of the loop of Henle, and secreted in the collecting
acid-base balance. Transport processes in each duct using a combination of transporters.
segment of the tubule contribute to changes in pH Acid-base balance, as with other renal respon-
of the primary urine as a way of controlling whole sibilities, is regulated directly by prevailing condi-
body acid-base balance. Conversely, changes in tions in the tubule lumen and interstitial fluid, as
pH of the primary urine affect the ability of cells to well as by hormones that respond to systemic
use pH-dependent transporters to recover or se- changes and mediate compensatory responses.
crete ions. The main way that the nephron regu-
lates pH of the urine is through transport and
metabolism of H⫹, HCO3⫺, and ammonia. For ex-
The loop of Henle creates a countercurrent
ample, metabolic acidosis leads to secretion of H⫹
multiplier
and NH4⫹, and reabsorption of HCO3⫺. As we discussed the transport processes in the var-
Many transporters affect pH by expelling pro- ious segments of the tubule, we alluded to the exis-
tons into the lumen. For example, apical Na⫹/H⫹ tence of an osmotic gradient through the medulla:
exchangers recover Na⫹ and extrude H⫹, acidify- low osmolarity near the cortex and high osmolarity
ing the urine. These exchangers occur in the prox- deep into the medulla (see Figure 28). This osmotic
imal tubule, ascending loop of Henle, distal tubule, gradient is produced and maintained by the
535
concerted actions and arrangement of the loop of water between the tubule and the interstitial fluid,
Henle, the collecting duct, and the vasa recta. but it is maintained because the vasa recta (see
Let’s first consider how the descending and as- Figure 21) works as a countercurrent exchanger.2
cending flows through the loop of Henle create a In most tissues, capillaries drain the interstitium,
countercurrent multiplier that, in combination collecting solutes and water and emptying them
with differences in tubule permeability, allows the into the blood. The vasculature in the medulla is
urine to be remodeled in terms of both solute con- arranged in a way that it can meet the circulatory
centration and volume. As fluid moves through the needs (O2 delivery, CO2 removal) without disrupt-
descending limb, the surrounding interstitial fluid ing the osmotic gradient. Consider what would
has a slightly higher osmolarity. Since only water happen if the blood vessels flowed unidirectionally
can cross the descending limb, the osmotic gradi- from the cortex through the medulla and out of the
ent drives movement of water from the lumen to kidney; the blood would draw fluids and solutes
the interstitial fluid. This movement of water out of the kidney, rapidly dissipating the gradient
would tend to decrease osmolarity within the re- created within the medulla. Instead, the vessels of
gion, destroying the driving force for water recov- the vasa recta carry blood into the medulla, then
ery. To counteract this dilution, the region of the back out of the medulla. As blood leaves the effer-
ascending limb that is adjacent to the descending ent arteriole and enters the vasa recta, it is carried
limb actively pumps solutes from the lumen to the into the medulla where the higher osmolarity
interstitial fluid, increasing the osmolarity of the causes it to passively pick up solutes and lose wa-
interstitial fluid. In fact, the ascending limb pumps ter. As the vessels head back toward the cortex, the
more salt than is needed to negate the osmotic decreasing osmolarity causes the blood to lose
movements of water from the descending limb. solutes and gain water. The blood vessels exit the
This single effect —excessive salt pumping by the kidney at the junction between cortex and medulla,
ascending limb—is enhanced by the countercur- where interstitial fluid is isosmotic to blood. Thus,
rent arrangement of the loop of Henle. This mis- the countercurrent arrangement of the vasa recta
match between water and salt movements in ensures that the osmotic gradient within the
adjacent regions of the loop of Henle creates the medulla is maintained.
osmotic gradient within the medulla.
Another factor that contributes to the forma-
tion of the osmotic gradient within the medulla is
Micturition is regulated by reflex
and higher pathways
the permeability of the collecting duct to urea.
Urea enters the tubule through the glomerulus, but Excretion is the end product of the renal process-
travels through the tubule with little reabsorption ing of the primary urine. For any specific sub-
because of the low urea permeability of the tubule. stance, the amount excreted is equal to the amount
With much of the water removed from the original in the primary filtrate plus the amount secreted
filtrate, the urea concentrations increase dramati- minus the amount reabsorbed. After the urine
cally. The concentrated urea solution leaves the leaves the kidney, it enters the urinary bladder for
tubule and enters the collecting ducts. The cortical storage. The bladder is a hollow sac, with a capac-
regions of the collecting duct have low permeability of approximately 500 ml in humans. From the
ity to urea, but as the collecting duct moves deeper bladder, the urine exits through the urethra.
into the medulla, the permeability to urea in- Sphincters of smooth muscle control the flow of
creases due to the presence of specific urea trans- urine from the bladder to the urethra. The opening
porters. Movement of urea into the interstitium and closing of the sphincter is governed by a spinal
increases the local osmolarity, further contributing cord reflex arc, and can be influenced by voluntary
to the osmotic gradient within the medulla. and involuntary controls. The bladder wall con-
tains stretch receptors that are activated once the
bladder wall has been stretched. This triggers a
The vasa recta maintains the medullary
osmotic gradient via a countercurrent 2
Most commonly, countercurrent exchangers and countercur-
exchanger rent multipliers are distinguished by the need for direct energy
investment. That is, exchangers passively transfer molecules
The osmotic gradient may arise along the depth of (or heat) whereas multipliers require some form of active
the medulla through the movement of salts and transport.
536
signal via sensory neurons to the spinal cord, Three main forces determine net glomerular
which in turn stimulates parasympathetic neurons filtration pressure: glomerular capillary hydro-
to trigger the contraction of smooth muscle in the static pressure, Bowman’s capsule hydrostatic
walls of the bladder. This increases pressure on pressure, and the net oncotic pressure (Figure 31).
bladder contents. Simultaneously, there is an inhi- Let’s begin the discussion of these forces by con-
bition of the somatic motor neurons that induce sidering an analogy about the nature of the hydro-
the sphincters to close. When the balance of stim- static pressure in the capillaries of the glomerulus.
ulatory and inhibitory controls exceeds a thresh- Imagine a garden hose connected to a standard
old, the sphincter opens and urine is released. tap. Midway through the hose, a section of rubber
has been perforated with thousands of small holes
that act as a filter, allowing water to leak out of the
2 CO NC E P T C HE C K hose. In this analogy, the tap is the heart, the first
9. What is the role of the glomerulus in the section of hose is the renal artery that supplies the
nephron? kidney, the perforated region is the glomerulus,
10. Discuss movements of NaCl and water in the and the last section of hose is the efferent artery.
segments of the renal tubule. Now consider what happens to the rate of flow
through the leaky region of the hose (the GFR)
when we alter the system. When the tap is par-
tially closed (cardiac output is lower), there will be
Regulation of Renal Function a decrease in the volume of water leaking from the
Endocrine hormones have a central role in regu- system. Similarly, if you constrict the hose up-
lating osmotic and ion balance in mammals, act- stream of the leaky region (systemic blood pres-
ing on both the cardiovascular system and the sure is lower), there will be a decrease in
nephron itself to alter the nature of the urine. The hydrostatic pressure downstream of the constric-
steroid hormones that affect ion and water bal- tion and less water will leak through the filter.
ance (mineralocorticoids) act over hours to alter Conversely, if you constrict the hose downstream
transporter levels in the tubule. The peptide hor- of the leaky region (vasoconstriction), the increase
mones released from the hypothalamic-pituitary in hydrostatic pressure upstream will force more
axis act much more rapidly. Superimposed on the water through the filter. The process of filtration
natural, hormonal controls are dietary factors that therefore depends on the cardiac output, the sys-
affect urine properties; diuretics stimulate the ex- temic blood pressure, and the vasoconstriction of
cretion of water, and antidiuretics reduce the ex- the efferent arteries. About 20% of the liquid in the
cretion of water. Often, these dietary factors afferent arteries is forced through the filter at the
induce maladaptive changes—dehydration or wa- glomerulus because the efferent artery is normally
ter retention—that must be overcome by intrinsic quite vasoconstricted.
negative feedback pathways. In the previous analogy, the water leaked out
of the perforated region of the hose into the air
and there was no pressure to oppose the free
Glomerular filtration pressure is affected movement of the water out of the holes in the hose.
by hydrostatic pressure and oncotic In the tubule, the glomerular filtrate doesn’t empty
pressure into air, but into the interstitial fluid that bathes
Regulation of kidney function begins with the fil- the tubule. This interstitial fluid has its own hydro-
tration process at the glomerulus, which is af- static pressure. In a typical mammalian kidney,
fected by both the surface area available for the hydrostatic pressure within the glomerular in-
filtration and the pressure gradients across the fil- terstitial fluid is about 15 mm Hg. Since the
ter. The glomerular filtration rate (GFR) is the glomerular capillary hydrostatic pressure is about
amount of filtrate produced per minute (see Box 3, 60 mm Hg, there is a hydrostatic pressure gradi-
Methods and Model Systems: Measuring Glomeru- ent of about 45 mm Hg that drives fluid through
lar Filtration Rate). The GFR is controlled prima- the filter.
rily by factors that affect the net glomerular Proteins that are retained on one side of a
filtration pressure—the balance of forces acting on semipermeable barrier impart osmotic effects.
the fluids on either side of the filter. The osmotic pressure that arises because of the
537
Measuring Glomerular Filtration Rate
The porosity of the glomerular biological in the urine and in the plasma (U/P). In the laboratory, it
filter ensures that virtually all of the bloodborne, is convenient to use inulin, but the same approach can
low-molecular-weight molecules (<5000 MW) that enter be applied clinically to assess kidney function. GFR is an
the glomerulus will pass as filtrate into the lumen of the empirical parameter that holds for all low-molecular-
tubule. Many of these molecules are reabsorbed from weight molecules; it is a property of the kidney under
the lumen, and many others are secreted into the lumen specific conditions of blood volume and pressure. The
by tubule cells. Central to the understanding of kidney GFR measured in this manner can be used to explore
function is an estimate of the volume of fluid that enters how the kidney handles other types of molecules.
into the glomerulus per unit time—the glomerular fil- Renal clearance is a parameter that reflects the
tration rate, or GFR. amount of a solute passing from the plasma to the urine
Let’s begin our discussion of GFR calculations by in a given period. For a molecule like inulin, renal clear-
considering the fate of a molecule that is neither ab- ance and glomerular filtration rate are equivalent. How-
sorbed nor secreted. One such molecule is inulin, a low- ever, for situations where reabsorption and secretion
molecular-weight carbohydrate that is not normally play a role, renal clearance may be greater than or less
found in the blood. If a physiologist injects inulin into the than GFR. Disparities between renal clearance (C) and
blood, it will quickly distribute evenly throughout the en- GFR offer insight into kidney function. Consider the fol-
tire pool of blood. When the blood passes through the lowing examples, based on a kidney where an inulin ex-
glomerulus of the kidney, the inulin will pass through periment suggested that GFR equaled 120 ml of plasma
the filter with other plasma constituents and enter the filtered per minute.
lumen. In the luminal fluids, the inulin concentration If a solute is present in the plasma (P) at 0.1 μmol/ml,
will initially be equal to that of the blood. Since it is nei- in the urine (U) at 12 μmol/ml, and a filtrate volume (V)
ther reabsorbed nor secreted, the amount of inulin in of 1 ml is produced per minute, then
the urine over a given experimental period of time
C ⫽ VU/P ⫽ 120 ml/min
equals the amount of inulin that was filtered over that
same period of time. The inulin concentration in the In this case, the renal clearance is equal to the GFR,
urine will change as water flows in or leaves the tubule; suggesting that the solute behaves like inulin, with
it’s the total number of inulin molecules arriving in the highly efficient filtration and little reabsorption or se-
primary urine in a given time that is important to the cretion. This is the sort of result you would expect with
GFR calculation. The amount of inulin in the urine (ex- creatinine, which appears in the blood as a breakdown
pressed per unit of time) is calculated as the volume of product of muscle creatine. In fact, clinicians use crea-
urine per minute (V, ml/min) times the inulin concentra- tinine clearance much like a researcher uses inulin
tion in the urine (U, mol/ml). experimentally—as an estimate of a patient’s GFR. The
clinician would ask the patient to collect urine for
Amount of inulin in the urine per min ⫽ V × U
24 hours, then measure the average levels of creatinine
The other aspect of the inulin balance sheet is the in the urine and in the plasma over this period.
amount of inulin removed from the plasma. This depends If the experiment were repeated with another solute,
on the inulin concentration in the plasma (P, mol/ml) and and the clearance calculation resulted in an estimate of
the glomerular filtration rate (GFR, ml/min) 10 ml/min, this would suggest that the clearance of this
solute was only 10% that of GFR. This would suggest one
Amount of inulin removed from the blood ⫽ GFR × P
of two scenarios. First, it is possible that the solute never
Without reabsorption, all of the inulin filtered by the made it into the glomerular filtrate; perhaps it was too
glomerulus remains in the tubule, and without secre- big (a protein, for instance), or possibly it was bound to a
tion to augment the inulin in the lumen, the amount of protein (a steroid hormone, for example). A second pos-
inulin in the urine (VU) equals the amount of inulin re- sibility was that the solute was reabsorbed from the
moved from the blood (GFR × P): tubule, depleting the concentration in the urine.
If another experiment were performed focusing on
VU ⫽ GFR × P
another solute, and the clearance calculation resulted
Rearranging the equation to solve for GFR, we find that in an estimate of 240 ml/min, then we would note that
more of the solute appeared in the urine than could be
GFR ⫽ VU/P
accounted for simply by nonselective filtration. Thus,
GFR can therefore be measured as the product of the the excretion of this solute must have been augmented
volume of urine and ratio of the concentrations of inulin by secretion from the tubule cells.
538
Efferent Bowman’s capsule that integrate structural and chemical signals.

arteriole There are three intrinsic pathways that maintain
Glomerulus
GFR despite changing blood pressure: myogenic
regulation, tubuloglomerular feedback, and mesan-
gial control.
The smooth muscle cells of the vasculature
both interpret and respond to changes in blood
pressure to maintain GFR—a type of autocrine
regulation. An increase in systemic arterial blood
pressure would tend to increase GFR if not for a
Afferent
arteriole negative feedback loop that reduces blood pres-
sure within the glomerulus to prevent a maladap-
tive increase in GFR. An increase in blood pressure
increases the volume of blood in the small afferent
Blood flow Lumen blood vessels, which stretches the smooth muscle
Oncotic cells in the vascular wall. The deformation of the
pressure
Proteins gradient
cytoskeleton and plasma membrane activates
(30 mm Hg stretch-sensitive ion channels, which results in de-
oncotic pressure)
polarization of the plasma membrane of smooth
Hydrostatic muscle cells. This depolarization stimulates the
60 mm Hg pressure 15 mm Hg contractile apparatus, increasing tension and
(blood gradient (lumen hydrostatic causing vasoconstriction. The resultant decrease
pressure) pressure)
in blood flow in the afferent vessels reduces hydro-
static pressure, returning GFR to baseline levels.
Glomerulus Interstitium Bowman’s capsule
The same system responds in reverse when arte-
Figure 31 Glomerular filtration pressures The rial blood pressure decreases. Smooth muscle re-
overall pressure for fluid movements is the difference between laxes, vasodilation results, and the increase in
inward and outward pressures. The hydrostatic pressure
gradient, the difference between the mean blood pressure and
blood flow increases the hydrostatic pressure and
the hydrostatic pressure of the lumen, favors movement into returns GFR to baseline.
the lumen. The oncotic pressure gradient, due to the proteins Tubuloglomerular feedback regulates GFR by
that remain in the plasma, opposes movement into the lumen. altering arteriole resistance. Changes in the flow
of fluids through the tubule exert negative feed-
back on the arteriole. In tubuloglomerular feed-
protein concentration gradient is known as the back, the cells in a region of the distal tubule,
oncotic pressure. Since the filter at the glomeru- called the macula densa, contact specialized jux-
lus allows the movement of fluid and small solutes, taglomerular cells in the walls of the afferent arte-
but prevents the movement of protein, there is a rioles (Figure 32). When flow through the distal
residual osmotic pressure gradient due to the pro- tubule increases, the tubule cells signal the affer-
teins that remain in the blood. Because the pro- ent arteriole, causing vasoconstriction, a decrease
tein concentration is higher in the capillaries in hydrostatic pressure, and a decrease in GFR. It
than in Bowman’s capsule, fluids tend to move is not yet clear which factors facilitate this
back into the capillary. This oncotic pressure is paracrine communication.
about 30 mm Hg in opposition of filtration. In a Myogenic control and tubuloglomerular feed-
typical mammalian kidney, the net glomerular fil- back are two important means of intrinsic control
tration pressure is about 15 mm Hg (60 mm Hg ⫺ of blood pressure that affect GFR by altering the
15 mm Hg ⫺ 30 mm Hg). vasculature (Figure 33). Another intrinsic
mechanism also acts on GFR, but does so by chang-
ing the filtration apparatus of the mesangial cells.
Intrinsic and extrinsic regulators When the blood vessels swell in response to an in-
control GFR crease in arterial blood pressure, the mesangial
The kidney maintains function over a range of cells of the blood vessel also stretch. Since these
blood pressures using multiple pathways of control cells control the dimensions of the filter itself, their
539
Bowman’s capsule Juxtaglomerular Glomerular capillary

apparatus
Efferent arteriole
Lumen of
Proximal Bowman’s
Distal tubule tubule capsule
Afferent arteriole Efferent

arteriole
Distal tubule
Macula
densa
Direction of
blood flow
Loop of
Henle
Afferent
arteriole
Juxtaglomerular cells
Figure 32 Macula densa and the juxtaglomerular apparatus
stretching increases the permeability of the filter, contributes to an increase in peripheral resis-
thereby increasing the GFR by a mechanism that is tance, increasing mean arterial pressure.3
independent of vascular effects. A fourth mecha- In addition to the sympathetic neuronal con-
nism by which the kidney uses intrinsic controls to trol, several endocrine hormones contribute to
alter blood pressure is pressure natriuresis. Recall the control of blood flow and GFR. For example,
that a small proportion of the blood vessels enter- angiotensin II is a potent vasoconstrictor that de-
ing the kidney penetrate into the medulla without creases GFR, and prostaglandins are potent va-
passing through a glomerulus. When the pressure sodilators that increase GFR.
in these renal arteries increases, the renal intersti-
tial hydrostatic pressure increases. This reduces
the ability of the tubule to recover solutes and wa-
Vasopressin alters the permeability
ter from the primary urine, contributing to a de-
of the collecting duct
crease in blood pressure. Vasopressin, also known as antidiuretic hormone
The four intrinsic pathways—myogenic regu- or ADH, is the main hormone responsible for re-
lation, tubuloglomerular feedback, mesangial con- covery of water from the tubule. After this peptide
trol, and pressure natriuresis—act as negative hormone is produced in the cell bodies of hypo-
feedback loops over a relatively narrow range of thalamic neurons, it travels down the neurons to
blood pressures. Other regulators are recruited the pituitary gland where it is released into the cir-
when blood pressure increases or decreases more culation. At the target tissue, the effects of vaso-
significantly or for longer periods, such as in dehy- pressin occur within a few minutes.
dration or following blood loss. The main effectors High vasopressin levels increase the reabsorp-
are the baroreceptors, reflexes that are part of the tion of water by the collecting duct. Although wa-
sympathetic nervous system. A large decrease in ter is also reabsorbed in the loop of Henle, the
mean arterial pressure induces these sympathetic collecting duct is the main site of hormonal regu-
neurons to fire, causing vasoconstriction in both lation of water uptake. Vasopressin alters water
afferent and efferent vessels. With the resulting re-
duction in GFR, and recovery of more Na⫹, the 3
Mean arterial pressure is often abbreviated as MAP, which is
body conserves more water and increases blood an acronym that is also used for microtubule-associated pro-
volume. The decrease in renal circulation also teins and mitogen-activated protein kinase (MAP kinase).
540
uptake by affecting the number of aquaporins in

MAP
the apical membrane of the principal cells of the
collecting duct (Figure 34a). When the hormone
Afferent Stretch of Constriction
arteriolar arteriolar of afferent
binds to its G-protein-linked receptor in the
pressure smooth muscle arteriole plasma membrane, it triggers a signaling pathway
that acts via cAMP and protein kinase A to translo-
Resistance
cate vesicles containing preformed aquaporins to
of afferent the apical membrane. The process is similar to the
arteriole way synaptic vesicles are sent to the synaptic
membrane of neurons in response to neuronal
Glomerular Glomerular stimulation (though in synaptic vesicles, the sec-
capillary capillary ond messenger triggering fusion is Ca2⫹ rather
pressure pressure
than cAMP). Once vasopressin levels fall, the path-
way reverses and aquaporins are removed from
Glomerular Glomerular
filtration filtration
the membrane by endocytosis.
pressure pressure Vasopressin is secreted by a complex pathway
involving both positive and negative regulators.
– Negative When plasma osmolarity increases, the osmore-
GFR GFR
feedback ceptors in the hypothalamus respond by stimulat-
(a) Myogenic regulation ing the posterior pituitary to secrete more
vasopressin. Other inputs to the pituitary involve
stretch receptors in heart atria and baroreceptors
MAP
in carotid and aortic bodies. When blood pressure
increases, these receptors activate, sending action
Afferent potentials through neurons that terminate in the
arteriolar
pressure cardiovascular control center in the medulla ob-
longata. This center signals hypothalamic neurons
that terminate in the pituitary to inhibit the secre-
Glomerular Glomerular
capillary – Negative
capillary tion of vasopressin.
feedback
pressure pressure
Aldosterone regulates sodium

Resistance
of afferent and potassium balance
arteriole
Steroid hormones also play a role in kidney func-
tion. In tetrapods, aldosterone is the main miner-
Constriction alocorticoid; however, fish lack aldosterone.
of afferent
arteriole Instead, in fish, cortisol probably acts as the main
mineralocorticoid, in addition to its role as the ma-
jor glucocorticoid. The origins of the steroid recep-
Glomerular Chemical
filtration signals tor gene family are actively studied. Recent studies
pressure suggest that fish, like tetrapods, may possess sepa-
rate receptors for glucocorticoid and mineralocorti-
Flow at
GFR macula coid functions, even though different hormones are
densa employed.
(b) Tubuloglomerular feedback
Mineralocorticoids stimulate Na⫹ reabsorp-
tion (and secondarily water recovery from the
Figure 33 Intrinsic control of GFR An increase in urine) and enhance K⫹ excretion. The mineralo-
mean arterial pressure (MAP) triggers a change in
glomerular filtration pressure. (a) Myogenic regulation corticoids are produced by the adrenal cortex in
controls vasoconstriction by triggering contraction of the tetrapods and the interrenal tissue in fish. These
vascular smooth muscle of the afferent arterioles. (b) The tissues, both physically close to the kidney, release
tubuloglomerular feedback loop involves signaling factors aldosterone into the blood. Aldosterone targets the
released from the macula densa that alter smooth muscle
contractility. Two other modes of intrinsic control—mesangial
principal cells of the distal tubule and collecting
control and pressure natriuresis—are described in the text.
541
Vasopressin 1 Vasopressin binds

G-protein-linked receptor.
1
Aquaporin
AC
2 Receptor activates adenylate
4 cyclase, increasing cAMP
cAMP and activating protein kinase A.
G protein ATP 2
3
Cytoskeleton
PKA
3 Phosphorylation of cytoskeletal
and vesicle proteins occurs.
ER
4 This triggers translocation of

vesicle to the cell membrane,
Nucleus with insertion of aquaporins.
(a) Vasopressin
1 Aldosterone enters the cell

Aldosterone
by diffusion.
1
Proteins
2 It binds to its receptor, a
transcription factor.
5
3 Activated transcription factor
stimulates transcription of
Cytoskeleton genes for transporters.
4
4 New transporter proteins are
made in the ER and exported
in vesicles.
3 5 Vesicles containing proteins

2 ER
are sent to the plasma
Nucleus membrane.
(b) Aldosterone
Figure 34 Control of nephron function by vasopressin and aldosterone (a)

Vasopressin controls water movements in the tubule by altering the levels of aquaporins.
(b) Aldosterone changes the levels of ion transporters by altering the pattern of gene expression.
ducts, binding to a cytoplasmic hormone receptor Na⫹ and low in K⫹. As the loss of aldosterone con-
and entering the nucleus to stimulate transcrip- tinues unabated, the animal slowly dehydrates as it
tion of genes involved in ion transport (Figure draws fluids from the extracellular spaces to main-
34b). The effects of aldosterone manifest over sev- tain blood volume and blood pressure.
eral hours because the process involves gene tran- Aldosterone exerts its effects on K⫹, Na⫹, and
scription, translation at the endoplasmic water by stimulating the expression of genes en-
reticulum, processing in the Golgi apparatus, coding transport proteins. Na⫹/K⫹ ATPase is pro-
packaging into vesicles, and the fusion of the vesi- duced in the principal cells and sent to the
cles with the plasma membrane. basolateral membrane; K⫹ channels and Na⫹
Insight into the role of aldosterone comes from channels are produced and targeted to the apical
studies of lab rats with the adrenal gland surgically membrane. The interaction between Na⫹ and K⫹
removed (adrenalectomy). Within only a few hours, transport causes the net exchange of plasma K⫹
the rats produce copious volumes of urine, high in for Na⫹ in the urine. The actions of the Na⫹/K⫹
542
ATPase increase intracellular [K⫹], driving K⫹ ef- increases the synthesis and release of aldosterone
flux into the tubule lumen through the K⫹ chan- from the adrenal cortex and vasopressin from the
nels. As the Na⫹/K⫹ ATPase pulls K⫹ from the pituitary.
plasma, it expels Na⫹ from the cytoplasm. This
Na⫹ enters the tubule cell through Na⫹ channels in
the luminal (apical) membrane from the primary
Natriuretic peptides also play a role
urine. Aldosterone exerts no direct effects on wa-
in sodium balance
ter transport (unlike vasopressin); the stimulation Mammals produce a group of hormones called na-
of water recovery from the urine is a consequence triuretic peptides (NPs), which as the name sug-
of the reabsorption of Na⫹. gests, favor the appearance of Na⫹ in the urine.
There are three main NPs: atrial NP (ANP), brain NP
(BNP), and C-type NP (CNP). All three peptides are
The renin-angiotensin-aldosterone encoded by separate genes. They are secreted as
pathway regulates blood pressure longer propeptides, then cleaved by specific pro-
Circulating [K⫹] is a major determinant of aldos- teases into the active hormone. The first natriuretic
terone synthesis—another example of a negative hormone to be identified was atrial natriuretic
feedback loop. However, aldosterone production is peptide (ANP). Cardiac atrial cells produce ANP
also regulated by the hormone angiotensin II in and excrete it in response to excessive stretch,
the renin-angiotensin pathway. Juxtaglomerular which would accompany an increase in blood vol-
cells in afferent and efferent arterioles of the ume. Upon release, ANP travels to the kidney where
nephron secrete the enzyme renin, which converts it increases Na⫹ excretion by several mechanisms
the plasma protein angiotensinogen to an- dependent upon activation of guanylyl cyclases and
giotensin I. Another enzyme called angiotensin- cGMP. The natriuretic and diuretic effects of ANP af-
converting enzyme, or ACE, found on the epithelia fect both the renal vasculature and tubular function.
of blood vessels, converts angiotensin I to an- The effects of ANP serve to increase the GFR.
giotensin II. The secretion of renin is controlled in ANP increases blood flow to the glomerulus, acting
three ways. First, juxtaglomerular cells release on either the afferent glomerular arteriole (vasodi-
renin when blood pressures decline; the juxta- lation) or efferent glomerular arteriole (vasocon-
glomerular cells may be baroreceptors them- striction). It also causes relaxation of the
selves, or they may rely on neighboring cells to mesangial cells, increasing the surface area avail-
sense and respond to pressure changes through able for filtration. It may also target the foot
local signaling factors. Second, decreases in blood processes of the podocytes, increasing the size of
pressure activate sympathetic neurons in the car- the filtration slits of the glomerulus.
diovascular control center of the medulla oblon- The effects of ANP on renal tubules are medi-
gata, triggering an increase in renin secretion. ated through antagonistic effects on other hor-
Third, the macula densa cells in the wall of the dis- mones. It decreases aldosterone release by the
tal tubule respond to a decrease in urine flow and adrenal cortex, preventing aldosterone from en-
Na⫹ delivery by releasing a paracrine signal that hancing Na⫹ reabsorption in the distal tubule. It
induces the juxtaglomerular cells to increase renin decreases renin release, thereby decreasing an-
secretion. giotensin II. In many ways, ANP acts antagonisti-
Angiotensin II acts at a number of different cally to the renin-angiotensin system and the
sites including the kidney, brain, heart, adrenal aldosterone pathway. It is also an antagonist of the
cortex, and blood vessels. Recall from what you’ve production and release of vasopressin, reducing
learned, that angiotensin II is an important regu- water reabsorption in the collecting ducts.
lator of the cardiovascular system, exerting effects
on cardiac growth and angiogenesis. In terms of
ion and water balance, angiotensin II stimulates Hypothalamic factors regulate thirst
Na⫹ reabsorption in the proximal tubule and vaso- Water balance is, of course, affected by water con-
constricts postglomerular blood vessels. It can also sumption. The perception of thirst can arise in re-
stimulate the synthesis and release of other hor- sponse to dehydration or Na⫹ overload. Hormones
mones that exert their own effects on the kidney to that reflect the systemic state of the animal, includ-
increase solute and water recovery. Angiotensin II ing the osmotic condition and the cardiovascular
543
state, exert effects on the central nervous system to Invertebrates have primitive kidneys
affect thirst. called nephridia
The hypothalamus is responsible for sensing
Sponges, the simplest animals, act much like pro-
the external conditions and controlling thirst. Re-
tists when it comes to water excretion. They use
call that this region of the brain has an incom-
simple contractile vacuoles to expel cellular wastes,
plete blood-brain barrier, allowing hypothalamic
including water, directly into the environment. The
neurons to detect plasma conditions, including
true metazoans possess specific cells and tissues
circulating hormones. The osmotic condition is
that are dedicated to excretion. Many simple ani-
detected by a combination of osmoreceptors and
mals, including most of the diverse worm taxa,
hormone receptors. The osmoreceptors in cir-
possess protonephridia, a primitive functional ana-
cumventricular organs monitor the osmolarity of
logue of the vertebrate kidney tubule (Figure 35a).
the cerebrospinal fluid that bathes the hypothal-
The protonephridium in flatworms consists of a
amus. Angiotensin II, which exerts water-sparing
branched tubule with a pore (nephridiopore) at one
effects on the kidney, also binds to receptors in
end and a cap cell at the other. Fluids are propelled
this region of the brain. This hypothalamic region
through the duct of the protonephridia by flagella
then sends signals to the thirst center elsewhere
or cilia that extend from specialized cells. Some
in the hypothalamus, likely the dorsomedial hy-
species have flame cells, which possess a tuft of
pothalamic nucleus. Stimulation of the thirst cen-
cilia. Other species have solenocytes, which
ter increases the motivation to drink.
possess one or two flagella that extend into the lu-
men. The role of protonephridia varies among
species and in relation to the environment. In
2 CO N CEP T C HE C K general, protonephridia are important in
osmoregulation, and are best developed in the
11. Compare and contrast how vasopressin and
aldosterone regulate kidney function.
freshwater species that must export water. They
probably have no role in ammonia excretion in
12. What factors affect glomerular filtration rate
(GFR)? most species that possess protonephridia; these
Evolutionary Variation in the Nephrostome Lumen
Structure and Function of Excretory Flame

Systems cell
The cellular composition and functional proper-
ties of kidneys vary widely among animals. Up to
this point, we have used the structure and func-
Flagella
tion of the typical mammalian kidney to illustrate
the role of the different regions of the kidney
Lumen
tubule and how the structural and functional
properties produce an appropriate urine. Of
course, there is no such thing as a typical any- Tubule
thing in animals as diverse as vertebrates. The cell
Storage
model we described most closely resembles the bladder
kidney of a large mammal living on a mixed diet
with ample access to freshwater. In other ani- Nephridiopore
mals, even other mammals, there is considerable (a) Protonephridium (b) Metanephridium
variation in kidney structure and function. Figure 35 Primitive kidneys of invertebrates
Armed with an understanding of the roles of each (a) Primitive invertebrates, such as flatworms, possess
of the main regions of the nephron, we can ex- protonephridia, which use ciliated or flagellated cells to draw
interstitial fluid into the lumen of tubules. (b) More advanced
plore the basis of variation in nephron and kid-
invertebrates, such as annelids, possess metanephridia,
ney structure in other animals, beginning with which collect fluids directly from the circulatory system or
the invertebrates. coelom.
544
animals excrete ammonia directly across the body Gastric

surface. The number of protonephridia differs cecum Malpighian tubule
widely among species, from as few as two with a

pair of nephridiopores, to thousands of units.
More complex nephridia, called metanephridia, Mouth Crop
occur in the molluscs and annelids. Most molluscs
have a single metanephridium, with a sac possess- Midgut Hindgut
ing deeply invaginated walls to increase the surface (a)
area (Figure 35b). Solutes and water are collected
and expelled through a short tube called a ureter.
Annelids possess a metanephridium in each body Stellate cell
segment. The tubule begins at the nephrostome,
which collects fluids from the coelom. The fluid
passes through the long tubule, which winds
through the body segment. Tubule length depends
on habitat; marine species, with little need for water Principal cell
excretion, have shorter tubules than do freshwater
species. The nephridium passes through the septum
between body segments, and joins the body wall at Cl– channel Aquaporin
the nephridiopore, releasing waste products from H+
the animal. In some cases, the nephridium expands ATPase
into a saclike bladder that is able to store fluids. Cl– H2O
The cellular structures of these primitive kid-
neys vary widely among the invertebrates, but the
main difference between a protonephridium and a
metanephridium is in the relationship with the in- Cl– Solute
Cl– channel
tracellular fluids. Protonephridia use their beating K+ transports
K+ channel
flagella and cilia to draw interstitial fluid into the
lumen of the tubule. In contrast, the duct of a Stellate cell Principal cell
metanephridium has an internal opening that col- (b)

lects body fluids, either blood or coelomic fluid. Figure 36 Insect Malpighian tubule structure
One unusual group among the invertebrates and function (a) The Malpighian tubules, the insect
are the nematodes. Unlike other worms, nema- kidney, empty into the digestive tract. Although many insects
have four Malpighian tubules, the numbers can range from
todes lack nephridia altogether. Their excretory
two to more than 250. (b) The tubule itself is composed of
system employs rennette cells, which secrete principal cells and stellate cells.
waste into a duct that empties through an excre- (Source: Modified from O’Donnell et al., 1996)
tory pore. Nematodes differ in the morphology of
the rennette cells—glandular or tubular—and the insects, such as hemipteran bugs, possess two
extent of the canal system that links the rennette very long, coiled tubules, whereas other species
cell to the excretory pore. have many shorter tubules, up to 250 in the locust
Schistocerca. Although an insect Malpighian tubule
is typically only one cell layer thick, there is consid-
Insects use Malpighian tubules and the erable variation among species in the structural
hindgut for ion and water regulation complexity, which can be related to the nature of
In insects, no single tissue fulfills the function of the diet. Species that consume a great deal of
the vertebrate kidney or invertebrate nephridium; water, such as sap feeders, blood feeders, and car-
water and ion balance in insects is regulated by rion feeders, may have more complex structures
concerted actions of the Malpighian tubule and that improve filtration.
the hindgut. The hindgut, which includes the rectum and
The Malpighian tubule is a tubelike structure rectal gland, receives the flow from the Malpighian
with a blind sac at one end of a long tube that tubule. The fluid is typically slightly hyposmotic to
empties into the hindgut (Figure 36). Some the hemolymph. As it passes into the hindgut, the
545
fluid is further modified by reabsorption and secre- to act by stimulating the synthesis of cAMP in
tion. When it leaves the hindgut, the final osmolar- Malpighian tubule cells, which activates cation
ity may be hyposmotic, isosmotic, or hyperosmotic. transport at the basolateral and apical regions
The Malpighian tubule of a typical dipteran of the principal cells.
(flies and mosquitos) is composed of two main cell 2. Insect (myo)kinins are short peptide hormones,
types: large principal cells and small stellate cells. usually eight amino acids, that possess a char-
Principal cells, often called secretory cells, possess acteristic C-terminal sequence of five amino
extensive apical microvilli. The microvilli contain acids. These hormones act on the stellate cells
long, slender mitochondria that move in and out of of the Malpighian tubules, activating phospho-
the microvilli as needed. The mitochondria provide lipase C to increase the production of IP3, which
the ATP required for ion pumping. The main role of in turn causes a release of Ca2⫹ from intracel-
the principal cells is cation transport, and the apical lular stores. This increase in [Ca2⫹] causes an
cell membrane is rich in ion exchangers that are ul- increase in Cl⫺ transport into the lumen, al-
timately driven by the activity of a proton-pumping though the mechanisms are not yet clear. The
ATPase (H⫹ ATPase). Stellate cells have fewer mito- movement of Cl⫺ causes a parallel movement of
chondria and lack the complex apical microvilli. Na⫹ and K⫹, leading to a net movement of NaCl
Their main role is the control of Cl⫺ transport. and KCl from the hemolymph to the lumen.
The Malpighian tubule produces the primary
3. Cardioacceleratory peptides were first identi-
urine without filtration. Instead, secretions from fied by their ability to increase the heart rate.
the tubule cells form the primary urine. Solutes However, these hormones also stimulate the
and water enter the blind end of the tubule by ei- secretion of fluid into Malpighian tubules. This
ther paracellular transport or transcellular trans- diverse family of hormones appears to stimu-
port. The basolateral membrane of principal cells late phospholipase C in principal cells. The in-
imports K⫹ from the hemolymph by K⫹ channels; crease in IP3 and then Ca2⫹ activates a cascade
Na⫹ and K⫹ are imported by a Na⫹-K⫹-2Cl⫺ co- involving Ca2⫹-calmodulin-dependent nitric
transporter (NKCC). At the apical membrane, the oxide synthase and guanylyl cyclase. These
H⫹ ATPase exports H⫹, creating a driving force second messengers and regulatory enzymes
lead to an increase in H⫹ ATPase activity.
that can be coupled to exchangers (Na⫹/H⫹ or
K⫹/H⫹) that expel other cations. Unlike most other While these diuretic hormones have been well
transport epithelia, there appears to be little role characterized, much less is known about antidi-
for Na⫹/K⫹ ATPase in most species. The increase uretic hormones in insects. Some, called antidi-
in osmolarity draws water into the lumen of the uretic factors, act by reducing the movement of
tubule. The lumen contents are modified by selec- water into the Malpighian tubule. Others, such as
tive reabsorption of solutes and water as the pri- neuroparsins and ion-transport peptide, act by in-
mary urine flows down the tubule from the blind creasing water reabsorption in the gut, after the
end to the opening in the hindgut. lumen contents empty into the hindgut.
Once the lumen fluid is formed in the ends of
the tubules, it progresses down the tubule where Chondrichthian kidneys produce
it encounters mechanisms of selective reabsorp- hyposmotic urine and retain urea
tion. Malpighian tubules are not innervated, and
Recall that sharks have an unusual osmotic strat-
the control of secretion and reabsorption is under
egy among vertebrates, maintaining their body
the control of intrinsic regulators and circulating
fluids slightly hypertonic to seawater and accumu-
hormones. Three main classes of diuretic hor-
lating urea to high concentrations (300–400 mM).
mones have been identified in insects.
Sharks have two long kidneys lying along the dor-
1. CRF-related diuretic hormones have struc- sal wall of the body cavity. The kidney tubules are
tural similarities to vertebrate hormones of long and complex in structure (Figure 37).
the corticotropin-releasing factor (CRF) family, The tubules weave back and forth across the
such as urotensin and urocortin. Fifteen dif- kidney to form two layers: a sinus zone where
ferent CRF-related diuretic hormones have tubules are loosely packed and separated by fluid,
been identified in insects, ranging in size from and a more compact zone where tubules are bun-
30 to 47 amino acids. These hormones appear dled together and wrapped in a membranous
546
Marine fish
Hagfish Shark Glomerular Aglomerular Freshwater fish Amphibian Reptile Mammal
G G G G G G
Glomerulus N
N N
Neck (ciliated)
PT N N PT PT PT
Proximal tubule PT
PT PT
IS
IS Loop of
Distal tubule Henle
DT DT Inter-
segmental DT
Collecting region DT
CT DT
tubule CT
DT CT
CT
CT
CT
Figure 37 Variation in the vertebrate kidneys Each vertebrate kidney possesses

regions specialized for absorption and secretion. However, the dimensions of each region vary
among taxa.
(Source: Modified from Willmer et al., 2000)
sheath. This complex arrangement may set up a kidneys occur in species from three unrelated taxa.
countercurrent exchanger that allows the shark Since the other species in these taxa have glomeru-
kidney tubule to recover as much as 90% of the lar kidneys, the aglomerular state has evolved at
urea from the primary urine. The exact mecha- least three separate times in fish.
nism by which urea is recovered remains unclear,
and may occur through active reabsorption via
Na⫹-urea cotransporters. The urine produced by The amphibian kidney changes
the shark is slightly hyposmotic (relative to the in metamorphosis
shark tissues) and close to the osmolarity of sea- Like freshwater fish, most amphibians living in
water. Sharks that move into dilute seawater water must rid themselves of excess water ab-
reduce their internal osmolarity by producing sorbed from the environment across highly per-
copious amounts of dilute urine. meable skin. In their aquatic life they have little
need for water retention mechanisms. However,
when amphibians are on land, they must conserve
The role of the fish kidney differs water. Like freshwater fish, amphibians possess a
in freshwater and seawater kidney that lacks a loop of Henle, which enables
In bony fish, two paired kidneys run along the dor- the mammalian kidney to produce hyperosmotic
sal surface of the inner body cavity. The function urine. An amphibian meets the conflicting de-
of the kidney depends on the osmolarity of the wa- mands of life on land and water by (1) regulating
ter. The glomerulus, which produces the primary the glomerular filtration rate to control the rate of
urine, is much larger in freshwater fish than in water loss and (2) recovering water from the urine
marine species. The distal tubule, which functions stored in the urinary bladder. Whereas most ter-
in salt recovery and water excretion, may also be restrial animals use the bladder only for short-
much larger. The kidneys of freshwater fish pro- term storage of urine prior to micturition,
duce large volumes of hyposmotic urine. amphibians use the bladder for water storage.
The kidneys of marine fish play a much-reduced The reabsorption process is under the control of
role in ion and water balance. They produce very lit- the amphibian homologue of vasopressin.
tle urine, which is isosmotic to body fluids. The The nature of the amphibian kidney changes
nephrons of marine fish have a less complex during development. Larval amphibians, as well as
glomerulus, shorter proximal tubules, and distal larval fish, have a simple nephron called a
tubules that are reduced or absent. Some marine fish pronephros. Recall that the mammalian kidney
lack a glomerulus altogether. These aglomerular tubule, also known as a metanephros, empties fluid
547
from the circulation directly into the interior of the of the nephron to produce concentrated urine
nephron at the Bowman’s capsule. In a pronephric takes into account the size of the kidney. Since the
kidney, the filtrate first enters the coelom, then is loop of Henle spans the medulla, the potential to
swept into the pronephric tubules through the produce concentrated urine is best expressed as
nephrostomal funnels. As with true nephrons, the relative medullary thickness: the width of the
water, ions, and organic molecules are reabsorbed medulla relative to the total width of the kidney
in the tubule and returned to the blood. The urine (Figure 38). Mammals that live in environments
is then sent along the pronephric duct and expelled with abundant water, such as beavers, have a low
through the cloaca. Whereas a mammalian kidney relative medullary thickness and nephrons with a
may possess a million nephrons, a larval frog pos- short loop of Henle that produce dilute urine. Con-
sesses just a pair of pronephros. As the larva meta- versely, mammals that live in very dry environ-
morphoses to an adult, the pronephros is replaced ments, such as the kangaroo rat, have a high
by a kidney that much more closely resembles the relative medullary thickness and nephrons with a
mammalian version. long loop of Henle that produce highly concen-
trated urine, typically four to five times more con-
centrated than that of most mammals.
Terrestrial animals have kidneys that help
conserve water
The variations in kidney morphology among rep-
tiles, birds, and mammals reflect different solu-
tions to the challenge of avoiding dehydration. The Short loops
challenges of reducing water loss are greatest in
desert animals (see Box 1, Evolution and Diversity: Medulla
Life Without Water), but all terrestrial animals
have multiple means of matching kidney function
to the constraints of environmental water avail-
ability. (a) Beaver
Modern reptiles reduce the need for water by
producing uric acid as a nitrogenous end product.
Since uric acid is insoluble, water is not wasted as Short loops
a solvent, although some water is used to wash
the uric acid down the tubule lumen. This water Long loops
can be reabsorbed in the cloaca. The reptilian kid-
ney has much-reduced glomeruli, and in some
species the glomerulus is absent. As with the am-
phibians, the reptilian nephron lacks a loop of
Henle, and therefore cannot produce hyperos- (b) Rabbit
motic urine.
One of the major innovations in terrestrial ver-
tebrate evolution was the loop of Henle. This ex-
tended segment between the proximal and distal Long loops
tubules occurs only in birds and mammals, al-
though birds have some nephrons that lack a loop
of Henle. Because of the loop of Henle, most mam-
mals can produce urine with an osmolarity that is (c) Kangaroo rat
about five times greater than the plasma osmolarity. Figure 38 Relative medullary thickness in
If it were simply the total length of the loop of mammalian kidneys Animals that produce a more
Henle that determined the ability to produce con- concentrated urine, such as the kangaroo rat, have nephrons
with a longer loop of Henle and a thicker medulla than do
centrated urine, the elephant would be a cham- animals that produce dilute urine, such as a beaver. Most
pion; it has a long loop of Henle simply because its species, including rabbits, fall between these extremes.
kidney is so large. The best predictor of the ability (Source: Adapted from Schmidt-Nielsen and Dell, 1961)
548
Integrating Systems Interaction of the Cardiovascular

and Excretory Systems in the Regulation
of Blood Pressure
In our discussion of kidney function, we focused on how pressure reduces filtration across the capillaries, and
the kidney produces urine to control water balance. causes fluid to shift from the interstitial space to the
However, the excretory system and cardiovascular sys- blood. This helps to return blood volume and blood
tem have overlapping responsibilities in regulating pressure to normal.
blood pressure. The cardiovascular system responds The decrease in blood pressure as a result of dehy-
primarily to changes in blood pressure, whereas the ex- dration also reduces the amount of stretch on the
cretory system responds to changes in both blood pres- carotid and aortic body baroreceptors. This causes them
sure and blood osmolarity. Animals regulate blood to reduce the frequency of action potentials in the affer-
pressure by controlling both the volume of blood and its ent neurons leading to the cardiovascular control center
osmolarity, which depend on water and salt fluxes but in the medulla oblongata of the brain. This decrease in
can vary independently of each other. action potential frequency causes the cardiovascular
Consider how different foods affect water and salt control center to decrease parasympathetic output and
balance, and how the excretory system must respond to increase sympathetic output, and these changes in turn
maintain homeostasis. If you drink a large amount of wa- increase heart rate and the force of cardiac contraction,
ter without ingesting anything salty, the total body fluid increasing cardiac output. At the same time, the sympa-
volume quickly increases and osmolarity decreases. In- thetic neurons leading to many systemic arterioles
creasing the volume of urine corrects this situation. stimulate the arteriolar smooth muscle to contract. The
Conversely, if you eat salty food without drinking, the os- resulting vasoconstriction increases total peripheral
molarity increases but your body fluid volume remains resistance (TPR). Since mean arterial pressure is equal
unaltered. The kidneys must increase the excretion of to cardiac output times total peripheral resistance,
salt, but retain as much water as possible. Both volume these two mechanisms lead to an increase in blood
and osmolarity increase if you eat salty food and drink a pressure, helping compensate for the decreased blood
large amount of liquid at the same time. The kidney must pressure caused by dehydration.
increase both the volume of urine and the total amount The decreased blood pressure caused by dehydra-
of salt in the urine. However, the response to changes in tion also stimulates the juxtaglomerular (JG) cells of the
volume and osmolarity is not always this simple. High kidney, causing them to increase the secretion of renin.
osmolarity could arise from excessive salt (so a re- The increased renin increases the conversion of an-
sponse of salt excretion is appropriate) or dehydration (a giotensinogen to angiotensin I. Angiotensin-converting
response of water consumption is appropriate). enzyme (ACE) then catalyzes the conversion of an-
Dehydration is, in fact, the most common cause of giotensin I to angiotensin II. Simultaneously, the in-
disturbances in fluid volume and osmolarity. If you were crease in sympathetic output also stimulates the
to exercise on a hot day, you would lose water in the sweat juxtaglomerular cells, further increasing the level of
and in the expired air. Without drinking, you become de- angiotensin II. As we learned in this chapter angiotensin
hydrated; blood volume will decrease and osmolarity will II has wide-ranging effects on the circulatory and excre-
increase, with negative effects on the cardiovascular sys- tory systems. Angiotensin II can directly promote the re-
tem. The decrease in blood volume leads to decreases in absorption of sodium and water at the level of the
venous return to the heart, cardiac output, and mean ar- proximal tubule and indirectly in the distal nephron via
terial blood pressure. Thus, during dehydration, blood the actions of aldosterone released from the adrenal
pressure drops while blood osmolarity increases. cortex. In dehydration, however, the latter process is
Various pathways are involved in homeostatic com- blocked due to direct effects of increased plasma osmo-
pensation for severe dehydration (Figure 39). These larity on the adrenal cortex. Decreased blood pressure
pathways involve the cardiovascular system, the renin- also affects glomerular filtration rate (GFR). Lower
angiotensin system, renal mechanisms such as blood pressure has a small direct effect on
glomerular filtration, and mechanisms coordinated by GFR, reducing filtration pressure in the glomerulus,
the hypothalamus. and slowing the rate of urine production. However,
One of the fastest responses to the decrease in recall that glomerular filtration rate is actually
blood pressure is the fluid-shift mechanism. Low blood rather tightly regulated even in the face of changes
549
Dehydration
Blood volume Plasma osmolarity

Blood pressure
Capillary Stretch on aortic Stimulate Stimulation of

hydrostatic and carotid body JG cells atrial volume
pressure baroreceptors of kidney receptors, carotid
and aortic
baroreceptors
Capillary Frequency of Renin
filtration action potentials secretion
Hypothalamus
Fluid shift Cardiovascular Production of

from interstitial control centers of angiotensin I Vasopressin
space to blood medulla oblongata release from
pituitary
ACE
Parasympathetic Sympathetic Angiotensin II Thirst

output output
Heart rate Contraction Aldosterone

Force of cardiac of arteriolar
contraction smooth muscle
Na+ reabsorption H2O reabsorption H2O

Cardiac output Vasoconstriction by kidney by kidney intake
TPR GFR
Urine
production
Blood pressure Blood volume Osmolarity
Figure 39 Regulation of blood pressure and kidney function in response to

dehydration
550
in mean arterial pressure, so these direct effects are dosterone reduces the expression of Na⫹/K⫹ ATPase in
minor. Instead, increased sympathetic stimulation (as a the membranes of the distal nephron, reducing Na⫹
result of the decrease in blood pressure) has a major ef- reabsorption, and helping to return osmolarity to nor-
fect. Sympathetic stimulation causes vasoconstriction mal. Note that reducing Na⫹ absorption also reduces
of the afferent arteriole of the glomerulus, reducing water reabsorption, which could impede the return of
glomerular filtration pressure, and thus GFR and urine blood volume and blood pressure to normal. Cardio-
production. The reduction in GFR also decreases flow of vascular reflexes can help to restore blood pressure in
fluid through the kidney tubules. The cells in the mac- the short term, but they cannot address changes in os-
ula densa detect this decrease in flow and stimulate the molarity. In contrast, the excretory system generally
juxtaglomerular cells to secrete renin, thus further in- attempts to restore osmolarity, while dealing with
creasing the levels of angiotensin II. blood pressure over longer terms.
The decrease in stimulation of the atrial volume re- Because of the intimate links between the two sys-
ceptors and the carotid and aortic body baroreceptors tems, many pathological conditions have elements of
as a result of low blood pressure also has a direct effect both kidney disease and cardiovascular dysfunction.
on the hypothalamus, increasing vasopressin secretion Kidney disease may be either a cause or consequence of
and thirst. Together, these responses increase water cardiovascular disease. Kidney dysfunction can arise
reabsorption by the kidney and water intake, resulting in from renal artery defects or maladaptive regulation of
increased fluid volume and decreased osmolarity. the renin-angiotensin system or other vasoactive
Most of the mechanisms we have discussed so far agents. The changes in blood volume create a hyperten-
involve the stimulus of decreased blood pressure, but sive condition that challenges normal heart function.
increased osmolarity also has important effects. Os- Many people with congestive heart failure worsen when
moreceptors in the hypothalamus directly sense the the changes in blood pressure affect kidney function.
increased osmolarity and stimulate the hypothalamus When cardiac function deteriorates, the kidney re-
to release vasopressin as well as stimulate thirst. Os- sponds with renal vasoconstriction, leading to the re-
molarity also has direct effects on the adrenal cortex, tention of water and sodium. The increase in blood
reducing the secretion of aldosterone. The drop in al- volume in turn exacerbates the cardiac problems.2
Summary
Ion and Water Balance k The epithelial tissues of terrestrial animals cre-
k Epithelial tissues are the interface between inate water-resistance osmotic barriers. Other
ternal fluids and the external environment, cre- specialized epithelial tissues mediate osmotic
ating osmotic and ionic barriers, and regulated and ionic regulation, including gills, the diges-
to control ion balance, water balance, and ni- tive tract, and the specialized excretory tissues,
trogen excretion. such as the rectal gland of elasmobranchs and
the salt glands of reptiles and birds.
k Solutes can be distinguished by their effects on
macromolecular structure and function as per- k Animals remove toxic ammonia by excretion or
turbing, compatible, or counteracting. metabolism to less toxic forms. The three main
strategies, defined by the major form of nitroge-
k Animals move ions into and out of cells to main-
nous end product, are ammoniotelism (NH4⫹),
tain or change cell volume. Regulatory in-
uricotelism (uric acid), and ureotelism (urea).
creases in volume (RVI) and regulatory
Most aquatic animals are ammoniotelic,
decreases in volume (RVD) are part of compen-
whereas terrestrial animals are uricotelic (rep-
satory strategies to regain normal cell volume,
tiles and birds) or ureotelic (mammals).
and contribute to signaling pathways that act by
changing cell volume.
551
k Urea is produced in the ornithine-urea cycle, hydrostatic pressure and oncotic pressure gra-
which is regulated by enzyme levels and al- dients between the glomerulus and Bowman’s
losteric regulation. Cartilaginous fish produce capsule. The glomerular filtration rate is regu-
urea as a solute rather than an excretory lated by factors that influence the filtration pres-
product. sure as well as the surface area available for
filtration.
Kidney
k The majority of the responsibility for ion and k Various hormones and neurotransmitters con-
water regulation in vertebrates falls on the kid- trol naturesis and diuresis. Vasopressin alters
ney. The functional unit of the kidney is the the permeability of the collecting duct. The
nephron, a combination of complex vasculature renin-angiotensin system, the sympathetic ner-
and renal tubule composed of epithelial cells. vous system, and aldosterone act in concert to
regulate sodium, potassium, and water balance
k Urine is formed by four processes: filtration, re- as well as blood pressure. Atrial natriuretic
absorption, secretion, and excretion. Filtration peptide also plays a role in sodium balance.
occurs at the glomerulus, a ball-like network of
capillaries surrounded by the Bowman’s cap- k Invertebrates have primitive kidneys, such as
sule of the nephron. From the Bowman’s cap- protonephridia and metanephridia. Insect ion
sule, the primary urine enters the proximal and water balance is mediated by Malpighian
tubule, and then proceeds through the loop of tubules and the hindgut.
Henle, with its descending and ascending limbs.
k Vertebrate kidneys differ among taxa and in re-
The fluid then flows into the distal tubule and
lation to the environmental conditions. Shark
through collecting ducts into the ureters, the
kidneys retain urea while producing a hypos-
urinary bladder and, after a period of storage,
motic urine. Kidneys of freshwater fish produce
out the urethra.
copious amounts of dilute urine, whereas the
k Central to nephron function is the countercur- marine fish have much-reduced kidneys and
rent system set up between the loop of Henle produce little urine. The kidneys of reptiles and
and collecting duct, in conjunction with the cap- birds can produce hyperosmotic urine. Desert
illaries that serve the nephron. vertebrates also produce small volumes of hy-
perosmotic urine as a water conservation
k Kidney function is regulated at multiple levels. mechanism.
Glomerular filtration pressure is affected by the
Review Questions
1. Compare the structure and function of the 7. Compare the energetic costs in the different
salt gland of birds with the rectal gland of excretory strategies.
elasmobranchs. 8. How is energy used in ion pumping?
2. Discuss how countercurrent systems aid renal 9. Discuss regulatory volume increases and de-
function. creases in relation to the membrane potential.
3. Compare the types of nephrons in the inverte- 10. In a normal kidney, which of the following
brates and vertebrates. would cause an increase in GFR?
4. What are the six main roles of the kidney? (a) Constriction of the afferent arteriole
5. How is glomerular filtration rate controlled via (b) Decrease in the hydrostatic pressure in the
intrinsic and extrinsic mechanisms? glomerulus
(c) Increase in hydrostatic pressure in the
6. There is a relationship between the volume of
Bowman’s capsule
urine produced and the type of nitrogenous
waste excreted by an organism. What is this
relationship, and why does it occur?
552
Synthesis Questions
1. Is more water derived from oxidizing glyco- 6. The kidney of a cactus wren is less efficient at
gen, protein, or lipid? concentrating urine than are the kidneys of a
2. Discuss the integration of the respiratory and kangaroo rat, yet the cactus wren produces
excretory systems in controlling pH balance. less urine. In one or two sentences, explain
this apparent contradiction.
3. Describe the role of nerves and muscles in
control of ion and water balance. 7. A person with cirrhosis of the liver has lower
than normal levels of plasma proteins (because
4. We discussed the variation of kinetic proper-
production of albumin, one of the major
ties and localization of the enzymes in urea
plasma proteins, decreases) and a higher than
synthesis. What genetic processes could be re-
normal GFR. Explain why a decrease in plasma
sponsible for these changes during the course
protein concentration would increase GFR.
of evolution?
8. Most freshwater fish are unable to survive in
5. Angiotensin-converting enzyme inhibitors
water with high concentrations of bicarbon-
(ACE inhibitors) are used to treat high blood
ate. Draw a diagram of a freshwater fish gill
pressure. Using a flowchart, explain why these
and, using this diagram, outline a possible
drugs are helpful in treating hypertension.
physiological reason for this observation.
1. If an aquaporin can pass 109 molecules of wa- 3. Explain why an individual with a plasma glu-
ter a second, how many channels would be cose concentration of 375 mg/100 ml of blood
needed to reduce the volume of a 1-µl cell by will have glucose in the urine. (Note: Normal
half in 1 second? (Hint: How many water mol- plasma glucose is approximately 100 mg/
ecules are in 1 µl of water?) 100 ml of blood, normal GFR is approximately
2. Assuming complete dissociation, which of the 180 l/day, and the kidney’s maximal transport
following solutions will have the greatest osmo- rate for glucose is approximately 375 mg/min.)
larity: 150 mM glucose, 80 mM NaCl, 90 mM
Na2SO4, or 210 mM urea?
For Further Reading

See the Additional References section at the end These three papers discuss the way cells sense
of the chapter for more readings related to the and respond to changes in cell volume arising
topics in this chapter. either from osmotic stress or in response to
signaling pathways.
Goldmann, W. H. 2002. Mechanical aspects of
This paper discusses the role of the skin as a cell shape regulation and signaling. Cell
barrier to osmotic movements. Biology International 26: 313–317.
Alibardi, L. 2003. Adaptation to the land: The Lang, F., G. L. Busch, M. Ritter, H. Volkl,
skin of reptiles in comparison to that of S. Waldegger, E. Gulbins, and D. Haussinger.
amphibians and endotherm amniotes. Journal 1998. Functional significance of cell volume
of Experimental Zoology, Part B: Molecular regulatory mechanisms. Physiological Reviews
and Developmental Evolution 298: 12–41. 78: 247–306.
553
Mongin, A. A., A. Sergei, and N. Orlov. 2001. In this paper, the author asks what we can learn
Mechanisms of cell volume regulation and about human kidney disease by studying the
possible nature of the cell volume sensor. kidneys of primitive vertebrates. He focuses on
Pathophysiology 8: 77–88. the paradox of the few species of fish that survive
without a glomerulus.
These classic papers from two pioneers of Beyenbach, K. W. 2004. Kidneys sans glomeruli.
comparative physiology discuss the history of American Journal of Physiology (Renal
early research in the ionic and osmotic Physiology) 286: F811–F827.
regulation of aquatic animals.
Krogh, A. 1939. Osmotic regulation in aquatic Although elasmobranchs are osmoconformers in
animals. Cambridge: Cambridge University seawater, many species are able to survive long
Press. periods in brackishwater and freshwater. This
Smith, H. W. 1953. From fish to philosopher. review discusses the role of urea in osmotic
Boston: Little, Brown. balance of euryhaline species.
Hazon, N., A. Wells, R. D. Pillans, J. P. Good,
Fish are a diverse group of vertebrates that W. G. Anderson, and C. E. Franklin. 2003. Urea
collectively survive a very wide range of based osmoregulation and endocrine control in
environmental salinities. This review discusses elasmobranch fish with special reference to
current concepts about the regulation of ion euryhalinity. Comparative Biochemistry and
balance in freshwater species that must acquire Physiology, Part B: Biochemistry and Molecular
ions and expel water. Biology 136: 685–700.
Perry, S. F., A. Shahsavarani, T. Georgalis, Regulation of Kidney Function
M. Bayaa, M. Furimsky, and S. L. Thomas.
2003. Channels, pumps, and exchangers in the These papers provide in-depth reviews on the
gill and kidney of freshwater fishes: Their role transport capabilities of the various regions of
in ionic and acid-base regulation. Journal of the renal tubule.
Experimental Zoology, Part A: Comparative Muto, S. 2001. Potassium transport in the
Experimental Biology 300: 53–62. mammalian collecting duct. Physiological
Reviews 81: 85–116.
Reilly, R. F., and D. H. Ellison. 2000. Mammalian
Nitrogen Excretion distal tubule: Physiology, pathophysiology, and
molecular anatomy. Physiological Reviews 80:
Many aspects of nitrogen metabolism changed 277–313.
in the early evolution of vertebrates. These
three papers discuss urea metabolism in fish, Wright, S. H., and W. H. Dantzler. 2004.
focusing on the evolutionary origins of Molecular and cellular physiology of renal
ureotelism. organic cation and anion transport.
Physiological Reviews 84: 987–1049.
Barimo, J. F., S. L. Steele, P. A. Wright, and P. J.
Walsh. 2004. Dogmas and controversies in the These two papers discuss the insect Malpighian
handling of nitrogenous wastes: Ureotely and tubule from different perspectives. One reviews
ammonia tolerance in early life stages of the what is known about the regulation of these
gulf toadfish, Opsanus beta. Journal of excretory organs to better understand how they
Experimental Biology 207: 2011–2020. function. The other reviews the utility of insect
Mommsen, T. P., and P. J. Walsh. 1989. Evolution models to explore the epithelial function from the
of urea synthesis in vertebrates: The piscine perspective of human disease.
connection. Science 243: 72–75. Cagan, R. 2003. The signals that drive kidney
Walsh, P. J. 1997. Evolution and regulation of urea development: A view from the fly eye.
synthesis and ureotely in (batrachoidid) fishes. Current Opinion in Nephrology and
Annual Review of Physiology 59: 299–323. Hypertension 12: 11–17.
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of control of insect Malpighian tubules: about the regulation of enzyme activity in urea
Synergism, antagonism, cooperation and production, including the transcriptional control
autonomous regulation. Journal of Insect of their synthesis.
Physiology 46: 107–117. Morris, S. M., Jr. 2002. Regulation of enzymes of
the urea cycle and arginine metabolism.
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of K-Cl cotransport: From function to genes. Journal of excretion in fish: Unanswered questions and emerging
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555
Credits
470 Image Quest Marine, Masa Ushioda/Image Quest Marine.
471 Image Quest Marine, Peter Batson/Image Quest Marine.
471 Philip Chapman/Nature
Picture Library.
482 Photo Researchers, Inc., George Holton/Photo
Researchers, Inc.
482 Photo Researchers, Inc., Dee Breger/Photo Researchers,
Inc.
485 Images courtesy of Dr. Steve Perry, University of Ottawa.
487 Images courtesy of Ryan Pellis and Dr. Steve McCormick,
Cortes Anadromous Fish Laboratory.
488 Photo courtesy of Dr. Robert H. Rothman, Rochester
Institute of Technology.
556
557
Digestion
The physiology of digestion remained largely mysterious shot victim saved the patient’s life, but also left a persist-
until well into the late 18th century. Around 1780, Lazzaro ent hole, or fistula, that ran from the abdominal wall
Spallanzani began to explore the chemical events that oc- through the stomach. This enabled Beaumont to sample
curred in the gut. Like earlier researchers, he knew that gastric juices from his cooperative patient at various points
something in the stomach caused food to change in texture after a meal. The fistula remains a useful experimental
and consistency. He studied gastric processing by collect- tool, providing researchers with a means to sample fluids
ing stomach contents from living animals. He force-fed an- with little stress to the animal. By 1820, it was known that
imals tethered dry sponges and metal tubes, which, upon the gastric juices of unfed animals were neutral but be-
recovery, served as reservoirs for gastric juices. When came acidic upon feeding. Beaumont established that
Spallanzani mixed the gastric juices with foodstuffs, he acidity alone was insufficient to explain how gastric juices
found that chunks of meat softened and milk curdled. broke down foods. In 1836, Theodor Schwann proposed
In the early 1800s, several European researchers ex- that gastric juices contained a chemical substance he
panded Spallanzani’s studies to explore the chemical ca- called pepsin that was capable of digesting foods. It be-
pabilities of gastric juices. At the same time, an American came widely accepted that the digestive juices from the
surgeon named William Beaumont began his own studies saliva, stomach, and pancreas each possessed agents that
of stomach processes. The surgery he performed on a gun- could break down food. Many scientists of the day, includ-
558
Digestion
Lemur and berries.
ing Claude Bernard, believed that each tissue produced the Cows with fistula.
same digestive agent, but that its behavior differed as a re-
sult of variation in acidity. It was first shown in the mid-
1800s that juices from the pancreas, saliva, and stomach one in three sailors from a disease called beriberi, a disease
had different digestive capacities as a result of distinct accompanied by loss of nerve and muscle function. Within
chemical agents therein. Salivary diastase (amylase) could three years of changing to a diet used by British seamen,
break down potato starch within seconds, but pepsin could deaths from beriberi had all but vanished in the Japanese
not. These observations were presented long before the navy. The nature of the protective agents in the diet re-
concept of enzymatic catalysis was formulated. By the late mained unclear until vitamins were discovered in the early
1800s the general notion of enzymes was accepted, al- 1900s. We now know beriberi is a symptom of thiamin defi-
though their nature as proteins continued to be disputed ciency, and that scurvy is a deficiency of vitamin C.
into the 1920s. With a greater understanding of catalysis and the role
The metabolic side of digestive physiology became the played by vitamins, the early enzymologists began to dis-
passion of the early enzymologists. In his autobiography sect complex metabolic pathways. Studies on yeast fer-
For the Love of Enzymes, Arthur Kornberg describes the mentation yielded important discoveries about how
early years of metabolic biochemistry and nutrition. The enzymes combine to perform intermediary metabolism.
1920s to 1930s were dominated by the “vitamin hunters.” It Unlike the physiologists, who tended to focus on specific
had long been recognized that certain diets could cause types of animals, the metabolic biochemists were more
dramatic dysfunction and disease. British sailors suffered egalitarian in their choice of experimental models. Bio-
from scurvy, a disease that manifests as deterioration of chemists in this era, including Kornberg, studied bacteria,
the connective tissue. Scurvy could be prevented if limes or fungi, plants, and tissues of many animal species to unlock
other citrus fruits were included in the sailors’ diet, which the secrets of enzyme function and metabolic pathways.
incidentally was the origin of the term limey. Until the These studies provided the mechanistic links between nu-
1880s, the Japanese navy subsisted on a rice diet and lost trition, digestion, energy metabolism, and biosynthesis. 2
559
Digestion
Overview neurosensory machinery, such as an insect’s anten-

nae or a knifefish’s electrical sensors, is recruited to
Digestive physiology is concerned with all of the tis- locate food. Once food is located in the broad envi-
sues that contribute to the physical and chemical ronment, it must be captured using specialized
breakdown of food: the sensory system used to lo- anatomy, such as the lobster’s claw, the eagle’s
cate food, the physical structures that mechanically talon, or the mosquito’s proboscis. Once acquired,
disrupt the food, and the chemical processes that food is usually mechanically disrupted with the help
break food into forms that can be transported and of other specialized structures, such as a mammal’s
metabolized into other molecules (Figure 1). teeth or the snail’s tongue. Animals then use chem-
Assimilation—the sequential process of nutri- ical processes to convert the large food items to
ent acquisition and absorption—begins when the macromolecules and small molecules. The food
may be macerated, or softened, by
soaking in fluids such as saliva.
Nostril Chemical breakdown is primarily en-
(gustatory Nutrient zymatic and in most cases takes place
receptors) sensing outside the animal. Note that the in-
Eye ner surface of the gastrointestinal
Teeth Mechanical tract is contiguous with the external
Tongue digestion environment.
The gastrointestinal tract, or GI
tract as it is more commonly known,
is wondrous in its complexity. It is
composed of many cell types: ab-
sorptive cells that take up nutrients,
glands that secrete suites of chemi-
Chemical
processing cals (mucus, acid, ions, and en-
Esophagus and zymes), muscles that control the GI
assimilation
tract shape and motility, and nerves
that regulate GI tract function. Once
GI tract Stomach the nutrients are broken down in the
lumen of the GI tract, they are
brought into cells. Undigested food
Intestine is expelled from the body by the
process of egestion.
The Nature and

Acquisition of Nutrients
Egestion
Every organic molecule on the
planet possesses chemical energy,
yet animals are able to capture this
energy from only a small subset of
these molecules. Food is a sampling
of the external environment, a het-
erogeneous mixture of digestible
and undigestible materials. Nutri-
Figure 1 Digestion Animals use combinations of sensory and mechanical ents are the external molecules that
processes to acquire and ingest food. Vision and smell are central to the feeding allow an animal to build and main-
strategies of most vertebrates. Once acquired, the food begins to undergo the process
of digestion. Frequently, ingestion begins with mechanical disruption in the upper
tain cells. We begin our discussion
digestive tract, followed by chemical processing of the food material that is required of digestive physiology by consider-
for assimilation. Undigestible material is expelled from the animal. ing the nature of the nutrients.
560
Digestion
Nutrients ure 2). If you ate nothing but wood chips

(4 kcal/g), you would obtain little energy because
Ingestion is the primary route that an animal uses you can’t digest the plant material to liberate the
to gain access to environmental chemicals. Al- chemical energy trapped within the cellulose mol-
though many aquatic animals obtain some essen- ecules. The gross energy that can be broken down
tial ions by importing them across the external is the digestible energy, and the remainder is
epithelial surfaces, such as the gills and skin, most lost in the feces. Of this digestible energy, only a
animals absorb nutrients across the epithelium of fraction is metabolizable energy, with the re-
the gastrointestinal tract. Some of the assimilated mainder of the absorbed nutrients lost in the
nutrients are degraded to liberate chemical en- urine. Much of the metabolizable energy is used by
ergy; the rest are used as building blocks. Many of the animal to support maintenance, growth, and
the macromolecules that animals need for biosyn- reproduction. This is called the net energy. The
thesis cannot be synthesized de novo, so a dietary remainder of the metabolizable energy is lost as a
source is critical. Essential nutrients, those chem- result of the digestion process. This energy, called
icals that must be obtained in the diet, include specific dynamic action (SDA), is reflected in the
most vitamins and minerals, as well as several increase in metabolic rate during the digestive
amino acids and fatty acids. Nonessential nutri- process. Anyone who has overindulged in a holi-
ents are those chemicals that the animal can pro- day meal will recognize the effects of SDA. The
duce from other molecules. heat warms the body, and in combination with
neurotransmitters can induce drowsiness. Many
large predators, such as lions and snakes, sleep af-
Diets provide energy for activity, growth, ter gorging in feeding bouts.
maintenance, and reproduction The SDA, or heat increment as it is often
The diet provides animals with nutrients that can termed, is an important source of thermal energy
be oxidized for energy. Every diet has an energy for the animal. The heat of digestion is rapidly
content that can be described in the standard units transferred to the rest of the body by the abundant
of energy: joules or calories. There must be enough vasculature that serves the GI tract. Thus, SDA con-
energy in the diet to match the metabolic demands tributes to heat production in endothermic animals,
of the animal, also measured in joules or calories.
The energetic needs of an animal depend on
many factors. Its long-term metabolic energy con- Gross Energy
sumption reflects the long-term dietary needs for
(Feces)
energy. In the short term, energy consumption and Indigestible Energy
utilization frequently fall out of balance, and en-
ergy status must be buffered by the use of fuel stor-
Digestible Energy
age depots. Body size, activity levels, growth rate,
reproductive state, and environmental stress are (Urine)
Unmetabolizable Energy
the most important factors that influence the meta-
bolic rate of an animal, and therefore dietary en-
ergy demands. These factors also account for the Metabolizable Energy
differences in energy demands between species.
Each macromolecule has a corresponding en- Specific Dynamic Action (SDA)
ergy content, measured as a caloric equivalent. A
gram of protein or carbohydrate possesses 4 kcal
Net Energy
of energy, whereas fat has 9 kcal per gram. Thus,
for an animal to obtain an equivalent amount of Figure 2 Dietary energy Not all food energy is
energy, it would have to eat more than twice as digestible. Indigestible material, such as dietary fiber, is lost
much protein as fat. Gross energy is measured ex- in the feces. Some of the nutrients taken up by the gut are
perimentally by calorimetry. The food material is lost in the urine, unmetabolized by the animal. A portion of
the metabolizable energy is released as heat during the
burned to ash, and the resulting heat production
process of digestion. The remainder can be used to fuel
reflects the total energy content. However, not all activity, growth, reproduction, and other energy-dependent
of the food an animal consumes is digestible (Fig- processes necessary for life.
561
Digestion
reducing the need for specific thermogenic path- can be problematic, however, because they are
ways. For a hummingbird feeding on a cold morn- stored in lipid depot tissues and can be released in
ing, SDA is an important contribution to whole body a toxic pulse when fats are mobilized.
heat production, helping it cope with cold air tem- Some animals obtain selected vitamins from
peratures as well as cold nectar; ingesting a normal- symbiotic bacteria living in the GI tract. For exam-
sized nectar meal at 4°C creates a thermal challenge ple, the gut flora of most mammals produces all
equivalent to that experienced when the entire the vitamin C needed in the diet. Humans, unlike
hummingbird is at 15°C. In some ectothermic ani- most mammals, must obtain their vitamin C pre-
mals, SDA causes local warming to speed the rate of formed in the diet. Fortuitously, some of the pio-
digestion. The bluefin tuna, for example, possesses neering studies on vitamin C were performed on
countercurrent heat exchangers to help retain heat guinea pigs, which also derive vitamin C from the
within the GI tract, accelerating digestion. diet. Vitamin absorption is one of the main bene-
fits of an unusual feeding strategy known as cop-
rophagy. Rabbits, for example, eat their own feces
Vitamins and minerals participate as a way of regaining vitamins lost in indigestible
in catalysis material. While coprophagy increases the risk for
Vitamins are a group of chemically unrelated mol- parasites and disease, it provides important nutri-
ecules with diverse functions. For simplicity, they tional advantages to some animals, including a
are usually categorized based on their solubility. second opportunity to extract nutrients from the
The fat-soluble vitamins are A, D, E, and K; the vegetation they eat.
water-soluble vitamins include the B family and vi- Mineral nutrients are a collection of metallic
tamin C (Table 1). Solubility influences both the elements that participate in protein structure, in-
mode of uptake and the potential toxicity. An ani- cluding the structure of enzymatic proteins.
mal can consume copious amounts of water-soluble Aquatic animals obtain many of their essential nu-
vitamins with little ill effect because any excess is trients directly from the water, transporting them
readily excreted in the urine. Fat-soluble vitamins across the gills or skin. Most minerals, however,
Table 1 Vitamins.
Vitamin* Functions Deficiency symptoms

Fat-soluble vitamins
A, retinol Visual pigments, gene regulation Night blindness, epithelial damage
D, calciferol Calcium and phosphate absorption Ricketts
E, tocopherol Antioxidant Anemia
K, menadione Blood clotting Hemophilia
Water-soluble vitamins
B1, thiamin Coenzyme: thiamin pyrophosphate Beriberi
B2, riboflavin Coenzyme: FAD, FMN Various skin disorders
B3, niacin Coenzyme: NAD, NADP Pellagra
B5, pantothenic acid Coenzyme: Coenzyme: A Adrenal and reproductive dysfunction
B6, pyridoxine Coenzyme: pyridoxyl phosphate Peripheral neuritis
Biotin Coenzyme: biotin Hair loss, skin problems
Folic acid Coenzyme: tetrahydrofolate Megaloblastic anemia
B12, cobalamin Coenzyme: methylcobalamin Pernicious anemia
C, ascorbic acid Antioxidant, connective tissue growth Scurvy
*The vitamins are listed in the form in which they appear in the diet. Some are modified by the animal to produce vital molecules. For example retinol is
converted to retinal to produce the visual pigment.
562
Digestion
are absorbed from the diet. Calcium enters the in- are deficient in tryptophan. A herbivore can avoid
testinal cell through Ca2⫹ channels and is exported amino acid deficiencies by eating plants with dif-
into the blood by Ca2⫹ ATPases. The entire trans- ferent combinations of deficiencies.
port process is accelerated in the presence of the
protein calbindin. Ca2⫹ uptake is controlled by vi- Animals require linoleic and linolenic acid
tamin D, which regulates the synthesis of cal- in the diet
bindin. Phosphorus is imported into the intestinal
Animals use lipids for many purposes, including
cells as inorganic phosphate, transported using
energy production, cellular membranes (phos-
Na⫹ cotransporters. Iron is imported into the cell
pholipids), and cell signaling (prostaglandins,
in the ferrous form (Fe2⫹) by a nonspecific divalent
leukotrienes). They can produce de novo a broad
metal transporter, cotransported with H⫹. If the
suite of fatty acids that differ in chain length and
iron arrives in the diet incorporated into heme, it
desaturation. For instance, animals can produce
can be transported into the cell in that form. Cop-
palmitate from acetyl CoA using the enzyme fatty
per, zinc, and other minerals are also transported
acid synthase, then metabolize it into other forms
into intestinal cells by specific carriers. Once ab-
by elongases (which increase fatty acid chain
sorbed, these minerals are pumped out of the in-
length) and desaturases (which introduce double
testinal cell into the circulation. The target tissues
bonds). However, animals cannot produce suffi-
import the minerals from the blood as needed for
cient amounts of omega-3 (ω 3) and omega-6 (ω
their own biosynthetic processes.
6) fatty acids de novo. Instead, animals require ω
3 and ω 6 fatty acids from the diet, typically as
Inadequate supply of essential amino acids linoleic acid (18:2 ω 6) and ␣-linolenic acid (18:3
compromises growth ω 3). Humans can most readily meet ω 3 require-
ments by consuming fish. Fish also obtain their ω
Most of the 20 amino acids that animals use to
3 fatty acids in the diet, derived ultimately from
build proteins can be produced de novo but a sub-
the photosynthetic phytoplankton at the base of
set of amino acids must be obtained preformed in
the food chain. Plant seeds are the best dietary
the diet. Typically, there are eight essential amino
source of ω 6 fatty acids.
acids: isoleucine, leucine, lysine, methionine,
phenylalanine, threonine, tryptophan, and valine.
Some species have additional essential amino
Digestion of specific nutrients requires
acids. For example, histidine and arginine are es-
specific enzymes
sential amino acids for domestic dogs and sea tur- Digestive enzymes allow animals to convert the
tles. Although the amino acid taurine is not used complex macromolecules arriving in the diet to
in proteins, it is necessary for other processes, in- forms that can be absorbed by the animal and
cluding digestion, nervous function, and osmoreg- processed into usable forms. Although the nature
ulation. Taurine is an essential amino acid for of diets is very diverse, most animals rely on the
several animals, including each of the 30 species same suites of digestive enzymes.
of cats examined to date. In other words, don’t
• Lipases release fatty acids from triglyc-
feed dog food to your cat.
erides (triglyceride lipases) and phospho-
If a diet is persistently deficient in any of the
lipids (phospholipases).
essential amino acids, the animal may experience
developmental defects or slower growth. Since di- • Proteases (trypsin, chymotrypsin) break down
etary protein is the source of these amino acids, proteins into shorter polypeptides. Peptidases
protein quality—the profile of amino acids in di- are proteases that cleave successive amino
etary protein—is a critical nutritional concern. An- acids from the end of a polypeptide. Amino-
imal tissues provide a higher-quality dietary peptidases attack the first (N-terminal) peptide
protein than do plant tissues, because they pos- bond, whereas carboxypeptidases attack the
sess an amino acid profile that more closely re- last (C-terminal) peptide bond. A dipeptidase
sembles the needs of other animals. In contrast, breaks the peptide bond of a dipeptide, pro-
plant proteins are often deficient in one or more of ducing two amino acids.
the essential amino acids. For example, maize • Amylases such as dextrinase and gluco-
proteins are deficient in lysine and wheat proteins amylase break down polysaccharides into
563
Digestion
oligosaccharides. Disaccharidases such as The ants consume both the fungi and the plant
maltase, sucrase, and lactase break down material that has been partially degraded by the
specific disaccharides. fungi. Many marine animals form symbiotic rela-
• Nucleases break down DNA into nucleotides, tionships with photosynthetic organisms that
which are then broken into nucleosides and grow interspersed with their own cells as en-
nitrogenous bases for absorption. dosymbionts. Cyanelles are cyanobacteria living in
association with sponges. Dinoflagellates live as
Not every macromolecule ingested is sub- symbionts of corals. Zooanthellae are small uni-
jected to the digestive process. Many animals are cellular brown algae that live in cnidarians and
unable to produce the enzymes needed to assimi- some molluscs. Zoochlorellae are green alga that
late a dietary macromolecule. In some cases, the live in association with sponges, cnidarians, flat-
levels of enzymes can vary among individuals. For worms, and some molluscs. These symbionts use
example, many humans show an age-dependent photosynthesis to produce carbon skeletons that
reduction in production of lactase, the enzyme are taken up by the animal cells. Zooanthellae pro-
that breaks down the disaccharide lactose. When duce glycerol, and zoochlorellae produce mono-
lactose-intolerant people consume milk products, saccharides such as glucose and maltose. These
lactose can escape the upper intestine undigested, symbiotic cells gain protection from predators by
passing into the lower intestine. The methane- living in the confines of the animal tissues. Perhaps
producing gut flora can feast on this rich energy the strangest endosymbiotic relationship is seen in
source, much to the discomfort of the individual the animals that survive in the diverse sulfur-based
and displeasure of those in the immediate vicinity. food webs (see Box 1, Evolution and Diversity:
Chemolithotrophic Symbionts).
Symbiotic organisms contribute to animal Cellulose is an important nutrient for many an-
digestive physiology imals, although most species require the help of
Despite their impressive capacity to break down symbiotic organisms. As yet, no animal has been
food, many animals benefit from the assistance of shown to possess a gene for cellulase, the enzyme
symbiotic organisms. Three main types of sym- that is capable of breaking the ␤1-4 glycosidic bond
bionts participate in digestion. Enterosymbionts that distinguishes cellulose from digestible polysac-
live within the lumen of the GI tract itself. Since the charides, such as glycogen (␣1-4) and starch (␣1-6).
inside of the gut is contiguous with the external en- Most animals excrete cellulose undigested, forming
vironment, in principle these symbionts live outside the bulk of what is generally called dietary fiber.
the animal tissues. They are called enterosymbionts However, some herbivores can liberate the energy
to distinguish them from exosymbionts, which are in dietary cellulose with the assistance of symbiotic
symbionts that are actively cultivated outside the organisms that live within the gut. These animals
body. Endosymbionts are organisms that grow can absorb some of the glucose generated by cellu-
within the animal, typically embedded between lase activity, but most of the glucose is fermented by
host cells in a tissue or, less often, within a host cell. the bacteria to produce anaerobic end products, in-
Many species of animals are able to consume cluding the volatile fatty acids acetate, butyrate,
and digest unusual fuels because they possess spe- and propionate. The animals then absorb these fer-
cialized symbiotic bacterial populations, often mentation products for use in biosynthesis or en-
maintained in ceca (singular: cecum; blind sacs ergy metabolism. For example, termites digest
branching from the gut). Some species of birds eat wood fibers with the help of protists and fungi.
the wax found in beehives. Bacteria within the Many species possess fermentation chambers that
bird gut break down the wax into shorter carbon house cellulolytic bacteria.
units that can be absorbed by the animal. Marine In addition to benefiting from bacterial assis-
animals that feed on plankton can digest the chitin tance in liberating energy, animals can digest the
exoskeleton with the help of symbiotic bacteria. bacteria. Animals secrete the enzyme lysozyme
Whales hold chitinolytic bacteria in gastric ceca. into the gut to break down the bacterial cell wall.
Not all symbionts are bacteria. Fungi are im- The lysozyme of ruminants has adapted to func-
portant enterosymbionts in many types of plant- tion under the harsh conditions of the ruminant
eating insects. Leaf-cutter ants feed leaf fragments fermentation chambers, whereas the lysozyme
to exosymbiotic fungi, cultivated by the ant colony. from most mammals is nonfunctional under these
564
Chemolithotrophic Symbionts
Most food webs begin with the photosyn-

thetic organisms that use the energy of the sun to
grow. However, a few animals living far from sunlight sur-
vive in a food web that is based on another form of energy
input: chemical oxidation. The organisms that live at the
base of these alternative food webs are chemolithotrophic
bacteria. They produce energy by metabolizing inorganic
molecules such as ammonia and various sulfur com-
pounds. There are two main types of harsh environments
in which chemolithotrophic bacteria form the base of food
webs: sewage outfalls and deep-sea vents.
Sewage outfalls are rich in organic matter and pos-
sess high levels of toxic compounds. Anoxia-tolerant The rich biodiversity of a deep-sea vent.
chemolithotrophic bacteria thrive on the sulfides and
organic material of the sewage, producing hydrogen
sulfide (H2S), which is also toxic to many organisms. anterior of the worm is a bright red featherlike structure
Few animals can tolerate the oxygen limitations and called the plume. The red color comes from high con-
toxic sulfides of sewage outfalls. A few species of larval centrations of extracellular hemoglobin. The posterior
insects and molluscs thrive in sewage outfalls. They are of the worm is permanently housed in a tube. Left
able to tolerate the harsh conditions, and feed on the undisturbed, the pogonophoran extends the plume out
rich chemolithotrophic bacterial populations. into the water, where it is used for respiration.
Another environment that depends on the A pogonophoran is unusual in that, as an adult, it lacks
chemolithotroph-based food web is the deep-sea vent. a mouth and GI tract. While it may absorb some nutrients
The fissures in these undersea volcanoes release ex- across the epithelium, most of the nutrition comes as
tremely hot water, rich in sulfides. While the surround- a result of an unusual symbiotic arrangement with
ing waters are cold, deep-sea deserts, the vent waters chemolithotrophic bacteria. The bacteria are housed at
are undersea oases, with warm, oxygenated water very high concentrations in an internal sac called a tropho-
rich in biodiversity. In this environment, sunlight—not some. The worm ensures that the bacteria receive the
oxygen—is the limiting factor. Here, as in the sewage precursors for biosynthesis—CO2 and H2S—and then col-
outfall, chemolithotrophic bacteria are the nutritional lects the biosynthetic products: sugars and amino acids.
base of the ecosystem, providing food for many species Many anatomical and biochemical adaptations allow
of invertebrates. Some animals, like the vent mussel these animals to survive at the high sulfide concentra-
Bathymodiolus thermophilus, collect bacteria from the tions necessary for survival of their symbionts. The
water by filter feeding. Others, such as the polychaete worms reduce their H2S uptake by remaining in tubes,
Alvinella pompejana, graze on the thick bacterial mats. thereby limiting diffusion. Pogonophorans also have an
These invertebrates in turn are food for predatory inver- unusual hemoglobin that resists inhibition by H2S. In
tebrates and vertebrates, which live on the fringe of the most animal hemoglobins, H2S binding prevents O2
toxic zone created by the sulfides emanating from the binding. Pogonophoran hemoglobin is unusually large
vents. Some species of animals enter into symbiont rela- and is able to bind H2S without affecting its ability to
tionships with the chemolithotrophic bacteria. Several carry O2. Thus, the hemoglobin can provide the oxygen
species appear to cultivate chemolithotrophic bacteria for the worm and also deliver H2S to the symbionts. Fur-
on their body surfaces. A few species, such as the giant thermore, the worm hemoglobin binds H2S so well that
clam (Calyptogena magnifica), house chemolithotrophic it prevents H2S from escaping into the worm tissues,
bacteria within their bodies as endosymbionts. This rela- where it would inhibit cytochrome oxidase and poison
tionship is perhaps best understood in an unusual group the electron transport system. Interestingly, there is no
of worms called pogonophorans. evidence that the pogonophoran cytochrome oxidase is
More than 80 species of pogonophorans have been any less sensitive to H2S than is the enzyme from other
discovered around the world since they were first iden- animals. Thus, the pogonophoran must ensure that H2S
tified in the early 1900s. In 1979, a remarkable find was does not reach the oxidative tissues.
made by a submersible exploring the deep-sea vents in References
the Pacific Ocean. Giant pogonophorans (Riftia pachyp- q Gaill, F. 1993. Aspects of life development at deep sea hydrother-
tila), measuring over 1.5 m in length, were discovered at mal vents. FASEB Journal 7: 558–565.
several sites, living at the interface between toxic sul- q Hochacka, P. W., and G. N. Somero. 2002. Biochemical adaptation.
fide emissions and cold, oxygen-rich seawater. At the Oxford: Oxford University Press.
565
Digestion
conditions. Interestingly, one lineage of primates, tion gradient, the cell may use a transporter that
the colobine monkeys, possesses foregut fermen- works by facilitated diffusion. For example, GLUT
tation chambers that allow them to digest vegeta- proteins are carriers that mediate facilitated diffu-
tion. Their lysozyme structure more closely sion of glucose across the plasma membrane. In
resembles that of a cow than that of their nearest liver, GLUT-2 allows glucose out of the cell,
primate relatives. This example of convergent evo- whereas in muscle GLUT-1 allows glucose into the
lution illustrates the constraints on animal enzyme cell. In both cases, glucose moves from higher con-
function, and the opportunities that are afforded centration to lower concentration. Conversely, if
animals that can digest an underutilized resource. the transport process must proceed against a con-
centration gradient, the cell must use some form of
active transport. For example, amino acids are
Nutrients move across the plasma taken into cells by a carrier protein that is driven
membrane via carriers or vesicles by the Na⫹ gradient, a form of secondary active
After digestion, nutrients are transported from the transport.
gut and transferred to the extracellular fluids Some nutrients are transported across the
where they can be imported by storage and target plasma membrane via vesicles. Cells engulf regions
tissues. Molecules can be transported across the of the plasma membrane to form vesicles. If the
plasma membrane in many ways. Polar mole- nutrients are in solution, the process is pinocytosis.
cules, such as monosaccharides and amino acids, If the nutrients are particulate, the process is
cannot penetrate the plasma membrane at a sig- phagocytosis. Similarly, cells can expel nutrients
nificant rate, and require specific protein trans- via exocytosis. These pathways of endocytosis and
porters to move them across the plasma exocytosis are critical for the movement of complex
membrane. The nature of the transport process lipids. In many cases, lipids are associated in ways
for a specific molecule depends on its transmem- that make it difficult for a membrane carrier to
brane gradient. If there is a favorable concentra- transport one molecule at a time. For example,
lipoproteins—complexes of lipid
Glycogen Starch Disaccharides Cellulose and protein—are exported from
cells via exocytosis.
Salivary
amylase Carbohydrates are
Mouth
hydrolyzed in the lumen
Glycogen Oligosaccharides Starch
and transported by
multiple carriers
Stomach The main types of carbohydrate
consumed by animals are poly-
saccharides—primarily glyco-
Glycogen Oligosaccharides Starch gen, starch, cellulose, and chitin.
Disaccharides such as sucrose,
Pancreatic
lactose, and maltose are also im-
Small amylase portant in some species. Polysac-
intestine charides and disaccharides must
Disaccharides be broken down to monosaccha-
Disaccharidases
rides for absorption. The various
amylases and disaccharidases at
Monosaccharides work in the gut ultimately break
these larger carbohydrates down
to produce monosaccharides,
Cellulose primarily glucose, fructose, and
galactose, which are absorbed
Figure 3 Carbohydrate digestion Starch and glycogen are broken down in the
mouth and duodenum by the action of amylase. The resulting disaccharides are further by the enterocytes of the small
processed in the duodenum by the specific disaccharidases. intestine (Figure 3). Animals use
566
Digestion
a combination of active transport and Lumen

facilitated diffusion to carry monosac-
Microvilli
charides from the lumen into the in-
testinal absorptive cells Glucose Glucose
Fructose Glucose Na+ Glucose Na+ Na+
(enterocytes). Glucose and galactose
typically enter enterocytes by a Na⫹-
glucose cotransporter, whereas fruc-
tose, which occurs at relatively low
SGLT-1
concentrations in the cytoplasm, en- GLUT-5
ters the cell via facilitated diffusion.
Many years of study have led to a Enterocyte
better understanding of the mecha-

nisms by which the GI tract absorbs
glucose. Much of the glucose is trans-
GLUT-5 GLUT-2
ported into intestinal cells by Na⫹-
glucose cotransporter 1 (SGLT-1). A
second type of glucose transport
mechanism facilitates the diffusion of Fructose Glucose Fructose Glucose
glucose into cells during periods of

high glucose concentrations in the lu- Interstitial fluid
men (Figure 4). The carrier is GLUT-2,
a member of the large GLUT family of (a) Low-glucose level (b) High-glucose level
transporters that mediate facilitated Figure 4 Carbohydrate transport into intestinal cells (enterocyte)
diffusion of glucose in various tissues. (a) Under low-glucose conditions, most glucose import occurs
⫹
In brief, when a bolus of glucose first on the Na -dependent glucose transporter 1 (SGLT-1). Fructose enters the cell
appears in the intestine, transport is via facilitated diffusion on the glucose transporter 5 (GLUT-5). (b) When glucose
levels rise, GLUT-2 transporters, another type of facilitated diffusion carrier, are
mediated primarily by SGLT-1. This translocated to the microvilli, greatly increasing the capacity for glucose uptake.
transporter also acts as a glucose sen-
sor, triggering a signaling pathway
that leads to rapid synthesis of GLUT-2 and intracel- Proteins are broken down into amino acids
lular transport of the carrier to the microvilli. by proteases and peptidases
An animal can increase its capacity for glucose The pathway for digestion of proteins begins with
transport in several ways, as indicated by inter- extracellular hydrolysis by proteases secreted from
species comparisons. Studies from Jared Dia- the cells of the GI tract and glands associated with
mond’s lab at UCLA have shown how SGLT-1 levels the GI tract. Gastric pepsin breaks proteins into large
can determine the rate of glucose transport. Ani- polypeptides. These polypeptides move on to the
mals can increase glucose uptake by increasing the small intestine, where pancreatic proteases (trypsin,
total number of SGLT-1 transporters in the gut by chymotrypsin, and carboxypeptidase) break large
(1) producing more transporters per unit surface polypeptides into small polypeptides, and peptidases
area of the gut, (2) increasing the surface area of the of the intestinal lining liberate free amino acids,
gut per unit length, or (3) increasing the total length dipeptides, and tripeptides (Figure 5). Dipeptides
of intestine. Comparisons between species are com- and tripeptides can be transported into the epithelial
plicated by phylogenetic differences, as well as di- cell and broken down cytoplasmically. Free amino
etary differences. Consider the differences in the GI acids are carried into the epithelial cells on amino
tract of a domestic chicken, which grows quickly, acid–Na⫹ cotransporters, much like glucose trans-
and the guinea jungle fowl, a slow-growing wild rel- port. Those free amino acids that are not used by the
ative. These species have a similar surface area enterocytes are released into the blood for use by
(per centimeter of intestine) and capacity for glu- other tissues.
cose transport (per unit surface area), but the birds While most proteins are broken down within
differ in gut length. The longer gut of the chicken al- the lumen of the stomach and small intestine,
lows it to assimilate nutrients at greater rates and, some proteins are carried into cells intact. First,
as a result, grow faster. they are removed from the lumen by endocytosis
567
Digestion
Proteins Lumen
Fat globule
Mouth
Lipase
Proteins Monoacylglycerides, fatty acids
Stomach Pepsin Microvillus Emulsification by

of enterocyte bile salts and lecithin
Large polypeptides
Fat droplets
Large polypeptides
Trypsin,
chymotrypsin, Triglycerides,
carboxypeptidases monoacylglycerides,
Fatty acids, cholesterol
Small glycerol
intestine
Dipeptides
Smooth ER
Dipeptidases
Transport
vesicle
Amino acids
Golgi
apparatus
Figure 5 Protein digestion and transport In the Vesicles with
acidic stomach, pepsin breaks down large proteins into large chylomicrons
polypeptides. Proteases from the pancreas (trypsin,
chymotrysin, carboxypeptidase) hydrolyze these polypeptides
into smaller polypeptides and peptides. Intestinal
aminopeptidases, carboxypeptidases, and dipeptidases Interstitial Chylomicron
complete the proteolysis to produce amino acids. space
Blood vessel
across the apical membrane of the enterocyte.
They can then be carried through the cell and
exocytosed into the bloodstream. For example, the
antibodies that arrive in the milk consumed by an Chylomicrons
infant mammal are transported to the blood intact,
transferring immunoprotection from the mother. Lacteal
Lipids are transported in many forms Figure 6 Lipid transport across the gut Lipids reach
the small intestine in the form of large insoluble globules.
Digestion and import of lipids are complicated by High pH, bile salts, and phospholipids (lecithin) emulsify the
their hydrophobicity. The gastrointestinal tract fat into smaller fat droplets. These make their way to the
overcomes the solubility limitations by secreting microvilli where fatty acids and monoacylglycerides can cross
into the enterocyte. Inside the enterocyte, the lipids are taken
chemicals that act as lipid emulsifiers. Bile is a
up by the ER and repackaged into vesicles that are secreted
mixture of cholesterol, phospholipids, pigments, from the cell into the surrounding lymph glands (lacteals).
and salts produced in the liver and secreted into
the intestine. The phospholipids, mainly lecithin,
act in conjunction with the bile salts to organize the components simply diffuse off the micelle, cross-
the lipids into small droplets called micelles. Di- ing the enterocyte cell membrane.
etary cholesterol and fat-soluble vitamins form the The fate of each lipid depends on its physical
inner hydrophobic core of the micelle. Fatty acids properties (Figure 6). Short chain fatty acids and
and monoglycerides coat the hydrophobic core and glycerol are sufficiently polar that they can be
interact with the outer coating of bile salts and carried in the blood without assistance. After be-
lecithin. The micelles diffuse to the microvilli, where ing taken up by the enterocyte, these molecules
568
Digestion
cross the basal membrane and enter the blood, lipoprotein complex (VLDL). As the VLDL moves
where they travel to the liver via the hepatic por- through the circulation, the triglyceride is hy-
tal vein. Longer chain fatty acids, monoacylglyc- drolyzed by lipoprotein lipase and is progressively
erides, and cholesterol are relatively insoluble depleted. The fatty acids released in the capillary
and must enter the systemic circulation by a dif- beds can be stored or oxidized, depending on the
ferent route. Once in the cytoplasm, the fatty acids specific needs and abilities of the tissue. What was
and monoglycerides are used to resynthesize once a triglyceride-rich VLDL becomes an inter-
triglyceride. The enterocyte smooth endoplasmic mediate lipoprotein (IDL), then eventually a cho-
reticulum takes up the lipids and packages them lesterol-rich LDL. The LDL can bind specific
into vesicles. The vesicles pass through the Golgi receptors on various tissues to unload cholesterol
apparatus and travel via secretory vesicles to the that will be used for membrane synthesis or other
basal membrane. During their travels, the lipids biosynthetic pathways. At any point in this cycle,
are arranged into small droplets coated by pro- lipoprotein complexes can be returned to the liver
teins. The vesicles fuse with the cell membrane, for repackaging.
and lipid complexes called chylomicrons are re- The proteins in the lipoprotein are important
leased into the lymph that bathes the cell. The in controlling the lipoprotein composition and me-
chylomicrons are carried through the lymph into tabolism. For example, some proteins in the VLDL
the venous system. As they travel around the and LDL complexes regulate lipoprotein lipase.
bloodstream, they can be processed by peripheral The proteins found in high-density lipoproteins
tissues. In the endothelial cells of the capillary (HDL) are important building blocks for other
beds, lipoprotein lipase breaks triglyceride down lipoproteins. For example, HDL donates proteins
to fatty acids and glycerol, which are absorbed by to the chylomicrons that exit the intestinal lymph,
the tissues. The chylomicron remnant, partially and to VLDL circulating in the blood.
depleted of triglyceride, is extracted by the liver
and repackaged into a lipoprotein complex en-
riched in cholesterol.
Lipids are carried throughout the body in the
Finding and Consuming Food
form of lipoprotein complexes. The lipoprotein You are familiar with the basic dietary strategies
complexes, classified by their buoyant density, ex- seen in animals—carnivory, herbivory, and
hibit a range of sizes and compositions (Table 2). omnivory—each with its advantages and disad-
Each class of lipoproteins possesses a characteris- vantages (see Box 2, Applications: Animal Diets
tic profile of proteins that regulate lipid transport and Human Health). The physiology of diges-
and metabolism. Lipoproteins control the transfer tion is matched to the chemical and physical na-
of triglycerides, phospholipids, and cholesterol be- ture of the diet. To find the food that matches their
tween tissues (Figure 7). When carbohydrate and dietary needs, animals use neurosensory systems.
fat intake exceeds energy demand, the liver re- Some feeding strategies, such as filter feeding, de-
sponds by synthesizing lipid and sending it to other pend on random encounters. Most animals, how-
tissues for storage. The liver produces and releases ever, actively seek out and often pursue their food.
triglyceride in the form of a very low-density Once found, the food must be ingested to
Table 2 Lipoprotein composition.
Composition (% of total mass)
Lipoprotein Density (g/ml) Diameter (nm) Protein Phospholipid Triglyceride Cholesterol

Chylomicron 0.95 75–1200 2 8 86 4
VLDL 1.006 30–80 7 18 58 17
IDL 1.006–1.019 25–35 17 22 22 39
LDL 1.019–1.063 18–25 22 18 8 52
HDL 1.063–1.210 5–12 50 28 8 14
569
Digestion
1 Digestion produces chylomicrons

Intestine that are taken up by blood
and sent to peripheral tissues.
2 Chylomicron remnant is taken up

Liver by liver.
3 Liver repackages lipid to produce

8 VLDL.
3
4 Triglyceride is depleted from
Chylomicrons VLDL, leaving IDL.
2
7
5 IDL exchanges material with HDL.
HDL 6 1 6 Liver removes IDL from

precursors LDL VLDL circulation.
Chylomicron 7 Liver removes LDL from

remnant circulation.
Extrahepatic
8 HDL precursors are produced by
tissues
5 liver and intestine.
IDL 4
Blood vessel of 9 HDL is produced.

9 adipose tissue
or muscle
10 10 HDL provide proteins to IDL.
HDL
Figure 7 Chylomicrons and lipoprotein complexes
begin the process of digestion. In the following sec- proline or reduced glutathione, it waves its tenta-
tion, we survey some of the ways animals find di- cles and opens its mouth. Complex animals use
ets that suit their nutritional needs. gustatory receptors and olfactory receptors to lo-
cate food, determine its palatability, and control
the drive to feed (appetite). Herbivorous insects,
Animals sense food using chemical, such as aphids, use gustatory receptors to detect
electrical, and thermal cues chemicals that either stimulate feeding (phagos-
The nature of food varies widely among animals, timulants) or deter feeding (phagodeterrents). The
and the mechanisms animals use to detect food most important phagostimulants in insects are
are equally diverse. Animals link some form of re- sugars and amino acids. Plants can deter insects
ceptor to a signaling pathway that leads to a be- from feeding by releasing secondary metabolites
havioral response that alters feeding. that an insect recognizes as toxic. Gustatory sig-
Many animals possess means of detecting the nals are also important in vertebrates. Carrion
presence of specific chemicals in the environ- eaters detect volatile compounds that escape rot-
ment. The chemical may be a nutrient, and move- ting flesh. Sharks are able to detect from great dis-
ment toward the source of the nutrient increases tances chemicals that are normally found in
the likelihood that the animal will find more food. vertebrate blood, a sign of an injured animal. Al-
For example, the cestode (tapeworm) though the chemical nature of the gustatory stim-
Hymenolepis diminuta undergoes diurnal migra- ulants is diverse, each works in combination with
tions up and down the GI tract of its host, follow- a sensory receptor that triggers a signaling cas-
ing the nutrients released from a meal under cade ultimately affecting central control of feeding
digestion. In other cases, the chemical that is de- behavior.
tected may not itself be a nutrient but rather a sig- Many animals find prey by sensing the energy
nal that prey is nearby. For example, when a emitted or reflected from the animal in the form of
Hydra detects small organic molecules such as light, sound, heat, or electricity. A bird of prey,
570
Digestion
BOX 2 APPLICATIONS
Animal Diets and Human Health
Warnings of potential links between diet affected young people, with a median age of death of 29.
and disease, rampant in the modern media, are In 1996, British health officials announced a potential
nothing new. In medieval times, pregnant mothers were link between the BSE outbreak in cows and the human
discouraged from eating too much rabbit for fear that nvCJD. This led to an international boycott of British
the infant would have a harelip. Purple babies, now rec- beef, followed by a massive program to kill existing
ognized as victims of hypoxia, were attributed to exces- cows in Britain and a revamping of agricultural policies
sive consumption of eggplant. The ancient Hebraic around the world.
dietary laws of kashrut originated in a perception that The practice that was most likely responsible for the
some foods were healthier than others. The only mam- BSE outbreak was rendering of unmarketable beef tis-
mals that could be considered kosher were herbivores, sues into feed for other cows. Infectious prions concen-
and only those that eat their own cud (ruminants). Car- trate in the nervous tissue of animals, and when cows
nivory has many nutritional benefits, but it is a feeding consume the brain material of infected cows, they too
strategy that poses greater risks for passage of disease. contract the disease. Unlike many infectious agents,
By creating a taboo on eating carnivores and scav- prions are virtually indestructible and readily survive
engers, the Hebraic dietary practices reduced the risks the acidity of the stomach and other lines of defense.
for dietary consumption of infectious agents. Ironically, This agricultural practice was not appreciated as
it took modern agricultural practices to convert a low- risky for humans, because it was widely held that prions
risk herbivorous cow to a high-risk carnivore, with dire could not cross the species barrier. British sheep had
consequences for human health. been infected with scrapie for hundreds of years without
A series of related diseases triggering dementia and evidence of transfer to other species. Although there re-
death arise spontaneously in animals. The best known is mains no direct experimental evidence of a link between
bovine spongiform encephalitis (BSE), or as it is more BSE and nvCJD, the indirect evidence is overwhelming.
commonly known, mad cow disease. Others include More than 98% of the cases of nvCJD occurred in people
Creutzfeldt-Jakob disease (CJD), kuru, and scrapie. CJD that lived in Britain during the mid-1980s outbreak of
causes dementia and brain damage in older people. BSE. Prions may find it difficult to cross the species bar-
Kuru is a form of human dementia first recognized in rier; however, even a low-probability event is a risk
cannibalistic tribes in New Guinea. Scrapie affects when a high number of animals are infected. By 2003,
sheep, as well as cats, mink, and other mammals. Each more than 183,000 British cows had been identified as
of these diseases is caused by a type of protein called a carriers of BSE, and nvCJD had claimed the lives of
prion. In 1972, Stanley Prusiner began experiments on more than 130 people. At present, the risks of BSE and
hamsters to study the basis of these diseases. He nvCJD are very low because of regulations that reduce
showed that a hamster would develop dementia if it was the risk of transmission. At one point, beef by-products,
fed an extract of the brain of a diseased hamster. By 1982, dead and dying cows, and even roadkill made its way
he had established that the infectious agent was a prion. into animal feed. Now many countries have moved to
The prion is not a genetic mutation, as occurs in cancer, eliminate the use of rendered animals in animal feed.
but rather a structural variant of a normal protein. By rendering infected animal tissues into food for a her-
Strangely, the function of this gene and the normal pro- bivore, humans bypassed the natural defenses that are
tein remains to be established. The protein is harmless intrinsic to feeding strategies, enabling an infectious
when folded properly, but when it misfolds it becomes an particle to make it into our own food chain.
infectious particle that can induce disease. Animals ge-
netically engineered with the prion gene knocked out are
References
immune to prion diseases, such as BSE.
q Prusiner, S. B. 1997. Prion diseases and the BSE crisis. Science
In the mid-1980s, British cows began to show high
278: 245–251.
frequencies of BSE. Although this was of great concern
q Richt, J. A., P. Kasinathan, A. N. Hamir, J. Castilla, T. Sathiyasee-
to the farmers, it received little public attention at the
lan, F. Vargas, J. Sathiyaseelan, H. Wu, H. Matsushita, J. A.
time. In the early 1990s, researchers noted an increase Koster, S. Kato, I. Ishida, C. Soto, J. M. Robl, and K. Yoshimi. 2007.
in the cases of CJD-like disease in Britons. Unlike most Production of cattle lacking prion protein. Nature Biotechnology
cases of CJD, this new variant of CJD (nvCJD) primarily 25: 132–138.
571
Digestion
such as the golden eagle, uses its visual system to line the pores, choanocytes as well as amoebocytes,
spot a field mouse moving in a distant meadow. engulf the particles using phagocytosis. Digestion
Some insects can detect the infrared light emission occurs inside these cells in endocytic vacuoles.
emitted from warm bodies of potential prey Breakdown products are released into the cell, and
species. Light can also be produced by animals in undigested material is exocytosed out of the cell.
conjunction with foraging strategies. For example, Other metazoans possess something akin to a
predatory firefly species attract a prey firefly mouth—an entrance to an internal compartment
species by producing a light pattern that mimics that carries out digestion. The challenge for many
the mating signal of the prey. Deep-sea fish use animals is to get the food to the mouth. Cnidari-
bioluminescent appendages to lure small prey. ans, such as corals and Hydra, use tentacles to
There are many examples of predator-prey coevo- capture small prey, such as zooplankton. Once the
lution, in which prey properties such as cryptic prey is captured, the tentacle bends to the mouth
color are selected on the ability to confuse the vi- to release the food. The mouth gapes to permit
sual system of its predator. Animals that rely on food to enter the gastrovascular cavity. Movement
sound energy as a feeding strategy employ a vari- down the tentacles and into the mouth is aided by
ety of sound detection organs ranging from the a layer of mucus secreted by the epithelial cells.
mammalian ear to the fish lateral line. The weakly The wall of the gastrovascular cavity is composed
electric knifefish, which lives in the murky waters of gastrodermal cells, including nutritive cells and
of the Amazon, uses electromagnetic receptors to enzymatic gland cells (Figure 9). The enzymatic
detect the muscle activity of potential prey items. gland cells release digestive enzymes that break
down prey into a slurry of nutrients. The nutritive
cells phagocytose the smaller particles and
Simple animals digest food process them within the endocytotic food vacuole,
within phagocytic vesicles releasing nutrients that escape the gastrodermis
The simplest of animals, the sponges, obtain nutri- and cross the gelatinous mesoglea to supply the di-
ents primarily by phagocytosis, much like protists verse cells of the epidermis, including the stinging
such as the amoeba. Sponges subsist on particles of cells, or nematocytes. Once the meal is digested,
various sizes, ranging from organic debris much the animal expels the remaining material from the
smaller than bacteria (<1 µm) to as large as zoo- gastrovascular cavity and feeds again.
plankton (>50 µm). Water carrying food particles
passes through the sponge’s network of pores and
channels, flowing in currents generated by flagel-
Feeding structures are matched to diet
lated cells called choanocytes (Figure 8). As the wa- Most animals have some form of specialized
ter permeates the animal, it flows through mouthparts to assist in feeding. The mouth itself
biological filters that sort particles by size. Cells that may be lined with hard structures that grasp or cut
the food. Some form of extension
Flagellum Collar Choanocyte may also protrude from the mouth to
manipulate, disrupt, or suck. Al-
Water flow though we typically identify these
structures as jaws and tongues, they
are extraordinarily diverse in struc-
ture and developmental origins.
Some species of invertebrates,
such as free-living worms, have a
simple mouth that engulfs particles.
Vacuoles Amoebocyte
Most invertebrates have structures
associated with the mouth to aid in
feeding. For example, some en-
doparasitic worms, such as the liver
Figure 8 Sponge digestion Water is brought through channels by the fluke, have a mouth that acts as both
flagellated choanocytes. Food particles are phagocytosed by choanocytes and a siphon and an attachment organ.
amoebocytes. Although cestodes possess an ante-
572
Digestion
rior attachment organ (a combina-

tion of suckers and hooks), they have Tentacle
no mouth and, in fact, lack the entire Nutritive cell
digestive system. These worms ab- Vacuole Enzymatic cell
sorb nutrients over the outer body
surface, which is decorated with
spikelike extensions of the cells Mouth
called microvilli. In many ways, the
Gastrovascular
cestode anatomy resembles a gut cavity
turned inside out.
Many animals possess oral ap-
pendages that are functionally ho-
mologous to a tongue. Snails have a Gastrodermis Epidermis
muscular tongue called a radula. Mesoglea
Sharp protrusions from the radula

help the snail to grind, rasp, or cut
away chunks of food. Many nectar-
eating butterflies and moths possess Basal disk
a long tubelike tongue, or proboscis.
The insect uncoils its proboscis to
Figure 9 Cnidarian digestive system A cnidarian, such as Hydra, captures
reach deep into the throat of flowers food with its tentacles, and carries it to the mouth in mucous streams. The food
to get to the nectar. Flower anatomy passes through the open mouth into the gastrovascular cavity for digestion. Particles
often coevolves with butterfly are phagocytosed by nutritive cells lining the cavity, and digested in endocytic
tongues, ensuring that flowers are vacuoles. Nutrients can then diffuse from the nutritive cells of the gastrodermal layer
to the other cells of the gastrodermis (gland cells) and epidermis (sensory cells,
pollinated by specific species of but- nematocytes, epithelial cells).
terflies. When Darwin studied an
unusual orchid from Madagascar, he predicted The most important feeding structure of verte-
that a moth would be found that had a tongue long brates is the jaw. With the exception of the primi-
enough to feed on the flower. The Madagascar tive agnathans, which lack jaws, all vertebrate
hawk moth, discovered about 40 years later, has a mouths are built upon a common plan of paired
proboscis that is nearly 30 cm long. jaws. In 1983, Gans and Northcutt suggested that
Many species possess hardened mouthparts or the single most important variation to arise in the
oral appendages that help penetrate or mechani- evolution of vertebrates was a “new head.” They
cally disrupt the surface of food. The squid uses a meant that the transition from agnathans to
hard beak to bite off chunks of prey captured by its gnathostomes was accompanied by a change in
tentacles. Arthropods possess complex mouth seg- the developmental pattern of the structures that
ments that help the animals acquire food. A spider give rise to the vertebrate head. The rearrange-
uses its chelicerae to attack and mechanically dis- ment gave vertebrates the developmental flexibil-
integrate its prey (Figure 10a). Hymenopterans, ity to tolerate evolutionary changes in the
which include bees and wasps, are chewing in- structure of the head and associated features. This
sects. The paper wasp, for example, has hinged facilitated adaptive radiation by permitting the
mandibles that can crush the tough exoskeleton of evolution of feeding structures that allowed verte-
the insects on which it feeds. Insects of the order brates to succeed in novel niches. Consider, for ex-
Diptera use their mouthparts to suck fluids. For example, the variations in the organization of the
ample, fruit flies siphon plant juices from rotting vertebrate jaw. In most species, the upper jaw is
fruit, and mosquitoes extract blood from verte- immobile and integrated into the skull, whereas
brates. However, anyone who has been bitten by a the lower jaw is hinged and movable. In contrast,
large horsefly will be difficult to convince that these several species have evolved a more mobile upper
dipterans are not biting insects but sucking insects. jaw. Some snakes can separate or disarticulate the
The horsefly uses hardened mouthparts like scis- jawbones. The egg-eating snake can disarticulate
sors to slice through the skin. It can then use its its jaw, allowing it to open its mouth more than
labium to suck the fluids that seep from the wound. four times larger than its normal gape, enabling it
573
Digestion
(a) Spider chelicerae (b) Egg-eating snake
Figure 10 Feeding appendages (a) Spiders have appendages associated with the
mouth that aid in holding, manipulating, and disrupting prey. (b) Many snakes can separate the
upper and lower jaw, expanding the gape to enable the animal to swallow large food items, such
as a whole egg.
to swallow an intact egg (Figure 10b). It then uses Diversity in the beak structure of Galapagos
strong neck muscles to crush the egg against the finches was central to Darwin’s theories of evolu-
spine. Once the egg contents slide down the throat, tion and natural selection. Beak morphology is
the snake vomits the eggshells. very diverse among birds, reflecting the type of
food each bird gathers. The Argentine birds
shown in Figure 11 demonstrate morphological
Bird beaks are composed of keratinized specialization for eating fish, seeds, and insects.
tissue Very long beaks can be used to reach deep into
The beak of a bird is composed of bone covered by flowers; the beak of the sword-billed humming-
overlapping scales called rhamphotheca. The cells bird is longer than the body of the bird itself.
in this epidermal layer produce a cytoskeleton that Flamingos use the beak as a sieve to strain food
is rich in the intermediate filament keratin. When out of water. Some birds, such as the puffin, pos-
the surface cells die, the layer of keratin remains sess toothlike ridges on the margins of the beak to
as a protective surface over the beak. Living cells assist in tearing apart flesh.
within this layer constantly repair the keratin layer It is important to remember that bird beaks
as it is damaged, particularly at the margins of the serve purposes other than feeding, including vo-
beak, which are often abraded during feeding. calization, defense, grooming, and courting. The
(a) Amazonian Kingfisher (b) Ultramarine Grosbeak (c) Pearly-vented Tody Tyrant
Figure 11 Bird beak diversity in Argentine birds (a) Amazonian Kingfisher—fish

eater. (b) Ultramarine Grosbeak—seed eater. (c) Pearly-vented Tody Tyrant—insect eater.
(Courtesy of Paul Handford, University of Western Ontario)
574
Digestion
morphology of beak structure reflects the evolu- larger incisors and molars. The profile of teeth can
tionary compromises that allow the beak to per- also change over the lifetime of an animal. Most
form each of its roles. For example, the subtle mammals replace their teeth once during the life-
differences in the beak shape of Darwin’s finches time: early teeth are replaced by the permanent
can influence the nature of the birdsong, which adult teeth. However, monotremes lose their teeth
has important ramifications for territorial behav- altogether when the animal matures. Most mam-
ior and courtship. While the adaptive significance malian teeth grow to a predetermined size and
of bird beak morphology is clear, the developmen- then stop growing. In contrast, rodent teeth grow
tal and evolutionary determinants of beak shape continuously, allowing the tooth to maintain length
have only recently been studied (see Box 3, Genet- as it is worn down from continuous grinding.
ics and Genomics: Variation in Bird Beaks).
Mammals have bony teeth 2 C O NC E P T C H E CK

Many vertebrates possess oral structures that re- 1. How is energy partitioned in an animal’s diet?
semble and function as teeth, but mammalian 2. What are the major nutrients in a diet, and what
teeth are structurally unique. Each tooth is com- enzymes metabolize them into the forms in
posed of a crown, neck, and root (Figure 12). The which they are transported into the digestive
crown extends above the gum, or gingiva; the root epithelium?
is embedded in the gum; and the neck is a narrow 3. How do the physical properties of nutrients affect
region between the crown and the root. A cross- their uptake and transport within the body?
section through the tooth reveals the three layers
of a typical tooth: enamel, dentin, and pulp. The
outer enamel is composed of calcium phosphate Integrating Digestion
crystals integrated into the extracellular matrix. with Metabolism
Enamel is so hard that it can be brittle, cracking
when an animal bites a hard food. Animal teeth With an understanding of the nature of nutrients,
differ in the thickness of the enamel layer as well and the way animals acquire food, we turn our at-
as its molecular composition. Beneath the enamel tention now to the ways that an animal uses its di-
is an intermediate layer of dentin and an inner gestive system to extract the nutrients from food.
layer of pulp. The dentin is a porous support for We begin with a discussion of the types of cells and
the enamel. The pulp is more cellular, and rich in tissues that make up digestive systems, and then
blood vessels and nerves. These two inner layers consider how the animal controls gut function.
are living tissues that help build and maintain the Hormones and neurotransmitters are central to the
tooth. control of digestion, ultimately matching whole an-
Mammals possess four main types of teeth: in- imal metabolic needs to feeding behavior, nutrient
cisors, canines, premolars, and molars (Figure uptake, storage, and mobilization. These controls
12b). Incisors and canines are long, sharp teeth are particularly important when the animal experi-
that aid in piercing and tearing flesh. The broad, ences physiological challenges and transitions
flat molars aid in grinding. Premolars are interme- associated with life history patterns, including de-
diate in shape and have a role in both tearing and velopment and reproduction.
grinding. Like beak morphology, the shape of
mammalian teeth differs markedly in ways that re-
flect the nature of the diet. The molars of insectiv-
orous bats have sharp cusps and elongated crests
Digestive Systems
to help crack insect exoskeletons. In contrast, fruit The evolutionary history of the digestive systems
bats have molars with broader cusps and basins is marked by increasing anatomical and functional
for crushing plant tissue. There are also many dif- specialization. Ancient invertebrates possess sim-
ferences in the number of teeth and their growth ple digestive sacs that food enters and leaves
patterns. Rodents, for example, possess only front through a single opening to form a two-way gut.
incisors and molars; the canines and premolars The two-way gut, such as the blind gastrovascular
are lost in early development to make room for the sac of cnidarians, was an important evolutionary
575
Digestion

Variation in Bird Beaks
Many of Darwin’s earliest studies focused

on the variation in beak morphology between
finch populations in the Galapagos Islands. He noted that
a single species could have a different beak morphology
on each island. Furthermore, the morphological proper-
ties appeared to be related to the nature of the food and
the abundance of other species that might compete for
that food. Although he proposed that these structural
variations arise due to natural selection, he was at a loss
when it came to understanding how the variations arose.
When he returned home, he extended these studies by
comparing the morphology of different local pigeon
breeds. “Each successive modification, or most of them, fb
may have occurred at an extremely early period . . . from
causes of which we are wholly ignorant,” he wrote. With-
mb
out knowing the mechanisms, Darwin realized that beak
morphology was established early in embryonic develop- r1
ment. Recent studies have helped us understand the cel-
lular factors that determine beak morphology within and r2
between species. r3
Since a bird emerges from the egg with its beak
formed, we know that the factors that establish beak r4
morphology begin well before hatching. Within the first r5
one or two days after fertilization, the bird embryo has
r6
established body segments that will eventually give rise
to all of the structures of the head. Four sequential seg- r7
ments give rise to most of the structures that make up
the adult beak: forebrain, midbrain, rhombomere 1, and
rhombomere 2 (Figure A). Within the next two to three Figure A Chick development at day 1 (dorsal view).
days, cells from the developing brain migrate to a new
destination, and differentiate to form many of the struc-
tures of the developing head. These cells, called neural lular progeny of these neural crest cells interact with
crest cells, move from the forebrain and midbrain to form neighboring cells to form the embryonic beak.
the frontonasal region, which becomes the upper beak. The importance of these cells in generating beak
Neural crest cells from the midbrain and rhombomere 1 morphological variation was recently shown in a study
and 2 migrate to form the mandibular and maxillary re- that compared the development of the beak in the duck
gions, which become the lower beak (Figure B). The cel- and the quail. Ducks use the beak to catch fish and har-
step because it allows the animal to isolate food in the sac wall. Once the food is broken down into
a controlled environment and bombard it with small particles, the cells that form the lining of the
degradative enzymes until it reaches a form that gut phagocytose the particles. Digestion continues
can be assimilated. Platyhelminths also have a within cells in acidic vesicles that become basic
two-way gut; it can be a simple sac, as in small over the next 8 to 12 hours. The cells that line the
flatworms, or as seen in larger flatworms, a more sacs have subtly different secretory and absorptive
complex sac with multiple side branches known as functions, allowing these animals to create regions
diverticula (Figure 13). Digestion begins in the lu- with specialized digestive processes, which in-
men of the sac when proteases are secreted from crease the efficiency of digestion.
576
Digestion
It is the timing of gene expression that distinguishes

neural crest cell behavior between species. Both quails
and ducks express the same developmental genes dur-
ing craniofacial development, but the timing of expres-
sion is quite different between species. In the transplant
studies previously described, the donor neural crest
cells caused genes in the host-derived tissue to take on
the timing of the donor cells.
Variations in beak shape occur between species,
but as Darwin observed there is also individual varia-
tion in beak morphology among populations of a
species. Neural crest cell regulation may also be re-
sponsible for these intraspecific variations. For exam-
Figure B Head structures (lateral view). ple, individuals may have subtle differences in the
timing of expression of these genes that cause the nat-
ural range of phenotypes within a population. Recent
vest aquatic plants and weeds, whereas a quail uses its studies have shown that the timing of expression of an-
beak to peck and crack seeds. A duck beak is long, broad, other regulatory protein, Bmp4, is central to the phe-
and flat in comparison to the quail beak. These differ- notypic features of bird beaks. The dominant beak
ences in beak morphology and developmental rate are phenotype within the population can change rapidly
determined by the neural crest cells. When researchers in response to changing environmental conditions. A
transplanted neural crest cells from a duck embryo into 30-year study of two Darwin finch species shows contin-
a quail embryo, the animal developed into a quail with a uous oscillations in the most common beak morpholog-
ducklike beak. Similarly, when quail neural crest cells ical phenotype within a population. Bmp4 expression is
were transplanted into a duck embryo, the animal devel- at least part of the answer.
oped a quail-like beak. Interestingly, the donor cells in
each of these experiments also modified the morphology
References
of other facial structures, such as the egg tooth (a nail on
q Abzhanov, A., M. Protas, B. R. Grant, P. R. Grant, and C. J. Tabin.
the end of the beak that the hatchling bird uses to break
2004. Bmp4 and morphological variation of beaks in Darwin’s
open the egg), even though the egg tooth is not derived finches. Science 305: 1462–1465.
from neural crest cells. The neural crest cells produce q Grant, P. R., and B. R. Grant. 2002. Unpredictable evolution in a
proteins that help coordinate structural development by 30-year study of Darwin’s finches. Science 296: 707–711.
regulating the expression of genes in neighboring cells. q Schneider, R. A., and J. A. Helms. 2003. The cellular and molec-
Even though the precursors of the egg tooth came from ular origins of beak morphology. Science 299: 565–568.
the duck, they obeyed the orders issued by the trans- q Wu, P., T. X. Jiang, S. Suksaweang, R. B. Widelitz, and C. M.
planted quail neural crest cells and developed into a Chuong. 2004. Molecular shaping of the beak. Science 305:
structure that resembled a quail egg tooth. 1465–1466.
With the evolution of the one-way gut, animals follows; in most animals this is an acidic compart-
were better able to create specialized regions. The ment. The upper intestine, or small intestine, neu-
nature of these regions varies widely among ani- tralizes the acidic solution released from the
mals. Our description of gut regions is based on stomach, and carries out much of the digestion and
the terminology used for mammals (Figure 14). nutrient absorption. The upper intestine also re-
The mouth opens into the upper region of the GI ceives exocrine secretions from digestive glands:
tract called the pharynx or esophagus. This upper the liver and pancreas in most vertebrates and the
region typically participates in the mechanical hepatopancreas in most invertebrates. The lower
breakdown of food. The gastric region or stomach intestine, or large intestine, is responsible for
577
Digestion
Enamel
Incisors Canine Premolars Molars
Crown Dentin
Gum
Neck
Pulp
Root
Bone
Incisors Canine Premolars Molars

(a) Tooth structure (b) Tooth types (dog)
Figure 12 Mammalian tooth structure (a) The mammalian tooth is composed of

three layers. The outer enamel is dead tissue. The inner pulp and intermediate dentin are
composed of living cells, nourished by blood vessels, and innervated. The shape and size of the
types of teeth vary among species. (b) Molars and premolars are generally flattened teeth used
for grinding and chewing. Incisors and canines are used for piercing and tearing.
Superimposed on the evolutionary variation in

gut design are modifications that arise in response
to diet and life history. The mammalian diet
Mouth changes as offspring transition from maternal
Diverticula
Pharynx bloodborne nutrients across the placenta, to mam-
mary gland secretions, to solid food. The develop-
Gut lumen mental transitions in digestion are perhaps most
Gut
Pharynx extreme in the insects, where the diet of larvae is
often completely different from the adult diet. For
Gut lumen Mouth
example, most larval lepidopterans (caterpillars)
Gut lumen eat plant leafy material whereas many adults (but-
terflies and moths) eat nectar. Many larval dipter-
ans are fully aquatic, feeding on the bacteria that
live on the surface of stagnant water (mosquitoes)
or in the sediment (chironomids). The adults are
(a) Simple gut (b) Complex gut fully terrestrial, feeding on a wide range of plant
Figure 13 Flatworm GI tracts Like the simple and animal material. Remarkably, male and female
animals, such as sponges and cnidarians, the flatworms have adult mosquitoes consume different diets; females
two-way guts. (a) Most flatworms, such as Macrostomum, feed on the blood of vertebrates, from tree frogs to
possess a simple gut with a single sac. (b) In some larger mammals, whereas males drink plant nectar.
flatworms, such as Dugesia, the gut can have three or more
side branches with lateral diverticula.
Gut complexity is linked to the appearance
reclamation of water and salts. Finally, indi-
of the coelom
gestible material is released through the anus. The evolutionary and developmental origins of a
Most species have side chambers that branch off one-way gut are intimately linked to the appear-
from the main GI tract. A single chamber is called ance of the coelom, an internal cavity that arises
a cecum; multiple chambers are ceca. Muscular in a developing embryo. The space between the GI
valves (sphincters) regulate passage through the tract and the body wall, known as the peritoneal
different compartments. cavity, is one part of the coelom of a vertebrate.
578
Digestion
The simplest of animals—cnidar- Esophagus

ians and sponges—lack a coelom; Large intestine
their guts are built from two germ cell
layers that form solid tissues without Colon Rectum
internal compartments. More ad-
Esophageal
vanced animals possess three layers sphincter
of germ cells—endoderm, meso-
derm, and ectoderm. Nemerteans
and flatworms remain relatively sim- Stomach
ple because the three layers of germ Gastric

sphincter Anus
cells stick together during develop- Cecum
ment and no coelom forms (Figure
15). In the development of rotifers
and nematodes, a gap appears be-
Duodenum Jejunum Ileum
tween the endoderm and mesoderm.
The gap persists in the adult, giving Small intestine
rise to a type of coelom called a Figure 14 Features of a typical gastrointestinal tract Although the
pseudocoelom. All other major ani- exact organization of the GI tract differs among species, most complex animals have
mal taxa possess a true coelom be- regions that are functionally analogous to the typical mammal, such as the horse
tween layers of the mesoderm. The shown here.
appearance of the coelom was im-
portant in the evolution of digestive physiology be- the small intestine. It also forms buds that develop
cause it allows greater specialization of internal into the pancreas and liver. The midgut endoderm
organs. develops into the posterior part of the duodenum,
The coelom arises early in embryonic develop- the remainder of the small intestine (jejunum and
ment. During early gastrulation, a region of the ileum), and much of the large intestine, including
blastula (a hollow ball of cells) migrates inward, cecum, appendix, and part of the colon. The
causing first a depression and then a pit called the hindgut endoderm develops into the remainder of
blastopore. In animals called protostomes (“first the colon and the rectum. The properties of these
mouth”) the blastopore becomes the mouth, and regions continue to change through development
the anus forms at a distant site. Arthropods, an- and after hatching, matching physiological capac-
nelids, and molluscs are all protostomes. In ities to the diet.
deuterostomes (“second mouth”), the anus arises
from the blastopore, and the mouth is formed sec-
ond. Deuterostomes include chordates, hemichor-
The digestive systems of complex animals
dates, and echinoderms. The coelom originates by
maximize surface area
two different routes in protostomes and deutero- In the simplest animals with a two-way gut, macro-
stomes (Figure 16). The coelom of protostomes molecule breakdown occurs primarily inside vesi-
forms when the mesoderm splits (schizocoelous), cles within the cells. Proteins, complex sugars, and
whereas the deuterostome coelom forms from lay- lipids are hydrolyzed, and the end products—
ers of mesoderm that pinch off from the gut (en- amino acids, monosaccharides, and fatty acids—
terocoelous). However, the coelom of chordates are released directly into the cytoplasm. More
(which are deuterostomes) forms by the schizo- complex animals carry out these reactions within
coelous process that is typical of protostomes. the lumen of the digestive tract. The end products
The early embryonic gut is derived from endo- of this extracellular digestion must then be taken
derm, and divided into three regions: foregut, into the cells lining the gut. Since this uptake step
midgut, and hindgut. In the chicken, the gut devel- requires many different digestive enzymes and nu-
ops into these regions within four days postfertil- trient transporters, the process can be slow. Com-
ization (Figure 17). These regions differentiate to plex animals increase the efficiency of transport by
form the embryonic gastrointestinal tract. The building guts with very large surface areas. This
foregut endoderm gives rise to the esophagus, can be achieved two general ways: increasing gut
stomach, and anterior region of the duodenum of length and increasing surface undulations.
579
Digestion
Mesoderm Protostome Deuterostome
Ectoderm
Endoderm Blastocoel Blastocoel
Blastula Blastula
Lumen of gut
(a) Flatworm (acoelomate)
Blastopore Blastopore
Mesoderm
Ectoderm
Endoderm Anus Mouth
Mouth Anus
Schizocoelous Enterocoelous
Coelom
coelom coelom
Lumen of gut formation formation
(Chordates)
(b) Nematode (pseudocoelomate)
Mesoderm Mesoderm
Ectoderm Mesoderm Blastocoel Blastocoel
Endoderm Gut lumen Gut lumen
Coelom
Coelom Coelom
Lumen of gut
Figure 16 Coelom formation in protostomes and
(c) Annelid (coelomate) deuterostomes The main distinction between
protostomes and deuterostomes is the fate of the
Figure 15 Acoelomates, pseudocoelomates, blastopore. In protostomes it forms the mouth, whereas
and coelomates With the exception of sponges and in deuterostomes it forms the anus. Later in development,
cnidarians, animals are distinguished on the basis of the the coelom of protostomes forms when a layer of
nature of the coelom. (a) Acoelomates lack a coelom. (b) The mesoderm separates to form an internal compartment
coelom appears between endoderm and mesoderm in (a schizocoelous coelom). In deuterostomes, the
pseudocoelomates, and (c) between two mesodermal layers coelom forms from outpouches of the embryonic gut
in coelomates. (an enterocoelous coelom). However, the coelom of
chordates forms by the schizocoelous route.
The overall length of the GI tract can be a frac- so functional length is usually much shorter than
tion of the length of the whole animal if it is a maximal length. Nonetheless, the relative length
simple, straight tube, as seen in agnathans. Alter- of the gut reflects the digestibility of the diet. Ani-
nately, the GI tract can be wrapped around itself, mals with diets that are difficult to digest often
allowing it to be many times longer than the ani- have longer guts to increase the efficiency of diges-
mal. Some species increase the passage time using tion. For example, carnivores tend to have shorter
internal channels. For example, the straight gut of guts than herbivores because the food is more eas-
a shark possesses an internal membranous net- ily digested. The importance of gut dimensions is
work, called the spiral valve, that increases the best shown by comparing closely related species
functional length of the gut. While most measure- with differences in diet. The cecum of a grouse,
ments of gut length are performed on dead ani- which browses on vegetation, is almost twice the
mals, in the living animal visceral smooth muscle length of the cecum of a similarly sized partridge,
compresses the GI tract into a much shorter tube, which eats seeds.
580
Digestion
4 days 10 days 20 days The surface of the gut has a complex topogra-
phy that serves to maximize surface area. We see
this at the organ level, where the gut has deep cir-
cular folds that run around the circumference of
the intestine (Figure 18). It is also evident at the
tissue level, where the surface of the gut tissue is
arranged into fingerlike projections called villi.
The maximization of surface area is even seen at
the cellular level. Enterocytes possess microscopic
protrusions, supported by the actin cytoskeleton,
called microvilli. The microvilli cause the surface
Foregut of the intestinal mucosa to appear fuzzy, which is
why the intestinal epithelium is often called the
brush border. As a result of the circular folds, the
villi, and the microvilli, the surface area of the gut
is several hundred times greater than it would be
if it were composed of flat sheets of smooth cells.
Midgut
Specialized compartments increase

the efficiency of digestion
Hindgut
The efficiency of digestion depends on the ability
of the animal to create regions of functional spe-
cialization. Even a simple GI tract can have such
Figure 17 Gut development The chicken embryo specializations. Ctenophores (comb jellies) have a
develops into a chick within 20 days. By day 4, the digestive simple digestive sac that is elongated and flat-
system has developed enough to recognize major structures. tened. Food enters the first region of the pharynx,
The embryonic gut is divided into three sections: foregut, which is acidic, then continues along the pharynx
midgut, and hindgut.
through two basic regions before looping back to
exit through the opening that serves as both
mouth and anus. With the exception of a small
area of confluence, the inward and outward flows
Villi Microvilli
Brush
border
Enterocytes
(a) (b) (c)
Figure 18 Intestinal topography (a) The inner surface of the intestine is a series of
folds or ridges that run circularly around the intestine. (b) The surface of the tissue is arranged
into fields of fingerlike projections called villi. (c) Each of the absorptive cells within the villi
possesses projections called microvilli. This structural topography—circular folds, villi, and
microvilli—increases the surface area that is available for absorption.
581
Digestion
are well separated. These specialized sequential Mouth Anus

compartments allow the two-way gut to function
much like a one-way gut, allowing the ctenophore
Agnathan (lamprey)
to process multiple prey items in different regions
at distinct stages of digestion. Spiral valve
Regional specializations are more developed
in animals with a one-way gut. In many cases,
muscular valves called sphincters control the pas- Chondrichthian (shark)
sage of food from one compartment to the next.
Regional properties are created and maintained Pyloric ceca
by specific types of cells. Some cells alter the pH of
the fluids in the lumen by secreting acids or bases.
Actinopterygian (gar)
Since most of the macromolecules that appear in
food are stable at a pH near neutrality, extremes in
pH can enhance their breakdown. Mucus secre-
tions help protect cells and lubricate the surface.
Secretory cells release the digestive enzymes— Amphibian (salamander)
proteases, amylases, lipases, nucleases—that ac-
celerate chemical breakdown of macromolecules.
The absorptive cells in each region also possess
specialized transport capacities.
The general plan of the GI tract is similar
among vertebrates, but taxa differ in the types of Reptile (turtle)
compartments (Figure 19). Many species possess Proventriculus Ceca

extra chambers or modified regions along the GI
tract. Birds and bony fish possess ceca that branch
from the GI tract and contain bacteria that aid in
digestion. The upper GI tract of birds is also more Crop
complex than that of other vertebrates. The crop is Avian (chicken)
an outpouching of the esophagus that enables a
bird to store partially digested food.
Many species of mammals possess elaborate
modifications of the typical gastrointestinal tract
that improve the digestibility of plant material. Ru-
minants (cows, deer, giraffe, goats, and sheep)
possess a modified digastric stomach that allows Mammal (pig)
vegetation to be more effectively digested. Rumi-
Figure 19 Vertebrate gut morphology The
nants possess a stomach composed of four cham- vertebrate gut differs widely in complexity and length among
bers divided into two functional groups (Fig- species. Each group of vertebrates is drawn to the same body
ure 20). Vegetation passes through the esophagus length to emphasize the differences in length.
into the first pair of compartments: the rumen and
reticulum. These interconnected regions house
the fermentative bacteria that digest cellulose and
produce volatile fatty acids and gases, largely car- Like ruminants, the closely related tylopods
bon dioxide and methane. The animal can regur- (camels, llamas) possess a digastric stomach, al-
gitate food from the rumen back to the mouth, though these animals lack the omasum. Many of
where it can chew the partially degraded material the other groups of mammalian grazers possess
again. When the food returns to the esophagus, it fermentation chambers. However, unlike the ru-
enters the second division, comprising the oma- minants and tylopods, their fermentation cham-
sum and abomasum. The abomasum serves as the bers branch from the hindgut and are much less
glandular stomach, secreting digestive enzymes. efficient.
582
Digestion
Salivary glands secrete water Small intestine
and digestive enzymes Duodenum Jejunum Ileum

Digestion depends on secretions
from multicellular exocrine glands Large
working in conjunction with single intestine
Rumen
secretory cells scattered throughout
the GI tract. Many species have
Esophagus
glands located near the mouth, typ- Anus
ically called salivary glands. Sali- Esophageal
sphincter Cecum
vary gland secretions include
enzymes that initiate the chemical Reticulum Pyloric
breakdown of food. In terrestrial sphincter
animals, saliva provides fluid to Omasum Abomasum

help lubricate and dissolve food, Figure 20 Ruminants Many mammals possess chambers derived from the GI
which allows solubilized nutrients tract that house bacteria that can ferment cellulose. Ruminants, including the cow
to bind to gustatory receptors. The shown here, possess four chambers.
saliva may also have antimicrobial
properties to help cleanse the mouth. The salivary
glands are really a collection of different glands.
Intrinsic salivary glands, or buccal glands, are dis-
tributed throughout the oral cavity. A typical mam-
mal has multiple pairs of extrinsic salivary glands:
a dog has parotid glands just anterior to the ear, or- Parotid
bital glands near the eye, mandibular glands near Orbital gland gland
the lower jaw, and sublingual glands beneath the
Tongue
tongue (Figure 21). Each of these glands possesses
at least two types of cells: mucus-secreting cells
and serous cells, which secrete the degradative en-
zymes.
Because of the high water content of saliva, se-
cretions from these glands impinge on water bal-
ance. An average human, for example, might Sublingual
gland
secrete more than 1 liter of water in saliva every Mandibular
gland
day. The rate of secretion from salivary glands
is regulated by the parasympathetic system in Figure 21 Salivary glands Like most mammals, the
response to pressure-sensitive receptors and dog has multiple sets of salivary glands that secrete liquid
and enzymes into the oral cavity.
chemoreceptors in the mouth. When food is taken
into the mouth, the mechanical stimulation trig-
gers pressure-sensitive receptors that send signals mans under stressful conditions, such as public
to the region of the brain stem that controls serous speaking.
gland secretions. Similarly, when chemoreceptors
detect specific chemicals in the food, a signal is
sent to the brain. As Pavlov discovered long ago,
The stomach secretes acid and mucus
animals can also salivate in response to sights and The surface of the stomach is an epithelium com-
sounds that are associated with food. Salivary posed of columnar epithelial cells (Figure 22). The
gland secretions can also be inhibited. Dehydrated cells are linked together via tight junctions that
animals use the sympathetic nervous system to re- prevent the leakage of lumen fluids into the tissue.
strict blood flow to the salivary glands, preventing Dotted over the surface of the stomach are deep
secretion. The same sympathetic response in- gastric pits composed of four cell types. Mucous
duces dry-mouth, a response often induced in hu- neck cells, found near the pit opening, secrete an
583
Digestion
acid type of mucus. Parietal cells in the middle of The low pH of the stomach is optimal for many
the pit secrete acid, mainly HCl. Chief cells near of the gastric enzymes, but it is also harsh enough
the base of the pit secrete digestive enzymes, pri- to kill most bacteria and parasites that enter in the
marily the protease pepsin. Finally, diet. However, Helicobacter pylori, the bacterium
enteroendocrine cells secrete several hormones associated with peptic ulcers, survives the low pH
into the blood in response to stomach contents. of the stomach by proliferating deep within the
For example, the hormone gastrin is released from gastric pits, where the pH is higher.
enteroendocrine cells into the blood supply of the Not all vertebrates have acidic stomachs. The
stomach, inducing secretion by other gastric cells. platypus, for example, does not acidify the stom-
We discuss the function of other hormones reach for reasons that are not yet clear. Another in-
leased by enteroendocrine cells later in this chap- teresting exception is the gastric brooding frog,
ter when we consider the control of gut motility. Rheobatrachus silus. It swallows fertilized eggs,
which mature in the stomach. The developing
young secrete prostaglandin E2 to inhibit acid se-
cretion. Upon hatching, the tiny frogs hop up the
esophagus and escape through the mouth.
Most nutrients are absorbed

in the intestines
The intestines are also rich in histological diver-
sity. A cross-section through the intestine reveals
the four major layers: mucosa, submucosa, circu-
lar smooth muscle, and longitudinal smooth mus-
Gastric pits cle. The mucosal surface is composed of many
cell types, each with distinct roles (Figure 23).
Mucous
neck cells
Enteroctye Enteroendocrine
Mucosa Parietal cells cells
Arteriole
Chief cells
Venule
Enteroendocrine T cells
cells Lacteal Goblet cells
Lymphatic
vessel
Blood vessels
Submucosa
Oblique Epithelial cells

muscle
Crypt of
Lieberkühn
Circular
muscle Paneth cells
Smooth
muscle
Longitudinal
muscle
Figure 23 Intestinal cell structure The villi are
composed of multiple cell types. Enterocytes are absorptive
cells that possess microvilli (not shown). Goblet cells secrete
mucus. Interepithelial lymphocytes are T cells that help in
Figure 22 Stomach cell structure The smooth immunodefense. Enteroendocrine cells secrete the
surface of the stomach has numerous cavities called gastric hormones that control GI tract motility and other aspects of
pits. These pits are composed of four main cell types that digestion. At the base of the villi are the crypts of Lieberkühn.
control the secretions of mucus, acid, enzymes, and The epithelial cells within the crypts secrete the intestinal
hormones. They are also the location where Helicobacter juice. The Paneth cells at the base of the crypt secrete an
pylori accumulate. enzyme that breaks down bacterial cell walls.
584
Digestion
Much of the mucosa is composed of enterocytes, uptake of lipids. Bile salts help emulsify fats in the
the absorptive cells with abundant microvilli. duodenum. They are amphipathic molecules with
Mucus-secreting goblet cells are scattered among nonpolar regions that bind to fats, and polar re-
the enterocytes. Enteroendocrine cells secrete gions that interact with water. A coating of bile
the hormones that help regulate digestion and salts helps stabilize the small fat droplets. Liver
nutrient assimilation. At the base of each villus is cells (hepatocytes) produce bile and secrete it into
a region called the crypt of Lieberkühn. In addi- small ducts that run adjacent to the hepatocytes.
tion to enterocytes, each crypt possesses Paneth These ducts fuse and empty into the common he-
cells, which secrete antimicrobial molecules into patic duct, which joins the cystic duct from the
the lumen. Adjacent to the Paneth cells are stem gallbladder to form the bile duct. The gallbladder
cells that divide and differentiate to replenish the stores bile until it is needed, then empties into the
other cell types of the intestine. The intestinal duodenum via the bile duct.
submucosa, lying beneath the surface mucosa, is Part of the pancreas is an exocrine gland that
a layer of connective tissue through which blood secretes digestive enzymes into the duodenum.
and lymphatic vessels pass, as well as the nerves Proteases are produced in the form of inactive
that control the GI tract. It also contains the duo- proenzymes, which prevent the enzyme from di-
denal glands, whose cells secrete basic mucus gesting the secretory cell itself. For example,
through ducts that penetrate the epithelium to trypsin is secreted as the inactive precursor
help neutralize the acid arriving from the stom- trypsinogen (Figure 25). When it enters the intes-
ach. The inner and outer smooth muscle controls tinal lumen, the brush border enzyme enteroki-
the movement of food along the GI tract. nase converts it to the active protease. Trypsin in
The small intestine also receives secretions of turn activates two other pancreatic enzymes, car-
bile from the gallbladder (Figure 24). Bile is a com- boxypeptidase and chymotrypsin. Secreting these
plex solution of digestive chemicals and liver
waste products. Only two types of molecules in bile
have a role in digestion: phospholipids and bile
salts. Phospholipids, such as lecithin, aid in the
Pancreatic duct
Procarboxypeptidase
Chymotrypsinogen
Trypsinogen
Liver
Common Membrane-bound
hepatic duct enterokinase
Bile duct sphincter

Gallbladder
Bile duct
Trypsin
Duodenum Chymotrypsin
Carboxypeptidase
Small intestine
Figure 24 Bile production, storage, and
secretion Bile is produced by hepatocytes and released Figure 25 Trypsinogen cascade The pancreas
into small adjacent ducts. These ducts collect bile and empty secretes three important proteases, all in inactive forms.
into the common hepatic duct. When the bile duct sphincter Trypsinogen is activated by proteolytic cleavage by
is closed, bile is routed through the cystic duct to the enterokinase. The activated trypsin then activates
gallbladder for storage. When the sphincter opens, bile is chymotrypsinogen and procarboxypeptidase by proteolytic
released from the gallbladder into the duodenum. cleavage.
585
Digestion
enzymes as inactive proenzymes reduces the risk expose the feeder to predation. Feeding strategies
that the pancreas will digest itself. The pancreas evolve to provide an animal with the greatest
also releases enzymes that break down glycogen chance of obtaining nutrients while minimizing
(amylase), triglycerides (lipase), and nucleic acids the risk to its survival. In terms of digestive physi-
(nucleases). The hormones involved in control of ology, the most significant variables are the nature
GI tract secretions are summarized in Table 3. of the nutrients, the quantity of food consumed in
a given period, and how often the food is con-
sumed. Consider a day in the life of a filter feeder.
Filter-feeding animals, such as barnacles, are sur-
Regulating Feeding and Digestion rounded by their food and feeding is a continuous
Feeding is a necessary evil in the life of most ani- process, interrupted only when a potential preda-
mals; while they must feed to survive, the process tor is sensed in the proximity. Conversely, some
of feeding requires considerable energy and may deep-sea fish may encounter food once a year.
Table 3 Hormonal control of digestion.
Regulatory factor Source Stimulates Inhibits

Acetylcholine Cholinergic nerves Gastric secretion
Cholecystokinin (CCK) Duodenum Expulsion of bile from
gallbladder, pancreatic
enzyme secretion, appetite
Enkephalin Duodenum Gastric acid secretion Pancreatic enzyme
secretion
Epinephrine Intestinal nerves Gastric acid secretion
Galanin Intestinal nerves Gastric acid secretion
Gastric inhibitory peptide (GIP) Duodenum Gastric secretion
Gastrin Stomach and Gastric acid production
duodenum and secretion
Gastrin-releasing peptide Brain Gastrin secretion
Ghrelin Stomach Appetite
Glucagon Duodenum Pancreatic and intestinal
secretion
Glucagon-like peptide-1 (GLP-1) Jejunum, lower Appetite
intestine
Motilin Jejunum Gastric acid secretion
Pancreatic polypeptide (PP) Pancreas Appetite, gastric secretion
Peptide YY (PYY) Jejunum, lower Appetite, gastric secretion
intestine
Pituitary adenylate cyclase Pituitary Gastric secretion
activating polypeptide (PACAP)
Secretin Duodenum Water and bicarbonate
secretion, bile production
Somatostatin Duodenum Gastric acid secretion,
pancreatic secretion, blood
flow (vasoconstriction)
Vasoactive intestinal peptide (VIP) Duodenum Intestinal bloodflow
(vasodilation), pancreatic
and gastric secretion,
intestinal salt secretion
586
Digestion
Many animals feed during a narrow window in which integrates the information and controls
their lifetime, and display a life history strategy feeding behavior. Three main hormones control
that is choreographed around this meal. appetite: leptin, ghrelin, and peptide YY. These
Animals face the daunting challenge of match- hormones exert effects on multiple target tissues,
ing their dietary intake to their short-term meta- but in terms of appetite control, their main effects
bolic demands, while ensuring an opportunity for arise through receptors in the hypothalamus. Re-
long-term development and reproduction. For call that this region of the brain possesses an in-
many complex animals, the desire to feed (ap- complete blood-brain barrier, and thus is able to
petite) is regulated by the central nervous system sense the profiles of blood borne metabolites and
(CNS). Input to the CNS comes from environmen- small hormones. Leptin is too large to passively
tal factors such as photoperiod, as well as intrin- move across the endothelium of the capillaries
sic signals that reflect the nutrient levels or that feed the hypothalamus; it is likely transferred
metabolic status of the animal. Typically, animals from the blood across the blood-brain barrier
feed when their energy needs exceed the meta- through an active transport mechanism.
bolic potential of circulating fuels, allowing the an- Leptin is an appetite-suppressing hormone
imal to avoid drawing on nutrient stores. produced in white adipose tissue. It acts as an
Feeding and digestion are at the crossroads be- “adipostat,” ensuring that adipose lipid content is
tween ecology and mechanistic physiology. Regula- stable. When adipose triglyceride levels rise, lep-
tory physiologists focus on the pathways animals tin is secreted and appetite is suppressed. Restora-
use to absorb specific nutrients and metabolize tion of adipose lipid stores inhibits leptin secretion
them in intracellular pathways. Although each of and appetite increases. Though leptin exerts an
the steps—the transport and the enzymatic conver- important control over appetite, its effects are me-
sion—can be studied in a quantitative manner us- diated over the long term. Over the short term,
ing kinetic analyses, it is difficult to extrapolate ghrelin and peptide YY appear to be more impor-
from these studies to make predictions about the tant in controlling the desire to eat between meals.
whole system. Conversely, ecological physiologists Ghrelin is an appetite-stimulating hormone, re-
are often more concerned with how animals leased from gastric cells when the stomach is
match nutrient needs to feeding efforts, a concept empty. Peptide YY is an appetite-reducing hor-
called ecological stoichiometry. Researchers in mone, released from enteroendocrine cells when
these two fields—regulatory physiology and eco- the colon is full.
logical stoichiometry—were initially separated These hormones exert their effects on the ar-
because of the diversity of nutrients and the com- cuate nucleus of the hypothalamus. Recall that a
plexities of nutrient breakdown, absorption, and nucleus is a region where the cell bodies of the
assimilation. The two alternate experimental neurons are collected. The neurons of the arcuate
frameworks are brought together in gut reactor nucleus send their axons to other neurons in the
theory, which allows researchers to use mathe- region, as well as higher centers of the brain that
matical relationships to make qualitative and regulate behavior. Some neurons release appetite-
quantitative predictions about digestive physiol- stimulating factors, mainly neuropeptide Y (NPY),
ogy function and evolution (see Box 4, Mathemat- as well as agouti-related peptide and gamma-
ical Underpinnings: Gut Reactor Theory). aminobutyric acid (GABA). Other neurons release
the appetite-suppressing factor proopiomelanocortin
(POMC). It is the balance of activity of NPY-releasing
Hormones control the desire to feed neurons and POMC-releasing neurons that deter-
The control of appetite has been best studied in mines the appetite signal sent to the higher cen-
mammals because of the implications for human ters of the brain. This balance is influenced by the
obesity. These studies have identified more than hormones that stimulate and inhibit each type of
20 different regulatory factors that link nutrition, neuron, and how the neurons interact with each
metabolism, and feeding. Some regulatory factors other through antagonistic neurotransmitters. Both
are produced in the vicinity of the GI tract, control- NPY-releasing neurons and POMC-releasing neu-
ling local events and sending signals into the blood rons express leptin receptors, but connections
to affect other tissues. Hormones released by the between the receptor and neurotransmitter re-
GI tract make their way to the hypothalamus, lease are different. Leptin binding to its receptor
587
Digestion

Gut Reactor Theory
The animal digestive system shares the factors that determine the performance of the di-
many similarities with the reactors used in in- gestive system. For example, if a digestive system
dustry to convert one set of chemicals to another form. works like a batch reactor, then the animal stands to
Chemical engineers define three types of chemical regain the most energy if it digests a single meal enough
actors that have clear parallels to the animal digestive to gain the most nutrients in the shortest period of time.
systems we have discussed: batch reactors, tank reac- If the time is too short, the bolus of food is expelled with
tors, and plug flow reactors (Figure A). many nutrients remaining. If it holds on to the food too
Batch reactors receive a pulse of precursors and af- long, it may extract more nutrients but it forgoes an op-
ter a period of time convert the precursors into prod- portunity to feed again. Reactor theory can predict the
ucts. This is much like the two-way gut used by optimal retention time for food by plotting the relation-
cnidarians, which engulfs and digests food particles in a ship between net uptake (total uptake U minus foraging
gastrovascular cavity, then expels undigested material. costs C) and retention time τ, as seen in Figure B. This
Tank reactors receive a constant infusion of precursors curve can be used to predict the optimal residence time.
and generate a constant stream of products. The fer- Soon after the meal is consumed (τ ⫽ 0), the animal has
mentation chambers of some animals, such as the bird incurred costs (C) but gained no nutrients. As digestion
cecum or the cow rumen, are examples of tank reactors. proceeds (τ increases), there is an increase in the slope
In plug flow reactors, a bolus of precursors begins at of the curve. Think of this slope, termed U′(τ), as the rate
one end of a tube-shaped reactor and moves through at which the animal is gaining nutrients at that point in
the tube to the other end. The intestine of most animals time. At some point, the slope of the curve reaches its
works in this way, with food exiting the stomach and maximum, or U ′(τopt). After a longer period of digestion,
passing through the tubular intestine to the anus. nutrients continue to be absorbed but at a diminishing
Chemical reactor theory allows a researcher to rate. Mathematically, the relationship between these
model the digestive process mathematically, to assess parameters is defined by the equation
U1τopt 2 ⫺ C
U¿1τopt 2 ⫽
τopt
Ingestion Egestion
Graphically, the τopt value is identified by a line that
begins at the origin and intersects the curve at the point
where the slope begins to decrease. The red line shows
how an increase in foraging costs (C) shifts the entire
τ
curve downward; τopt increases. If it costs more to feed,
6
Batch reactor (Hydra)
Net uptake (U –C )
τ 2
Tank reactor (cecum)

0
Bolus
–2
τ
τopt τ (hours)
Plug flow reactor (upper intestine)
τopt (high U ) τopt (high C )
Figure A Figure B
588
Digestion
then the animal benefits from assimilating more nutri- they develop more sophisticated models to predict di-
ents from the first meal. Similarly, the blue line shows gestive physiology and feeding strategies. Reactor the-
how uptake increases when a meal is more digestible. ory has been best applied to animals with simple diets.
The entire curve shifts upward, and a shorter τopt is Dr. Carlos Martinez del Rio and his colleagues have
predicted. used it to study the feeding physiology of nectar-feeding
In the same manner, more complex equations can be birds. The simplicity of the diet facilitates the testing of
used to predict optimal feeding strategies in animals mathematical models incorporating plug reactor the-
with a digestive system that more closely approximates ory. A nectar-feeding bird converts sucrose to fructose
the plug flow reactor. In many ways, this model is like a and glucose using the intestinal disaccharidase su-
series of batch flow reactors, with a given volume of crase. It displays Michaelis Menton kinetics, with the
food progressing from one region to the next. Unlike the rate of hydrolysis (⫺rs) expressed as:
batch reactor, the plug flow reactor accepts a continu-
⫺rs ⫽ Vmax Cs (Km ⫹ Cs)⫺1
ous input, which has two consequences for predicting
the gain. First, because the animal feeds continuously, where Vmax is the maximal rate of sucrase averaged
its costs of feeding are spread out over time (in a batch along the gut, Km is the Michealis-Menton constant, and
reactor, the feeding costs are incurred first, but the gain Cs is the sucrose concentration. The retention time (τ)
is spread out over time). Second, for any given period, can be calculated as
multiple meals contribute to the gain.
τ ⫽ [(Km ln (Cs0 /Csf) ⫹ (Cs0 ⫺ Csf)] Vmax⫺1
In recent years, gut reactor theory has been used to
confront the biological complexity we discuss in this where Cs0 is the initial sucrose concentration and Csf is
chapter. First, whereas models generally assume that the final sucrose concentration.
the uptake rate is a linear function of nutrient concentra- Once τ is known the gut intake rate (V0) can be calcu-
tion, the kinetics are usually more complicated. The im- lated as
pacts of complex kinetics of digestive enzymes and
V0 ⫽ Gτ⫺1
intestine active transporters have only been resolved in
simple systems, such as nectar-feeding birds. Second, Martinez del Rio and his colleagues then compared
the volume of the plug is assumed to be constant, but in this model to actual experimental observations of
reality it changes as animals remove fluids from or se- hummingbirds feeding on different sucrose solutions.
crete them into the gut. Third, the models require thor- The more dilute the sucrose solutions, the larger the
ough mixing of the volume, but within the gut there are volume consumed by the birds. In another study, they
well-established concentration gradients as a result of used this same approach to find whether feeding be-
transport processes, such as unstirred layers. Fourth, havior reflected an attempt by the bird to match uptake
the animal can change the functional length of a gut to metabolic demand (compensatory feeding), or
through smooth muscle activity. Many of the studies that rather to ensure an uptake that kept the digestive ma-
use reactor theory operate on the premise that digestive chinery working at its maximal rate (physiological con-
systems work optimally. For example, it is assumed that straint). Hummingbirds were fed the same range of
animal digestive physiology (feeding behavior and nutri- sucrose solutions, but exposed to different ambient
ent uptake) strives to reach an optimal retention time. temperatures. The colder temperatures elevated
When a diet consists of a single major nutrient, it is plau- metabolic demands. They found that cold birds drank
sible that a single τopt exists. In a complex diet, each type the same amount of sucrose as warm birds, suggest-
of nutrient might have distinct optimal uptake kinetics, ing a physiological constraint.
yet the bolus of food progresses through the tubular gut
References
at a single rate. Thus, a single passage rate may be
q Martinez del Rio, C., J. E. Schondube, T. J. McWhorter, and L. G.
longer than required for some nutrients, and shorter
Herrera. 2001. Intake responses in nectar feeding birds: Diges-
than is necessary for others. The τopt in some cases may tive and metabolic causes, osmoregulatory consequences, and
reflect the need to expel indigestible or toxic material, coevolutionary effects. American Zoologist 41: 902–915.
rather than to take up nutrients. q McWhorter, T. J., and C. Martinez del Rio. 2000. Does gut function
Reactor theoreticians continue to incorporate these limit hummingbird food intake? Physiological and Biochemical Zo-
important physiological and morphological variables as ology 73: 313–324.
589
Digestion
in NPY-releasing neurons reduces neurotransmit- antiobesity treatments have not met with much
ter release, whereas binding to POMC-releasing success. Obese humans actually have very high
neurons stimulates neurotransmitter release. Each levels of leptin, yet their appetite is not sup-
of these effects contributes to the suppression of ap- pressed, suggesting that the hypothalamus can be-
petite in response to leptin. Ghrelin and peptide YY come resistant to leptin. It is also not yet clear how
each bind NPY-releasing neurons, though activa- leptin and other regulators of appetite act in other
tion of their respective receptors works antagonis- species of vertebrates with diverse feeding strate-
tically on neurotransmitter release (Figure 26). gies. Frequency of feeding differs widely among
The factors that control appetite have been animals. Large snakes and deep-sea fish may feed
studied intensively because of their potential for very infrequently, sometimes only once per year.
treatment of obesity. There are many animal mod- The hormonal and neuronal regulation of appetite
els with genetic defects that cause overeating is not well studied in such animals.
(hyperphagy) and obesity. For example, animal
models with defects in leptin signaling—loss of the
Hormones and neurotransmitters
ability to synthesize leptin or its receptor—are
control secretions
obese and exhibit many of the other physiological
problems associated with obesity. Unfortunately, Once food enters the gut, the GI tract secretes a
strategies to target the leptin signaling cascade in spectrum of chemicals and enzymes that digest
the food into forms that can be taken up. Control
of these secretions depends on complex regulatory
mechanisms that respond to both the anticipation
Hypothalamus (arcuate nucleus) of food and its physical presence in the digestive
NPY POMC system. Earlier in this chapter we discussed the
NPY-releasing POMC-releasing
neuron neuron nature of intestinal secretions—saliva, acid, mu-
NPY cus, bile, bicarbonate, and digestive enzymes—
– but not how animals control these secretions.
The stomach is acidified when parietal cells in
the gastric lining secrete HCl, or rather both H⫹ and
+ Cl⫺. Central to the secretion of acid is the activity of
+ –
– the enzyme carbonic anhydrase. Carbon dioxide is
Ghrelin PYY Leptin hydrated, forming H2CO3, which then dissociates to
form H⫹ and HCO3⫺. The parietal cells expel pro-
tons into the lumen via a proton pump, a K⫹/H⫹
ATPase. The bicarbonate is exported from the cell
to the blood via a Cl⫺/HCO3⫺ exchanger. The Cl–
then escapes the cell through a Cl⫺ channel. The se-
cretion of acid from parietal cells is triggered when
White adipose tissue
histamine binds to receptors (H2 receptors) on the
Stomach Colon
parietal cells, to initiate a cAMP cascade that acti-
Figure 26 Control of appetite Appetite is vates the proton pump. The histamine is released
controlled by the neurons of the arcuate nucleus of the
hypothalamus, which interacts with hormones secreted by enterochromaffin-like (ECF) cells in the stomach
from the GI tract and adipose tissue. Release of the lining. The ECF cells release their histamine in re-
neurotransmitter neuropeptide Y (NPY) stimulates sponse to gastrin, a peptide hormone produced by
appetite, whereas release of the neurotransmitter neuroendocrine cells (G cells) in the stomach and
proopiomelanocortin (POMC) depresses appetite. These
neurons, through their neurotransmitters, affect the appetite
duodenum, and released in response to adrener-
centers of the brain directly, or antagonize the release of gic and cholinergic nerve activity (Figure 27). Gas-
neurotransmitters from other neurons. Leptin exerts its trin also regulates pepsinogen secretion by chief
appetite-suppressing effects by inhibiting NPY–releasing cells of the gastric mucosa. The contents of the
neurons and stimulating POMC-releasing neurons. Appetite
is increased by the actions of other hormones on NPY-
stomach can interact with each of these cells—
releasing neurons: ghrelin stimulates and peptide YY inhibits parietal cells, ECF cells, and G cells—to alter acid
these neurons. secretion. Treatments for excessive acid secretion
590
Digestion
Sight/taste/smell Ingestion Acidic gastric fluids
Parasympathetic Chemoreceptors/ Acid Digestive products

neurons mechanoreceptors
Enteroendocrine Enteroendocrine
G cells Enteric nerves cells cells
Gastrin
VIP Secretin CCK
ECF cells Chief cells
Histamine
Pancreas Liver Gallbladder Pancreas
Parietal cells Pepsinogen
HCO3– Bile Bile Enzymes

Acid
Figure 28 Control of intestinal secretion The
Figure 27 Control of gastric secretion of acid acidic fluids that exit the stomach trigger intestinal
and pepsinogen Gastric cells secrete acid (parietal secretion. The secretions neutralize the acidic fluids (via
cells) and pepsinogen (chief cells) in response to signals bicarbonate and bile), and aid in digestion through digestive
relayed from the central nervous system and from the food enzymes (proteases, lipases, nucleases, amylases) and bile,
itself, acting through chemoreceptors and which emulsifies lipids.
mechanoreceptors.
Gut motility is regulated by nerves and

can target the K⫹/H⫹ ATPase (proton pump in- hormones that act on smooth muscle
hibitors) or the histamine receptors (H2 blockers). As with most physiological systems, muscles and
Gastrin also controls other secretory cells within nerves play important roles in regulating the di-
the gastric mucosa. For example, gastrin induces gestive system. Food is moved along the gastroin-
chief cells to secrete pepsinogen. The low pH of the testinal tract by visceral smooth muscles, which
stomach activates pepsinogen to form pepsin, a are under the control of nerves and hormones. By
carboxypeptidase, initiating protein degradation. increasing gut motility, an animal increases the
Once food passes from the stomach to the up- rate of passage of food down the GI tract, which in
per intestine, secretions alter the pH of the bolus turn affects the efficiency of absorption. It must be
and bombard it with a different suite of digestive fast enough to ensure that the animal is not carry-
chemicals. Bicarbonate secretions from the pan- ing around a mass of indigestible material, but
creas and bile from the gallbladder neutralize the slow enough to allow time for digestion and assim-
acidity. The pancreas also secretes digestive ilation. The interplay between gut passage rates
enzymes, including amylase, chymotrypsin, car- and digestibility is illustrated in the comparison of
boxypeptidases, aminopeptidases, nucleases, birds with different diets. Fruit-eating birds have
and lipases. When acidic material enters the up- fast passage rates. They must be able to move food
per intestine, it triggers duodenal secretion of se- quickly through the gut because indigestible mate-
cretin and vasoactive intestinal peptide (VIP) into rial is a load that must be carried around when the
the blood, which act at the pancreas to induce se- animal flies. Conversely, nectar-eating birds have
cretion of bicarbonate. Other intestinal cells a nutrient-rich diet that contributes little to body
sense the levels of amino acids and fatty acids mass. Slow passage rates allow these birds abun-
and secrete cholecystokinin (CCK) into the blood. dant time to absorb the nutrients.
CCK acts on the pancreas, inducing the secretion Gut motility is controlled by the actions of the
of digestive enzymes, and on the gallbladder, in- two layers of smooth muscle that line the intes-
ducing contraction of the smooth muscle to eject tinal tract. Each layer of smooth muscle in the GI
bile (Figure 28). tract is composed of muscle cells embedded in an
591
Digestion
extracellular matrix of elastin and collagen mole- rons involved in regulating gut motility and en-
cules, and interconnected into an electrical net- zyme secretion, whereas the submucosal plexus
work that allows the individual cells to contract regulates gut blood flow and plays an important
and relax as a unit. The thin outer longitudinal role in regulating ion and water transport by the
layer controls intestinal length. The thick inner gut. These components of the enteric nervous
circular layer, which controls the diameter of the system work together to regulate gut function.
lumen, is arranged into contractile units, each The gut also changes its contractile state to
about 1 mm long. Gut motility is determined by help propel food through the lumen. Peristalsis is
the contractile activity of the circular smooth a slow wave of contraction that progresses down
muscle. The smooth muscle has a resting con- the GI tract to push food toward the anus. It is con-
tractile tension, or muscle tone, that controls the trolled by the intrinsic myogenic activity of the
diameter of the lumen. Tonic contraction is con- smooth muscle cells, but also influenced by
trolled by intrinsic pathways within the muscle interstitial cells of Cajal that act as pacemaker
cells (myogenic) and by neurotransmitters re- cells. Much like the pacemaker cells of the heart,
leased from motor nerves (neurogenic). These these cells spontaneously depolarize to initiate a
motor nerves from the CNS do not act directly on wave of depolarization to the smooth muscle cells
smooth muscle, rather feeding into a network of to which they are attached via gap junctions.
nerves called the myenteric plexus (Figure 29). Suites of neurotransmitters and hormones
The myenteric plexus and the submucosal, or control gut motility (Table 4). In addition to en-
Meissner’s, plexus make up the enteric nervous docrine control, secretory cells in the stomach and
system. The myenteric plexus contains the neu- intestine produce paracrine and autocrine factors
that can act both directly and indirectly on the gut.
For example, secretory cells in the GI tract release
serotonin, which acts on both smooth muscle and
Villi
nerves. The nervous control of the GI tract in-
cludes signals from the CNS as well as local nerve
networks. Centrally, the hypothalamus and spinal
cord receive information from nerves in the GI
tract that respond to the activity of chemorecep-
Circular smooth tors and mechanoreceptors. The parasympathetic
muscle neurons send signals back to the gut to stimulate
Myenteric plexus motility by releasing acetylcholine; sympathetic
Longitudinal neurons inhibit motility by releasing norepineph-
smooth muscle rine, somatostatin, and neuropeptide Y. The
Circular smooth myenteric plexus compiles the stimulatory and in-
muscle hibitory signals, then transmits nervous signals to
Motor the smooth muscle.
neuron
Because of the overlapping regulatory path-
Myenteric
Inter- plexus ways, the control of gut motility is complex. Con-
neuron sider the mechanism by which one
Longitudinal neurotransmitter, acetylcholine, induces con-
smooth muscle traction. Recall from what you've learned that
smooth muscle contraction is regulated
directly by Ca2⫹ as well as by changes in the
phosphorylation state of thick and thin filament
To CNS (sympathetic and proteins. Acetylcholine stimulates contraction in
aparasympathetic nerves)
visceral smooth muscle by increasing Ca2⫹ lev-
Figure 29 Myenteric plexus The nerves of the els. This activates myosin light chain kinase
parasympathetic and sympathetic nervous systems send (MLCK), which phosphorylates the myosin light
their signals to the myenteric plexus that lies beneath the
chain of the thick filament. Acetylcholine acts
submucosa. This group of nerves integrates the various
signals and sends the appropriate neurotransmitters to the through a type of G-protein-linked muscarinic
circular smooth muscle to control contraction.
592
Digestion
Table 4 Neurohormonal effectors of GI motility.
Stimulatory Inhibitory
Acetylcholine Calcitonin gene regulating protein (CGRP)
Adenosine Gamma-aminobutyric acid (GABA)
Bombesin Galanin
Cholecystokinin (CCK) Glucagon
Gastrin-releasing polypeptide Neuropeptide Y
Histamine Neurotensin
Motilin Nitric oxide
Neurokinin A Norepinephrine
Opioids Pituitary adenylate cyclase activating polypeptide (PACAP)
Prostaglandin E2 Peptide histidine isoleucine (PHI)
Serotonin Peptide YY (PYY)
SP Secretin
Thyrotropin-releasing hormone Somatostatin
Vasoactive intestinal peptide (VIP)
Source: Hansen, 2003.
receptor that activates phospholipase C (PLC). levels of both cAMP and cGMP. Stimulation of PKA
This produces two second messengers, diacyl- and PKG leads to phosphorylation of critical pro-
glycerol (DAG) and inositol triphosphate (IP3), teins that reduce Ca2⫹ levels and change the sen-
which increase cytoplasmic Ca2⫹ levels (Figure sitivity of the contractile apparatus.
30). The IP3 and its metabolites open Ca2⫹ chan-
nels in the sarcoplasmic reticulum to release
Ca2⫹. When protein kinase C binds DAG in the
Metabolic transitions between meals
membrane, it phosphorylates and activates Ca2⫹ Once food is consumed and assimilated, the ani-
channels. Acetylcholine also acts via an inde- mal must regulate intermediary metabolism to
pendent route to impair relaxation. It binds to a ensure that the burst of nutrients is utilized and
second class of muscarinic receptors that in- stored. During the period immediately after feed-
hibits adenylate cyclase, reducing cAMP levels ing, known as the postprandial period, an animal
and PKA activity. Since PKA phosphorylates and utilizes some nutrients and stores others, en-
desensitizes contractile proteins, acetylcholine’s abling it to survive until the next meal. The nor-
actions also favor sensitization of contractile mal period between meals may be anywhere
proteins. In the absence of acetylcholine, relax- from seconds to months, depending on the ani-
ation is favored because the channels close and mal and its feeding strategy. In an animal with a
Ca2⫹ can be pumped back out of the cytoplasm. high metabolic rate, these energy stores are rap-
Relaxation is triggered by hormones that act idly expended and the animal enters a starvation
through both Ca2⫹-dependent and Ca2⫹-indepen- period, mobilizing energy stores and even de-
dent routes. The ␤ adrenergic effectors, such as grading structure. Many animals are subjected to
epinephrine, bind G-protein-linked receptors that very long periods between meals and possess
activate adenylate cyclase, elevating the level of strategies that combine reducing metabolic de-
cAMP and activating PKA. Nitric oxide stimulates mands and more efficiently using the available
guanylyl cyclase, elevating the levels of cGMP and resources.
protein kinase G (PKG). Vasoactive intestinal pep- For some animals, the food deprivation period
tide acts through both pathways, increasing the may persist for the life of the animal. Many insects
593
Digestion
1 Acetylcholine is released from

Cholinergic cholinergic nerve.
nerve
2 Muscarinic receptor is activated by

ACh, activating Gs protein.
3 Gs activates phospholipase C, which

ACh produces DAG and IP3.
1
Ca2+ Muscarinic
channel Phospholipase C receptor Adenylate
4 DAG stimulates protein kinase C, which
DAG cyclase
phosphorylates a plasma membrane
2 Ca2+ channel.
8
PKC 3
4 Gs 5 IP3 activates Ca2+ channels in
Gi ATP sarcoplasmic reticulum.
9
6
cAMP
Ca2+ IP3
6 Ca2+ levels in cytoplasm rise.
5 PKA
7 Ca2+ activates myosin light chain

7 kinase, which phosphorylates myosin
2+
Ca light chain.
MLCK
8 ACh also binds muscarinic receptors

Sarcoplasmic that activate Gi protein.
Smooth muscle cell reticulum
9 Gi inhibits adenylate cyclase, causing

[cAMP] to drop, and PKA to become
inactive.
Figure 30 Smooth muscle and the control of sarcoplasmic reticulum, and DAG, which activates PKC and
gut motility Acetylcholine (ACh) released from enteric opens Ca2⫹ channels in the cell membrane. ACh also
nerves induces contraction of smooth muscle by increasing antagonizes relaxation. It activates muscarinic receptors that
cytoplasmic Ca2⫹ levels. When it binds to muscarinic bind a Gi protein that inhibits adenylate cyclase, thereby
receptors, ACh activates phospholipase C (PLC), causing reducing cAMP levels and PKA activity.
an increase in IP3, which opens Ca2⫹ channels in the
have nonfeeding developmental stages. Typically, emerge and reproduce, then die one or two days
the early life stages feed actively, storing nutrients later. Adults do not feed, and prior to their emer-
for metamorphosis and reproduction. Most pupae gence the GI tract atrophies, acting as a nutrient
of insects do not feed, instead relying on nutrients store used to support reproductive maturation.
stored as larvae to reorganize the anatomy and
physiological systems. In a few cases, the adult
form of an insect is nonfeeding. Mayflies, for ex- Hormones control postprandial regulation
ample, spend as long as 2.5 years as nymphs, of nutrient stores
feeding as predators in the debris of waterways. After nutrients pass through the enterocytes to the
When waters warm in spring, the adult stages blood, they may be utilized directly by other tis-
594
Digestion
sues or stored in depot tissues. With each meal sulin and glucagon are most important to metabolic
there is a burst of readily metabolizable carbon fu- regulation in relation to the nutritional state, gluco-
els that can be oxidized to support the metabolic corticoids are most important as part of a metabolic
demands of tissues. In many tissues, the fuels stress response. For example, the intense metabolic
used to support energy metabolism are influenced costs of locomotion and reproductive behaviors are
by the spectrum of fuels in the blood. The verte- met when the glucocorticoid stress hormones cause
brate heart, for example, is capable of oxidizing mobilization and synthesis of fuels.
glucose, lactate, amino acids, or fatty acids, de- Invertebrate nutritional metabolism is best
pending on their availability in the blood. Immedi- studied in insects, mainly because of their impor-
ately after a meal, such tissues have many tance as agricultural pests. The main energy store
alternative fuels. Later, however, the levels of nu- in insects is the fat body. During energy-demand-
trients in the blood depend on the action of hor- ing situations, such as flight, adipokinetic hor-
mones that control the release of fuels from mone (AdK) is released from the corpora
storage tissues. This regulation is determined pri- cardiacum, causing the fat body to mobilize energy
marily by endocrine hormones. stores (Figure 31). Lipids are broken down to DAG
In vertebrates, the immediate fate of dietary and fatty acids. Glycogen stores are converted to
nutrients (oxidation or storage) depends on the lev- trehalose. The fat body also releases significant
els of the pancreatic hormones insulin and
glucagon, as well as glucocorticoids. During diges-
Corpora cardiaca
tion, these hormones act on peripheral tissues to
Insect head Corpora allata
control the pattern of fuel utilization and on storage
tissues to control rates of uptake and synthesis. In
the postabsorptive animal, these same hormones Brain
control the release of fuels from storage depots. Aorta
When the glucose level is high, as it would be after
a meal, pancreatic beta cells are induced to secrete
insulin. Insulin acts upon multiple tissues to pro- Gut
Prothoracic gland
mote glucose removal from the blood. In skeletal
muscle, it enhances glucose uptake by causing
translocation of glucose transporters (GLUT-4) to
Mouth
the cell membrane. In adipose, it promotes uptake
and conversion of glucose into fatty acids, for long- (a) Insect head
term storage as triglyceride. In liver, it impairs
glycogen breakdown and enhances glycogen syn- Adipokinetic
thesis. After the glucose level declines, insulin se- hormone (AdK) Phospholipase C
cretion decreases and glucagon is released by AdK
receptor
pancreatic alpha cells. This causes mobilization of
energy stores—glycogen hydrolysis and triglyc-
eride breakdown—and enhances the rate of gluco-
neogenesis in liver. Thus, the balance between GTP Gq
insulin and glucagon determines the balance be- + IP3
Triglyceride
tween glucose utilization and generation. lipase Ca2+
Glucocorticoids such as cortisol, corticosterone,
Glycogen +
and cortisone induce gluconeogenesis while reduc- phosphorylase
ing glucose uptake by peripheral tissues such as
skeletal muscle. This acts to increase circulating
glucose levels to ensure that those tissues that re- Sarcoplasmic
reticulum Ca2+
quire glucose have a steady supply. Glucocorticoids
also mobilize triglycerides, ensuring that fatty acids (b) Fat body cell
are available to tissues that are prevented from us- Figure 31 Hormonal regulation
ing glucose, such as skeletal muscle. Whereas in- of metabolism in insects
595
Digestion
amounts of proline in some species. AdK acts via a meet energy demands. Nervous tissue, for example,
G-protein-coupled receptor (Gq) to activate phos- relies almost exclusively on glucose as a fuel. In the
pholipase C (PLC). The increase in IP3 triggers early phases of food deprivation, vertebrates mobi-
Ca2⫹ release, which activates Ca2⫹-sensitive sig- lize the vast lipid stores in liver and adipose tissue.
naling enzymes that activate glycogen phosphory- Muscle, a major consumer of metabolic energy,
lase and triglyceride lipase. At the same time that shifts to rely more heavily on mobilized lipid, re-
AdK enhances lipid and protein breakdown, it inducing the reliance on glucose.
hibits lipid and protein synthesis. Since insect re- Despite these efforts to conserve glucose, after
production is intimately linked to nutrition, AdK a time the glycogen stores become depleted and
also inhibits egg production in females. the animal must find a fuel that can be used to pro-
duce glucose. After prolonged food deprivation,
the animal accelerates the rate of protein break-
Prolonged food deprivation can trigger down. Since there is no protein store, this usually
a starvation response
entails the degradation of the protein structures
Most animals are able to cope with short periods of within cells. One of the earliest tissues to suffer
food deprivation without incurring metabolic dis- protein degradation is skeletal muscle. Individual
tress. Short-term food deprivation, such as the pe- myofibers degrade contractile elements in the
riods between regular meals, can be met with process of atrophy. When intracellular proteins
existing energy resources. If the food-deprivation are degraded by lysosomes and proteasomes, the
period persists, the animal reorganizes metabolism liberated amino acids can be oxidized for fuel or
to ensure long-term survival. Most vertebrates trig- converted to other molecules, such as ketone bod-
ger mechanisms that preserve glucose in order to ies, fatty acids, or carbohydrate. These processes
protect those tissues that rely heavily on glucose to can occur either in the muscle itself or after trans-
port of the amino acids to other
tissues, primarily liver. Fatty
Adipose tissue Liver Muscle Brain
acids can also be converted to
TG TG Glycogen TG Glycogen Glucose ketone bodies, which can then
be utilized by tissues that can-
not oxidize fatty acids, such as
Fatty acids Fatty acids Glucose Fatty acids
nervous tissue. The main regu-
latory events that occur during
CO2 CO2 CO2 CO2 CO2 CO2 starvation are summarized in
Figure 32.
The rate at which a starva-
(a) Early starvation
tion response progresses varies
widely among species, prima-
Adipose tissue Liver Muscle Brain rily due to differences in meta-
bolic rate. An animal with a
TG TG Amino acids Amino acids Ketones
high metabolic rate will deplete
its energy stores faster than an
Fatty acids Fatty acids animal with a low metabolic
CO2 rate. Differences in metabolic
CO2 Ketone bodies CO2 CO2
rate arise in relation to body
size, activity levels, and temper-
ature. Since small animals have
(b) Late starvation
higher mass-specific metabolic
Figure 32 The metabolic cascade of starvation When animals are deprived of rates than do larger animals,
food, they respond by mobilizing internal energy stores. (a) In early starvation of they expend limited energy
vertebrates, stores of glycogen and triglyceride (TG) provide most of the metabolic needs of
tissues. Fatty acids are released from liver and adipose for use in other tissues. (b) During
stores at a faster rate. The ener-
late starvation, glycogen reserves are depleted and ketone bodies are produced from fatty getic state of a hummingbird or
acids from adipose and liver, as well as some amino acids derived from muscle proteolysis. shrew after one hour of food
596
Digestion
deprivation is similar to that of a human that has creases dramatically. The small intestine alone
not eaten for 12 hours. Active animals utilize en- nearly doubles in mass, and other tissues such as
ergy stores faster than similarly sized sedentary liver and kidney, increase by more than 60% in
animals. For example, a dog has a metabolic rate this rapid growth phase (Figure 33). The high
that is about twice that of a goat. Even within a metabolic cost of rebuilding the gut is an impor-
single individual, a persistent period of elevated tant component of the very high specific dynamic
metabolism draws on circulating fuels and stimu- action (SDA) seen in a python digesting a meal;
lates feeding. Prolonged periods of biosynthesis, while the costs are great, the cost of rebuilding the
arising during rapid growth, gestation, or lacta- GI tract must be less than the costs of maintaining
tion, can elevate metabolic rate dramatically. Sim- it between unpredictable meals.
ilarly, the elevation in metabolic rate during
muscle activity arising from exercise or shivering
stimulates appetite and fuel mobilization. The
Dormant bears recycle nitrogen
third factor that affects metabolic rate and nutri- Many organisms undergo periods of dormancy in
ent demand is body temperature. An increase in which the metabolic rate is reduced (hypometabo-
body temperature accelerates the basal metabolic lism), allowing the animal to survive adverse envi-
demands and more rapidly depletes available en- ronmental conditions. The various types of
ergy, thereby accelerating the rate of progression dormancy—torpor, hibernation, and estivation—
through the starvation responses. reduce demands on stored fuels. One of the great-
est challenges for dormant animals is the mainte-
nance of structure during prolonged periods of
Pythons rebuild the digestive tract inactivity. Although the animals do not grow during
for each meal dormancy, they must rebuild the protein structures
An animal that eats very infrequently must main- that naturally degrade over time. For example,
tain its GI tract in a condition that will allow it to even though their metabolic rates are lower than
function when needed. Hibernating ground squir- normal, dormant black bears remain relatively
rels that have been dormant for more than warm and metabolically active. As a result, pro-
12 weeks continue to express the degradative en- teins are constantly degraded and inevitably some
zymes that would be required to digest a meal. In of the amino acid building blocks are oxidized,
this way, these animals ensure that they will be causing the liver to produce urea. Most hibernating
able to eat and digest a meal immediately upon mammals accumulate urea and urine throughout
emergence from hibernation. However, some ani- the dormant period; however, dormant bears accu-
mals reduce their energetic costs between meals mulate very little urea. Bears are able to recycle
by allowing the GI tract to degrade. Large preda- this urea nitrogen, regenerating amino acids that
tory snakes, such as the Burmese python, may go can be used to rebuild proteins. They transport
months between meals. When a snake feeds, it urea from the blood into the GI tract, where it can
eats a very large meal. For example, in 1977, vil- be degraded by the enzyme urease. Although this
lagers in India killed an 18-foot Indian python and enzyme generates ammonia, it is not yet clear how
recovered the remains of a 45-year-old man. Be- the bear is able to use the ammonia to resynthesize
tween these large meals, much of the mucosa and all of the amino acids required for biosynthesis. It
submucosa of the GI tract degrades. The gut be- is likely that the GI bacterial flora help incorporate
comes thinner and the brush border of the intes- the ammonia into amino acids. As with other sym-
tine decreases. These structural changes reduce biotic relationships, the animal derives nutrients
the total surface area of the GI tract and the capac- from uptake of bacterial products as well as diges-
ity for nutrient transport. Although the absorptive tion of the bacteria themselves. The amino acids
epithelium is reduced, the GI tract maintains the produced in the bear’s GI tract can be transported
smooth muscle and nerves that control the gut. into the blood and used in biosynthesis. As a result
Once the animal feeds, the snake rebuilds its GI of this urea recycling, the levels of the dietary es-
tract in regions that are just ahead of the bolus of sential amino acids remain constant and the ani-
food. Within the first few days after a meal, the mals can maintain a nearly constant muscle mass
mass of the tissues associated with digestion in- during the many months of dormancy.
597
Digestion
32
Wet mass of small intestine (g)
4. What is the main function of each region of the
digestive tract?
24 5. How does cellular diversity contribute to
functional diversity in digestive physiology?
6. What are four ways vertebrates increase the
surface area of the intestine?
16
10 0 20 30
Days postfeeding
(a) Starvation and intestinal mass
180
Postprandial increase (%)
120
60
0
Stomach Lungs Heart Pancreas Liver Kidneys Intestinal
mucosa
(b) Tissue mass changes
Figure 33 Python digestion Large snakes that eat
infrequent meals allow their digestive organs to decrease in
mass between meals. Organ mass increases rapidly upon
feeding. (a) Intestinal wet mass doubles within three days
postfeeding. (b) Other tissues that participate in digestion
also increase markedly in the first few days after feeding.
(Source: Modified from Secor and Diamond, 1998)
Integrating Systems Obesity

Most animals face the continuing challenge of finding some animals, in humans it is entirely maladaptive. We
adequate food to support their short-term and long- evolved as a hunter-gatherer species, with adaptations
term metabolic needs. The metabolic status of an ani- for efficient nutrient storage during rare periods of
mal is monitored centrally, with deficits translated into food abundance. As a result of Western societal
“hunger,” spurring the animal to search for food, endur- changes—higher food availability, poorer diet quality,
ing risks of predation. Evolution has led to exquisite con- and reduced physical activity levels—there has been a
trols that match feeding behaviour, digestive physiology, dramatic increase in the prevalence of obesity in many
and energy metabolism. Some animals experience populations. To discover where you stand in terms of a
phases where they eat more than usual (hyperphagy), of- healthy body mass, calculate your body mass index
ten in preparation for migration, reproduction, or dor- (BMI): take your mass (in kilograms) and divide by your
mancy. For example, shorebirds may gorge on intertidal height (in meters) squared (BMI⫽ kg/m2). According to
crustaceans before flying south for the winter, doubling the World Health Organization, one in three North
their body mass with fat deposition. Likewise, ground American adults is overweight (BMI >25) and one in ten
squirrels more than double in mass by feeding through is obese (BMI >30). Although BMI is a good index of
the fall to obtain enough fat for insulation and nutrition obesity, the main culprit in terms of health problems is
while hibernating over the seemingly endless Canadian the fat localized around the midsection, termed ab-
winter. While hyperphagy is essential in the life history of dominal (or visceral) fat.
598
Digestion
The added biomechanical stress of carrying extra pertrophied, and these larger, lipid-rich cells are resis-
fat is a relatively minor component of the physiological tant to the insulin signal and respond by releasing nones-
disruption associated with being overweight. As shown terified fatty acids (NEFA). The reasons for the loss of
in Figure 34, excess adipose tissue (adiposity) affects insulin sensitivity in peripheral tissues are complex. In
numerous physiological systems, contributing to many the liver, it may be caused by metabolic disruption, such
diseases. Adipose metabolism affects whole body nutri- as elevated NEFA, or by changes in adipocyte regulatory
ent metabolism, and through these effects, alters the factors, such as tumor necrosis factor alpha (TNF␣). In
sensitivity to other important regulators of metabolism. either case, the loss of insulin-sensitivity causes the liver
Adipose tissue is also an endocrine tissue, secreting to increase lipid storage, creating a condition known as
diverse hormones related to dietary status (leptin, fatty liver disease. There are also dramatic increases in
adiponectin), blood clotting (plasminogen activator the triglyceride levels in skeletal muscle and around the
inhibitor-1), inflammation (interleukin 6, tumor necro- heart (epicardial fat). It also alters how the liver main-
sis factor alpha), and blood pressure (angiotensinogen). tains lipid profiles in the blood; more triglyceride is pro-
In overweight individuals, it is the combination of larger duced and released to the blood, and there is a
adipocytes and greater total adipose tissue mass that reduction in the levels of HDL, the lipoprotein that re-
affects the endocrine functions of the tissue. duces the negative effects of cholesterol. The main
The main metabolic consequences of obesity are re- metabolic effects of obesity—high blood glucose, high
lated to disruption of normal insulin signaling. In a blood triglyceride, insulin resistance, low HDL—are four
healthy individual, an elevated blood glucose level trig- of five symptoms of a condition known as metabolic syn-
gers the pancreas to secrete insulin, which in turn pro- drome (the fifth symptom, high blood pressure, will be
motes glucose uptake by adipose and skeletal muscle, discussed a bit later in this feature). People with three
and inhibits hepatic gluconeogenesis. In an obese indi- or more of these symptoms are at a much greater risk
vidual, the pancreas secretes insulin, but despite hyper- of cardiovascular disease.
insulinemia, the target tissues fail to respond to the Like the metabolic effects of obesity, the cardio-
hormone. As a result of the insulin resistance, glucose is vascular effects are complex. Obese individuals may
not cleared by metabolism and the blood maintains a very experience greater risk of numerous cardiovascular
high glucose level (hyperglycemia). At the heart of this disorders. Obesity and insulin-resistance interact to
disorder is insulin resistance in the adipose tissue. In cause high blood pressure (hypertension). Insulin is a
normal adipocytes, high insulin levels signal an “energy- powerful vasodilator, and if obesity makes the vascu-
rich” state, causing adipocytes to reduce triglyceride lature insensitive to its hypotensive effects, hyperten-
breakdown. In obese individuals, the adipocytes are hy- sion can result. Adipocytes are also a major site of two
Small adipocytes
Hypertrophy
Insulin Pancreas NEFA Large adipocytes
Glucose
Liver
Insulin
resistance Muscle Triglycerides IL-6 PAI-1 TNFα ANG
Heart
Inflammation Vasoconstriction
Thrombosis
Atherogenesis
Blood vessels Blood vessels
Ischemia Stroke Hypertension
Figure 34 The role of the adipose in mediating the physiological effects of

obesity ANG, angiotensinogen. IL-6, interleukin-6. NEFA, nonesterified fatty acids.
PAI-1, plasminogen activator inhibitor-1. TNF␣, tumor necrosis factor ␣.
599
Digestion
vasoconstricting factors: angiotensinogen and TNF␣. atherogenesis, thrombosis, and platelet aggregation.
These factors act on vasculature and also affect how the Collectively, the vascular effects can contribute to other
kidney regulates blood pressure. Apart from regulating cardiovascular complications. The combination of
vascular tone, obesity and insulin-resistance can also atherogenesis and thrombosis increases the risk that
affect vasculature structure by increasing endothelial plaques and clots will cause vascular blockage and is-
damage, promoting formation of vascular plaques chemia. This could cause a heart attack if the blockage
(atherogenesis) and clots (thrombosis). Again, there may is in the coronary arteries, or a stroke if the blockage is
be a metabolic link (such as increased plasma choles- in the circulation of the brain.
terol), but the main reason for the vascular effects is In relatively rare situations, an obese phenotype can
through the alterations in the regulatory factors re- be traced to genetic variants that affect the perception of
leased by the adipose tissue. Increases in TNF␣, inter- hunger or the appropriate control of metabolism. How-
leukin 6, and plasminogen activator inhibitor-1 exert ever, the most common cause of obesity is simply eating
complex effects on the vasculature. They act directly more calories than your body requires. Fortunately, many
and indirectly to promote inflammation, increasing ox- of the health problems associated with obesity can be re-
idative damage within the vascular tissue, promoting versed if a person returns to a healthy weight.2
Summary
The Nature and Acquisition of Nutrients k Simple animals such as sponges and cnidarians
k Animals must feed to obtain a spectrum of nu- digest food intracellularly, after phagocytosis of
trients that enable them to build and maintain particulate matter. More advanced inverte-
cells. Some building blocks cannot be synthe- brates break food down into macromolecules
sized by the animal and must be obtained pre- extracellularly and transport individual mole-
formed in the diet: eight to ten essential amino cules into the gastrointestinal epithelium.
acids, two classes of fatty acids (omega-3 and
k Many animals use oral feeding structures to find
omega-6), as well as vitamins and minerals.
and ingest food. Bird beaks display morphologi-
Much of the ingested food is used to produce en-
cal diversity, allowing them to meet the biome-
ergy to support activity and biosynthesis.
chanical challenges associated with different
k Simple carbohydrates and amino acids are ac- types of food. Mammals have bony teeth protrud-
tively transported into cells. Excess carbohy- ing from the jaw to help in mechanical disruption
drate and protein is typically converted to of food by grinding, tearing, and shredding.
glycogen for storage in liver and peripheral tis-
sues such as skeletal muscle. Integrating Digestion with Metabolism
k The appearance of a coelom early in animal evo-
k Lipids are transported into the animal in many
lution allowed the development of a gastroin-
forms. Fatty acids can be taken up directly by
testinal system with specialized compartments.
intestinal cells, but most lipids leave the intes-
tinal cells in the form of chylomicrons. When k Although simple invertebrates have short, tubu-
the lipids are removed from chylomicrons, their lar GI tracts, more complex animals maximize
remnants are taken up and repackaged into surface area by increasing the undulations of the
lipoproteins by the liver. gut surface, producing fingerlike projections
from the surface (villi) and cellular protrusions
k Animals find their food using chemical cues in-
from the absorptive enterocytes (microvilli).
volving chemoreceptors that sense specific
chemicals. Other animals find food based on vi- k The digestive epithelium in each compartment
sual cues, or other indices of prey location, such has special types of secretory cells that release
as electrical activity or heat production. digestive enzymes and also control the physi-
600
Digestion
cal properties with secretions of acid, base, mones such as insulin and glucagon regulate
and mucus. the fate of the major metabolic fuels. Insulin
promotes glucose utilization, whereas glucagon
k Many animals have fermentation chambers
antagonizes the insulin effect.
prior to the glandular stomach (ruminants) or
after the glandular stomach (nonruminants). k If deprived of food for long periods, a vertebrate
These specialized compartments house en- initiates a starvation response, converting some
dosymbiotic bacteria that possess cellulolytic of the stored lipids to ketone bodies for use in
activity. brain and other tissues that normally rely on
glucose for energy.
k Hormones interpret information from the GI
tract and metabolic storage tissues to influence k Many animals extend the duration of nutrient
the desire to feed (appetite). Once food is in- stores by entering hypometabolic states of dor-
gested, hormones control the secretions by the mancy. Hibernating animals face other chal-
stomach (acid, pepsin, mucus), pancreas (bicar- lenges, such as ion and water imbalances.
bonate, proteases, lipases, nucleases), and the Dormant bears cope with gradual loss in the ni-
gallbladder (bile). trogen pool by recycling nitrogen with the help
of the bacterial fauna of the gut.
k Smooth muscle of the gut controls the rate at
which the bolus moves down the digestive k Pythons allow the GI tract to partially degrade
tract. Numerous hormones and neurons, actin the period between meals, which can be as
ing both locally and centrally, control gut long as a year. After a python feeds, it uses some
motility. of the energy to rebuild the digestive tract just
ahead of the food bolus.
k Each of these digestive processes—digestion,
uptake, and assimilation—is influenced by k Digestion and reproduction often proceed with
temperature. conflicting goals. Many species separate their
reproductive cycle from digestion, simplifying
k Animals utilize nutrients that appear in the
the regulation of these processes.
blood after a meal, oxidizing some directly and
metabolizing others into storage forms. Hor-
Review Questions
1. Summarize the basic organization of the ver- 6. What roles do glands play in the process of
tebrate GI tract. What is the function of each digestion?
compartment? 7. How does specific dynamic action benefit an
2. Discuss the variation in the nature of fermen- animal?
tation chambers. 8. How do animals control the secretions along
3. How do animals use neurosensory systems to the gastrointestinal tract?
detect food in a complex environment? 9. Discuss the fate of glucose during a meal, after
4. Compare the different pathways for digestion a meal, and two days after an animal’s meal.
and uptake of the three main classes of 10. How might an animal alter its ability to im-
macromolecules: lipids, carbohydrates, and port monosaccharides from the gastrointesti-
proteins. nal tract?
5. A diet is rich in chemical energy, but not all of
this energy is available to the animal. How is
energy partitioned in a diet?
601
Digestion
Synthesis Questions
1. Discuss situations where digestion and repro- 5. Follow the path of glucose from the nectar
duction may be antagonistic processes. reservoir of a plant to the muscle of a hum-
2. An animal that feeds on a large meal under- mingbird. What steps control the rate of this
goes numerous changes that affect its other process?
physiological systems. Discuss how the diges- 6. What differences in digestive physiology sys-
tive process impinges on other systems. tems would you expect when comparing birds
3. When wild animals are domesticated, the that eat nectar (easy to digest, high energy per
years of artificial selection can alter the diges- gram), seeds (difficult to digest, high energy
tive physiology of the animal. Choose an exper gram), or fruit (easy to digest, low energy
ample of a domesticated animal and consider per gram)?
how its digestive physiology might differ from 7. The harsh chemical and enzymatic conditions
that of its wild ancestors, given the differences in the gastrointestinal tract break down nutri-
in diet and selective pressures. ents. How do animals protect themselves from
4. Why is digestion a metabolically expensive their own digestive secretions?
process?
For the following calculations, assume the following: 1. Assuming that your metabolic rate during
• The generic daily caloric requirements are sleep is equal to your basal metabolic rate (it’s
2500 kcal for men, and 2000 for women. actually lower), how many calories did you ex-
pend while sleeping for 8 hours Translate
• The caloric expenditures for someone with
those calories into units of body mass. Did you
an average lifestyle are attributed to basal
lose that much weight while you slept? How do
metabolic rate (about 70% of total), specific
respiration and urine production factor into
dynamic action (10%), and physical activity
this analysis?
(20%).
2. Assuming no change in basal metabolic rate or
• There are 9000 kcal in 1 kg of fat, and 4000
SDA, how long would it take to lose 1 kg of
kcal in 1 kg of protein or carbohydrate.
body mass (a) by reducing caloric intake by
• There are about 7000 kcal in 1 kg of body 500 kcal per day or (b) by doubling your phys-
mass. ical activity each day?
• A pint of beer has about 200 kcal. 3. If you jogged to your local pub, how far would
• You burn about 500 kcal by jogging for 1 h you have to go to ensure you expended enough
at 10km/h (though it depends on your calories to maintain caloric balance if you plan
weight and the running speed). to consume two pints of beer?
602
Digestion
For Further Reading

See the Additional References section at the end Digestive Physiology
of the chapter for more readings related to the For many years, the nature of intestinal sugar
topics in this chapter. transport was hotly debated by several important
General Reading and the History of Digestion research groups. These collected papers take
different perspectives on the subject.
This book, accessible to a general audience,
discusses the nature of energy and energetic Ferraris, R. P., and J. Diamond. 1997. Regulation
transformations in physiological function. of intestinal sugar transport. Physiological
Reviews 77: 257–302.
Brown, G. 1999. The energy of life. London:
HarperCollins. Kellett, G. L. 2001. The facilitated component of
intestinal glucose absorption. Journal of
These works discuss the history of enzyme Physiology 531: 585–595.
research. Kornberg’s autobiography focuses on
developments from the earliest days of Hormones and neurotransmitters are central to
nutritional biochemistry to the era when the regulation of intestinal function. This review
molecular biology began to influence the field. focuses specifically on the role of the regulatory
The essay by Fruton focuses specifically on the factors in the control of the smooth muscle that
enzyme pepsin, one of the first digestive enzymes determines gut motility.
to be studied. Hansen, M. B. 2003. Neurohormonal control of
Fruton, J. S. 2002. A history of pepsin and gastrointestinal motility. Physiological Reviews
related enzymes. Quarterly Review of Biology 52: 1–30.
77: 127–147.
Many animals survive periods of adverse
Kornberg, A. 1989. For the love of enzymes: The environmental conditions by entering a period of
odyssey of a biochemist. Cambridge, MA: dormancy. This book compares the various
Harvard University Press. modes of metabolic arrest used by animals.
This review discusses how the evolution of novel Hochachka, P. W., and M. Guppy. 1987.
developmental patterns led to the origins of the Metabolic arrest: Control of biological time.
diversity seen in the vertebrates. Oxford: Oxford University Press.
Manzanares, M., and M. A. Nieto. 2003.
Minireview: A celebration of the new head and
an evaluation of the new mouth. Neuron 37:
895–898.
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Digestion
Beamish, F. W. H., and E. A. Trippel. 1990. Heat increment: A Hulbert, A. J., and P. L. Else. 2000. Mechanisms underlying
static or dynamic dimension in bioenergetic models? the cost of living in animals. Annual Review of Physiology
Transactions of the American Fisheries Society 119: 207–235.
649–661. Karasov, W. H., and J. M. Diamond. 1988. Interplay between
Brown, J. H., and G. B. West, eds. 2000. Scaling in biology. physiology and ecology in digestion. BioScience 38:
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Calder, W. A., III. 1984. Scaling energetics of homeothermic King, J. R., and M. E. Murphy. 1985. Periods of nutritional
vertebrates: An operational allometry. Annual Review of stress in the annual cycles of endotherms: Fact or fiction?
Physiology 49: 107–120. American Zoologist 25: 955–964.
Chaudhri, O., C. Small, and S. Bloom. 2006. Gastrointestinal Kooijman, S. A. L. M. 1993. Dynamic energy budgets in
hormones regulating appetite. Philosophical Transactions biological systems. New York: Cambridge University Press.
of the Royal Society of London, Series B: Biological Martinez del Rio, C., J. E. Schondube,
Sciences 361: 1187–1209. T. J. McWhorter, and L. G. Herrera. 2001. Intake
Cone, R. D. 2005. Anatomy and regulation of the central responses in nectar feeding birds: Digestive and metabolic
melanocortin system. Nature Neuroscience 8: 571–578. causes, osmoregulatory consequences, and coevolutionary
Costa, D. P., and G. L. Kooyman. 1984. Contribution of effects. American Zoologist 41: 902–915.
specific dynamic action to heat balance and McWhorter, T. J., and C. Martinez
thermoregulation in the sea otter Enhydra lutris. del Rio. 2000. Does gut function limit hummingbird food
Physiological Zoology 57: 199–203. intake? Physiological and Biochemical Zoology 73:
Cummings, D. E., and J. Overduin. 2007. Gastrointestinal 313–324.
regulation of food intake. Journal of Clinical Miller, P. J., ed. 1996. Miniature vertebrates: The
Investigations 117:13–23. implications of small body size. Symposia of the Zoological
Darvall, K. A. L., R. C. Sam, S. H. Silverman, A. W. Bradbury, Society of London, no. 69. Oxford: Clarendon.
and D. J. Adam. 2007. Obesity and thrombosis. European Nagy, K. A. 1987. Field metabolic rate and food requirement
Journal of Vascular and Endovascular Surgery 33: scaling in mammals and birds. Ecological Monographs 57:
223–233. 111–128.
Darveau, C.-A., R. K. Suarez, R. D. Andrews, and P. W. Northcutt, R. G., and C. Gans. 1983. The genesis of neural
Hochachka. 2002. Allometric cascade as a unifying crest and epidermal placodes: A reinterpretation of
principle of body mass effects on metabolism. Nature 417: vertebrate origins. Quarterly Reviews of Biology 58: 1–28.
166–170. Prusiner, S. B. 1997. Prion diseases and the BSE crisis.
Dobson, G. P., and J. P. Headrick. 1995. Bioenergetic scaling: Science 278: 245–251.
Metabolic design and body-size constraints in mammals. Schneider, R. A., and J. A. Helms. 2003. The cellular and
Proceedings of the National Academy of Sciences, USA 92: molecular origins of beak morphology. Science 299:
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Gaill, F. 1993. Aspects of life development at deep sea Secor, S.M., and J. Diamond. 1998. A vertebrate model of
hydrothermal vents. FASEB Journal 7: 558–565. extreme physiological regulation. Nature 395: 659–662.
Grant, P. R., and B. R. Grant. 2002. Unpredictable evolution Walker, C. G., G. Zariwala, M. J. Holness, and M. C. Sugden.
in a 30-year study of Darwin’s finches. Science 296: 2007. Diet, obesity and diabetes: A current update.
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Credits
526 Karl Ammann/Nature
Picture Library.
527 Prism/SuperStock.
527 Nancy Hamilton/Photo
Researchers, Inc.
533 Agence France Presse.
542 Photo Researchers, Inc., Mona Lisa Production/Photo
Researchers, Inc.
542 Courtesy Paul Handford, University of Western Ontario.
542 Photo Researchers, Inc., Karl H. Switak/Photo
Researchers, Inc.
604
605
Locomotion
Animal locomotion has concerned humans since prehis- breeding and artificial selection were used to modify animal
toric times. For early human hunters, animal movement locomotor physiology to obtain animals with more favorable
was a source of frustration; animals that we now admire as features. Working animals were bred for strength and en-
majestic runners, they considered to be escaping food. With durance. Racing animals were bred for speed. Food ani-
the advent of animal husbandry, people confined wild animals were bred for growth rate and muscle mass, which
mals to supply the cook fires without a chase. Later, animal usually compromised the locomotor properties.
606
Locomotion
Muybridge’s horse photographs.

Photo courtesty of Jean-Michel Weber, University of Ottawa.
More than 2400 years ago, Plato, Hippocrates, and
Aristotle wrote about the nature of movement in animals, Much of our understanding of locomotor systems relies
including humans. For much of the next two millennia, our on the integration of the diverse fields that make up physiol-
understanding of the physiology of locomotion was con- ogy. In the mid-1900s, Sir Andrew Huxley and Hugh Huxley
strained by cultural taboos against the dissection of human applied modern physics to explain the basis of muscle con-
corpses. Renaissance artists, including Leonardo da Vinci traction. In the late 1900s, advances in microscopy and nu-
and Michelangelo, conducted clandestine autopsies to ex- clear magnetic resonance technologies provided windows
plore the structure of the human body. The anatomical de- into the cellular function of locomotor systems. Many fur-
tail of Renaissance artwork reflects Western culture’s first ther advances in the comparative physiology of locomotion
explorations into human locomotor physiology. As science arose when researchers devised ways to make physiological
matured in the Age of Enlightenment, locomotion research measurements of moving animals. In the late 1960s, C. R.
began to link studies of muscle anatomy and physics, cre- (Dick) Taylor and his colleagues began decades of studies
ating a new field called biomechanics. that combined biomechanics with respiratory physiology.
The study of locomotion was further aided by progress in They trained diverse animals to run on treadmills while they
photography. In the late 1800s, Eadweard Muybridge, a land- measured muscle activity and respiration. The largest ani-
scape photographer by training, was commissioned by mals they studied were elephants. The elephants were too
Leland Stanford to settle a wager on the position of a horse’s large to run on their treadmills, so the researchers devel-
legs during a trot. He employed a series of cameras that were oped golf carts that carried gas analyzers. Around the same
mechanically triggered to take sequential images of a trot- time, J. R. Brett developed a swim tunnel respirometer to
ting horse. He was able to show Stanford that at times all four study the locomotion of fish. His Brett respirometer could
of the horse’s feet were off the ground. Muybridge’s interest control water velocity and measure oxygen consumption and
in animal motion culminated in Animal Locomotion, a series carbon dioxide production. In the 1980s, wind tunnels were
of 11 books containing more than 100,000 photographs of used to fly birds specially fitted with masks to measure oxy-
moving animals. Advances in photographic technologies gen consumption. In recent years, more sophisticated
continue to benefit locomotion research. High-speed cine- respirometry gear has been used to measure the costs of
matography can capture more than 1000 frames per second. movement in animals as small as bees and ants and as fast
When combined with force-sensitive plates embedded in the as hummingbirds and tunas. By combining biomechanics
floor, biomechanics researchers can calculate the forces ex- and bioenergetics, researchers are able to explore the ori-
erted on the muscles and bones as animals move. gins of variations in muscle energetics and efficiency. 2
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Locomotion
Overview or starve. Regardless of how fast or how far an an-

imal travels, the ability to move requires coordina-
Locomotion is usually defined as the act of moving tion of diverse physiological systems.
from one place to another. To an animal physiolo- Superimposed on the control of body move-
gist, locomotion is an active process that is initi- ment are the constraints of the environment. Each
ated and controlled by the animal. Locomotor environment, whether aquatic, aerial, or terres-
systems integrate anatomy with several physiolog- trial, has physical properties that animals must
ical systems. Appendages such as fins, legs, and overcome in order to move.
wings allow animals to interact with the environ-
ment to generate or control forces that result in di-
rectional movement. The physical organization of
muscles into musculoskeletal systems allows ani- Locomotor Systems
mals to translate cellular contraction into whole
We begin our discussion of locomotor physiology
animal locomotion. The musculoskeletal system
by exploring the nature of the systems that sup-
acts in combination with the nervous system to
port movement. We turn our attention to the way
control the position and movement of appendages.
different types of muscles are integrated into a
Locomotion demands exquisite control of energy
musculoskeletal system composed of muscles and
metabolism and digestive physiology, mediated by
skeleton, held together by connective tissue, con-
the hormones that regulate fuel assimilation, stor-
trolled by the nervous system, and nourished by
age, and mobilization. The respiratory system en-
the blood supply. These musculoskeletal systems
sures that oxygen uptake eventually matches the
allow animals to translate changes in cell shape
increased oxygen demands that accompany muscle
into movement.
activity. The cardiovascular system delivers fuels to
the muscle and removes metabolic end products.
The interactions between these systems are sum-
marized in Figure 1.
A hallmark of locomotor systems is the ability
Muscle Fiber Types
to respond to changes in demand. This capacity is Most animals rely on muscles to generate the
particularly impressive in animals that undergo force required to move from place to place. Each
long-distance migrations. Prolonged changes in style of movement requires muscles that possess
activity (training or detraining) alter the locomotor appropriate biomechanical properties.
machinery. Humans are one of the few species The contractile properties of a muscle are
that has the luxury of becoming detrained. In the determined by the design and organization of the
natural world, detrained animals tend to get eaten proteins within the myofiber. The properties
of contractile proteins alter
crossbridge cycling dynamics. The
cellular machinery ofexcitation-con-
Motor neurons Muscles
traction coupling affects the
kinetics of contraction and relax-
Cardiovascular
system
Skeleton ation. The three-dimensional
Sensory Central nervous arrangement of sarcomeres deter-
system system
Respiratory mines how much force a skeletal
Blood vessels
system muscle can generate. Through dif-
ferences in protein properties and
Digestive Musculoskeletal structural organization, animals can
system system
produce muscles with particular
Figure 1 Control of locomotion Animals move in response to contractile phenotypes that enable
environmental cues, both favorable (such as food) and unfavorable (such as local animals to move in the environment.
hypoxia). Sensory neurons receive the information and signal the central nervous
system, which initiates locomotion by signaling via motor neurons to locomotor
muscle. The cardiovascular system controls the flow to blood vessels. Metabolites
from the digestive system and O2 from the respiratory system enter the blood and
serve the musculoskeletal system.
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Locomotion
In the following sections, we discuss how animals As with the gut musculature, these muscles al-
incorporate muscles into locomotor systems. low the animal to produce peristaltic waves of con-
traction. Earthworms use the same principle, but
because they are segmented, each body segment
Many invertebrates use simple circular works independently, giving the earthworm a
and longitudinal muscles to move much greater degree of control over movement
With the exception of the arthropods, most ter- (Figure 3).
restrial invertebrates move by crawling. Simple Directly beneath the outer layers of the earth-
muscles work in combination with a fluid-filled worm cuticle and epidermis lies the thin layer of cir-
internal chamber that acts as a hydrostatic cular muscle. The thicker longitudinal layer of
skeleton. Invertebrate locomotor muscles are
typically striated, although the myofibers are of- Direction of movement
ten organized in ways that differ from vertebrate
striated muscles.
Most wormlike invertebrates crawl using
overlapping layers of muscle fibers. Nematodes
use two layers of fibers running in different ori-
entations along the longitudinal axis (Figure 2). Contraction of Contraction of
When the muscle fibers contract on one side, longitudinal muscle circular muscle
coelomic fluid is forced into the opposite side and (a)
the worm bends. The nematode uses cycles of
contraction and relaxation to undulate through
the environment.
Earthworms organize locomotor striated mus-
cles into circular and longitudinal layers. This Cuticle
arrangement is reminiscent of the organization of Epidermis
Circular muscle
smooth muscles of our digestive tract
Longitudinal muscle
Direction of movement Setae
Protractor
Nematode muscle Seta
Retractor
muscle
Longitudinal
muscle
Circular
muscle
Muscle fiber
(b)
Figure 3 Earthworm locomotion (a) Earthworms

move using waves of muscle contraction that act in conjunction
with the hydrostatic skeleton. Contraction of circular muscle
reduces the diameter of the worm and pushes coelomic fluid
forward. Longitudinal muscle contraction pulls the posterior
segments of the worm forward. (b) This pattern of muscle
Muscle contracted Muscle relaxed
contraction translates into locomotion with the help of a series
of hairlike setae that anchor segments of the worm to the
Figure 2 Nematode muscles and crawling substratum. The attachment of setae is under muscular
Nematodes move through the soil using undulations. The control. Protractor muscles force setae outward to lock onto
body bends when overlapping muscle fibers contract on one the substrate. Retractor muscles pull setae back toward the
side of the body and relax on the other side, forcing a body, releasing the surface. Movement requires coordination of
redistribution of coelomic fluids. the muscles of the body wall and setae.
609
Locomotion
muscle is composed of groups of muscle cells Direction of movement

arranged into fan-shaped (pennate) bundles. Each
bundle is surrounded by a basement membrane,
and bundles are bound together by connective tis-
sue. A ring of nerves circles the segment, running Siphon Mantle
between muscle layers, with axons extending to-
ward the muscles. When the circular muscle con-
Water
tracts, the coelomic fluid is pushed forward to Mantle muscles contract
extend the segment. Once the segment is extended, (a)
tiny hairlike projections called setae attach to the
soil or other substrate surface. When the longitudi-
nal muscle contracts, the anterior end of the seg-
ment remains in place and the posterior part of the
segment is pulled forward. The nerve networks co-
ordinate the movement of circular and longitudinal
muscles and the patterns of activity in the inde-
pendent segments.
Squid, the fastest of aquatic invertebrates, also Circular fiber
(mitochondria-poor)
use complementary muscle layers to move, but the
arrangement is quite different. The muscles of the
outer body wall, or mantle, are intermingled in two
planes (Figure 4). Radial muscle fibers extend from Radial
the inside of the mantle to the outside. Contraction of fibers
the radial muscles reduces the thickness of the man-
tle wall and reduces its circumference. Circular mus-
cle, which surrounds the mantle, is composed of
three layers. A thick central layer of muscle with low
Circular fiber
mitochondrial content is covered on the inside and (mitochondria-rich) Skin
outside by a thin layer of mitochondria-rich muscle
cells. Squid use these complex mantle muscles to (b)
produce jet propulsion. Water enters the internal Figure 4 Squid jet propulsion (a) Squid produce jet
chamber when the mantle muscles relax. Upon con- propulsion by forcing water from the body cavity out of a
traction, water is rapidly ejected out of the mantle tubelike siphon. Water moves in and out of the body cavity in
response to muscular contractions of the body wall, or
cavity through a tube, or siphon, creating a flume of
mantle. (b) The mantle is composed of complex, intertwined
water that pushes the squid forward. The giant axon layers of muscle fibers. Radial fibers control the thickness of
ensures that electrical stimulation of the mantle the mantle. The diameter of the mantle is controlled by three
muscles occurs in unison to maximize the force of layers of circular muscles.
water expulsion. The anatomical complexity of the
muscles has made it difficult to assign specific roles for two main reasons. First, fish morphology dif-
to each muscle fiber type, but in general the squid fers widely for reasons that are intuitively linked
can use these muscles in combinations that allow it to locomotion. Second, swimming muscles of fish
to regulate the force of the water jet, enabling it to are composed of homogenous fiber types, in con-
hover, cruise, or dart from place to place. Flying trast to muscles of most other vertebrates. The
squid use the jet to leap as much as 3 m out of the natural diversity in anatomy, ecology, behavior,
water, then use their lateral fins to glide at velocities and evolutionary biology creates research oppor-
in excess of 25 km/h. tunities for physiologists studying the fundamental
principles of muscle function and the molecular
basis of different locomotor strategies. Or, put an-
Fish use two or three fiber types to swim other way, studies using fish have helped us un-
Much of our understanding of the importance of derstand muscle, and studies of muscle have
muscle fiber types comes from early studies on helped us understand the biology of fish.
fish. Comparative physiologists are lured to fish
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Locomotion
Fish build their locomotor muscle from two ments. Red muscle is an oxidative fiber type that
main types of muscle fibers: red and white muscle supports slow, steady-state cruising activity. Many
(Figure 5). Muscle fibers of fish are still described fish have a third type of locomotor muscle called
by these colorful terms, whereas the muscles of pink muscle that is intermediate in contractile
tetrapods are more commonly designated by their properties. Pink muscle is typically found at the in-
myosin isoforms (e.g., Type I, IIa, IIb, IIx). White terface between the white and red muscles. Each
muscle makes up most of the muscle mass of the region of locomotor muscle is virtually homoge-
fish, typically about 60% of the body mass and neous in fiber type. This anatomical organization
about 85% of the muscle. The white muscle is a is convenient for researchers who study the cellu-
glycolytic fiber type that is responsible for high-in- lar origins and physiological function of different
tensity, burst swimming. Red muscle is usually muscle fiber types.
confined to a narrow ribbon that extends along the The organization of fish muscle retains many of
side of the animal just under the lateral line. Small the properties established early in its development.
patches of red muscle are also found at the base of Many of us are familiar with fish muscle anatomy
fins, where they are used to power the fin move- from our experience at dinner. A well-cooked fish
filet can be dissected into parallel layers of white
muscle. Each layer is a myotome, one of the origi-
Single myotome
nal segments established early in embryological de-
velopment. Each myotome contains blocks of
parallel white muscle fibers separated by a thin
Rib
layer of connective tissue called the myoseptum.
Each myotome is attached to the posterior region of
Spine
the fish by tendons. The skin also acts as a sheath
that connects the different myotomes, helping to in-
tegrate the force of the different contractile units.
Contraction of a myotome generates force that is
transmitted in complex ways to other regions of the
body. Force is transferred to the next myotome
Lateral line
across myosepta, to the caudal fin along tendons,
and to the skin. These forces culminate in move-
ment of the trunk and tail to generate propulsion.
Force generation in red muscle also relies on the
skin and tendons that insert at the tail. This
arrangement converts contractile force directly to
movement of the trunk and tail.
The pattern of locomotor muscle

White muscle
contraction is controlled by motor neurons
The differences in the contractile properties of ox-
idative (red) and glycolytic (white) muscle enable
Red muscle the animal to produce different types of move-
ment. Although most easily shown in fish, these
same general rules apply to tetrapods. Red muscle
exhibits its maximal power output at much lower
tail-beat frequencies than does white muscle. Con-
Figure 5 Musculature of fish Fish white muscle is sequently, fish use red muscle in slow swimming
composed of more than 100 repeating units called myotomes. and white muscle at higher velocities. In living
They extend backward from the spine, twisting forward as fish, this pattern of sequential activation of muscle
they approach the exterior surface of the fish. Narrow strips
contraction, called recruitment, is determined by
of red muscle are found laterally along the length of the fish.
Pink muscle (not shown) often separates motor neurons, under the control of the central
the red from the white muscle. nervous system.
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Locomotion
Researchers study muscle recruitment in living are activated more frequently. At still faster speeds,
fish by fitting them with electromyograph (EMG) white muscle is activated. At high swim velocities,
electrodes and inducing them to swim at different red muscle may continue to be activated but it
velocities. The EMG output shows that at low swim doesn’t generate much power. Fish can swim con-
speeds only the red muscle is electrically active tinuously for hours at speeds where only red mus-
(Figure 6). As swim speed increases, red muscles cle is active. At faster speeds, where white muscle
is recruited, fish quickly become exhausted.
The importance of neuronal control of locomo-
tor movement can be illustrated using the lam-
White muscle
prey, a primitive fish that swims by simple
Power output
snakelike undulations. Like other fish, the lamprey

has superficial red muscle and deep white muscle
organized into about 100 myotomes. Nerve roots
Red muscle
from the corresponding segment of the spinal cord
innervate each myotome. Separate nerves inner-
vate the muscles on each side of the fish.
When the lamprey swims, one side of the
0 2 4 6 8 10 12 14 16 18
body contracts while the opposite side relaxes
Tail-beat frequency (Hz)
(Figure 7). Contractions begin anteriorly, then
(a) move posteriorly. When a lamprey swims in a
straight line, the nerves on one side fire, while the
contralateral nerves are silent. The alternative fir-
White muscle ing pattern of the motor neurons is coordinated
by excitatory and inhibitory interneurons. Nerves
along the spinal cord fire in rapid succession to
Red muscle
stimulate a wave of contraction along the body.
After a motor neuron has fired, the interneurons
allow the excitation of the motor neurons inner-
vating the opposite side. The wave of contraction
on one side is followed by a wave on the other
1 sec 1 sec 1 sec side. When a lamprey needs to swim faster, it in-
Red creases the firing frequency. This causes the body
muscle to undulate faster and more often, but the pattern
White
muscle
A B
1 body 2 body 3 body A
length/sec lengths/sec lengths/sec
C B
(b)
C
Figure 6 Swimming velocity and muscle
recruitment (a) Power output of isolated muscle can be D D
assessed over a range of frequencies of electrical stimulation.
Red muscle has a lower power output than white muscle, and it
generates its optimal power at a lower frequency. (b) Electrical 1 sec
activity of red and white muscle in living fish can be measured
by electromyography. The different muscle fiber types are Lamprey
recruited at different swim velocities. At low velocities (one
body length per second), only red muscle is active. As velocity Figure 7 Swimming lamprey The lamprey swims
increases, the frequency of contractions increases. Once swim by anguilliform movement, using waves of contraction of
velocity exceeds a threshold (in this example, two body lengths trunk muscles. Each burst of electrical activity on an EMG
per second), white muscle is activated. Red muscle continues recording signifies a muscle contraction. When muscles on
to contract, but the force it generates contributes little to one side of the body are activated, the muscles on the
locomotion at high velocities. opposite side are inhibited. The waveform is generated by
(Sources: Based on (a) Altringham and Johnson, 1990 and sequential activation of muscles along the length of the body.
(b) Johnston, 1981.) (Source: Orlovsky et al., 1999)
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Locomotion
of change in body shape (an S shape) is the same

at all velocities. This intricate pattern of motor
nerve activity is generated by the spinal cord in
response to signals sent from the brain.
Tetrapods have a multiplicity of fiber types

Fish locomotion using the trunk and tail is rela-
tively simple in terms of both muscle organization
and neuronal control. However, once vertebrates
made the transition to land, movement required
much more complex locomotor muscles and neu-
ronal controls. Whereas fish can get by with two
Figure 8 Mosaic of fibers in tetrapod locomotor
or three muscle fiber types, tetrapods build indi- muscle Most tetrapods possess muscles that are mosaics
vidual muscles using combinations of fiber types. of different fiber types. In the rat diaphragm muscle shown
The limb musculature of tetrapods is developmen- above, the fiber types are distinguished by
tally homologous to the fin musculature of fish. immunohistochemistry, using fluorescent antibodies that
bind to specific myosin heavy chain isoforms. Type I fibers are
Tetrapods have great diversity in how they use shown in red, Type IIa in green, Type IIb in blue, and Type IIx/d
their limbs in movement, but the organization of in black.
muscles is similar in amphibians, reptiles, birds, (Image courtesy of Dr. Gary Sieck, Mayo Clinic)
and mammals. Each group of tetrapods draws
upon large suites of muscle contractile proteins to ofibers can be a heterogeneous fiber type. When
create diverse fiber types. these myo-fibers contract, they demonstrate prop-
Much of our understanding of tetrapod muscle erties that are intermediate between pure fiber
function comes from studies on the hindlimb mus- types. Heterogeneity is also evident when looking at
cles that frogs use to jump. Like fish locomotor the whole muscle, which is a collection of hundreds
muscle, the jumping (extensor) muscle of a frog is of individual myofibers. Most tetrapod muscles are
relatively pure in fiber type. Researchers from mosaics of different fiber types (Figure 8). Consider
many physiological disciplines value the frog the composition of the soleus muscle of tetrapods,
hindlimb preparation as an experimental tool. the muscle that originates below the knee joint and
Frog extensors are easily removed from the ani- inserts at the Achilles tendon. The soleus muscle of
mal and remain stable, enabling researchers to most tetrapods is composed predominantly of
work with the preparation for long periods. Bio- slow-twitch fibers, but as many as 20% of the fibers
mechanics researchers focus on the hindlimb be- might be other fiber types. Other hindlimb muscles
cause of its activity during jumping. When frogs are also mosaics of several muscle fiber types. The
leap with their strongest contractions, virtually complexity of tetrapod muscle fiber types is neces-
every fiber of the extensor muscles is recruited. sary because the muscles are used in different com-
Cell biologists use frog extensors because they can binations to perform many distinct styles of
isolate intact, single fibers, which facilitates the movement. The frog uses its hindlimb muscles to
exploration of cellular and genetic properties. swim, walk, and jump. Mammals use hindlimb
The diversity in muscle composition in muscles to stand, walk, jog, swim, sprint, and jump.
tetrapods is evident at many levels of biological or- Forearm muscles enable birds to use their wings to
ganization. Recall from what you've learned that flap, glide, and undertake complex aerial maneu-
skeletal muscle cells, or myofibers, are multinucle- vers. The complex fiber type profiles of muscles are
ated cells. Each nucleus within a single myofiber essential to the versatility of muscle utilization.
usually expresses the same genes for contractile
proteins. That is, each myofiber is usually of a pure
fiber type because all nuclei within the cell express
Locomotor muscles are organized into
the same myosin heavy chain isoform gene. How-
locomotor modules and functional groups
ever, hybrid fibers can also occur, forming when in- Most tetrapods move using cyclical changes in the
dividual nuclei within a myofiber express different position of limbs. When a limb bends at a joint, the
myosin heavy chain genes. Thus, even single my- movement is called flexion. The limb straightens
613
Locomotion
during extension. Flexion and extension are in- tural muscles of the back and abdomen are re-
duced in response to the contraction of separate cruited to maintain balance during movement. All
antagonistic muscles (Figure 9). For example, of the muscles that are responsible for a type of
when a primate bends its arm (flexion), the biceps movement are grouped together into a locomotor
muscle contracts while the triceps is relaxed. Ex- module.
tension occurs when the triceps contracts while Bird flight musculature is another example of a
the biceps is relaxed. Limb movement in support locomotor module. The musculature that powers
of locomotion typically involves complex combina- flight in birds is derived from the same appendicu-
tions of muscles that work together to move each lar musculature that supports the movement of
segment of the limb in a coordinated manner. forearms in tetrapods. As in other vertebrates,
Consider the muscles used in the mammalian muscles work in antagonistic groups to power wing
hindlimb during walking. An extensor group of leg movements. The pectoralis muscle powers the
muscles works synergistically to move the leg for- downstroke. This is a very large muscle, often ap-
ward; a flexor group of muscles works synergisti- proaching 35% of the body mass of the bird. It is at-
cally to pull the leg back. The extensor group tached at one end to the keel bone, and at the other
includes the soleus and gastrocnemius, which end to the humerus. The supracoracoideus muscle
bend the foot; the quadriceps and rectus femoris, powers the upstroke. It attaches to both the keel
which straighten the knee; and the gluteus, which and the end of the humerus. Most birds use this
works at the hip to swing the leg forward. The muscle to rotate the humerus, and return the wing
flexor group includes the tibialis anterior, which to the correct position in preparation for the down-
moves the foot; the hamstring group, which bends stroke. The relative sizes of the pectoralis and
the knee; and the iliopsoas, which rotates the leg supracoracoideus muscles reflect the way a bird
at the hip. These muscle groups work antagonisti- flies (Figure 10). Hovering birds, such as humming-
cally; contraction of one muscle group requires re- birds, possess very large supracoracoideus muscles
laxation of the other muscle group. In addition to to rapidly pull the wing upward. More than 45 dif-
the muscles that move the leg, other suites of mus- ferent muscles contribute to the fine control of the
cles participate in movement. The fine muscles of wing, including the position of feathers.
the feet work in combination with sensory infor- In contrast to the simple nervous control of lam-
mation collected by proprioceptors in the skin to prey swimming, coordination of limb movement in
make fine-scale adjustments in position. The pos- tetrapods requires the integration of countless motor
nerves, interneurons, and overlapping
feedback controls. This complexity can
make it much more challenging to
study motor control in tetrapods. For
this reason, simple systems such as fish
swimming musculature and frog exten-
Biceps Biceps
relaxes contracts sor muscles remain valuable tools for
exploring neuronal control of verte-
brate locomotor muscle.
Triceps
Triceps relaxes
contracts
Energy Metabolism
Extension Flexion
Muscle activity demands a great deal
of energy, mainly in the form of ATP.
The actinomyosin ATPase uses ATP to
provide the energy for cross-bridge
cycling. The Na⫹/K⫹ ATPase uses ATP
to reestablish ion gradients across the
Figure 9 Antagonistic muscle groups A limb straightens when extensor
muscles contract and bends when flexor muscles contract. In the forelimb of
sarcolemmal membrane after each
primates, the biceps is the primary flexor muscle and the triceps is the main action potential. The Ca2⫹ ATPase
extensor muscle. uses ATP to transport cytoplasmic
614
Locomotion
Upstroke Downstroke Humerus

Scapula
Coracoid
Pectoralis
Keel
Supracoracoideus
(a) Flapper
Upstroke Downstroke
Pectoralis
Supracoracoideus
(b) Hoverer
Figure 10 Bird flight muscles Birds use their pectoralis muscle to power the
downstroke, and their supracoracoideus muscle for the upstroke. (a) Birds that fly by flapping
their wings, such as the seagull, have a very large pectoralis muscle. (b) The hovering flight of
hummingbirds also requires a strong supracoracoideus muscle because force is generated on
both the downstroke and the upstroke.
Ca2⫹ back into the sarcoplasmic reticulum. Since these preexisting energy pools can support loco-
working muscles can have high rates of ATP motion only for very short periods, other path-
turnover, let’s discuss how the unique features of ways of ATP production are critical. Most
the pathways of energy metabolism are integrated locomotor activity is supported by some combina-
into muscle structure and function. tion of anaerobic glycolysis and mitochondrial
aerobic metabolism. These two pathways differ in
five main respects that determine how they sup-
Glycolysis and mitochondria support port muscle activity.
different types of locomotion 1. Metabolic efficiency. Oxidative phosphoryla-
Muscle contraction is an energetically expensive tion produces more ATP per glucose molecule
process, and shortfalls in energy production can than does glycolysis (36 versus 2 ATP per glu-
compromise locomotion. Muscles meet energy de- cose). As a result, all muscles rely on oxidative
mands using a combination of preformed phos- phosphorylation to support metabolism at rest
phagens and ATP-producing pathways. The and during recovery from activity. Slow-twitch
preformed phosphagens include the adenylate muscles (such as fish red muscle) rely on oxida-
pool (ATP and ADP) as well as the phosphoguani- tive phosphorylation to support muscle activity.
dine compounds; vertebrates use phosphocrea- 2. Rate of ATP production. Though less efficient,
tine, and invertebrates use one or more of glycolysis can generate ATP faster than oxida-
phosphoarginine, phosphoglycocyamine, phos- tive phosphorylation. When an animal must
photaurocyamine, or phospholambricine. Since move very quickly, ATP must be produced at
615
Locomotion
rates that cannot be met by mitochondria. A and the evolution of aerobic capacity. The network
cheetah chasing a gazelle relies on glycolysis to of mitochondria, or reticulum, is particularly well
provide the ATP that allows it to reach high developed in the locomotor muscles of active organ-
sprint speeds. Although glycolysis allows the isms, allowing the mitochondria to operate as a
muscle to produce ATP very quickly, limited more efficient electrical network. Antarctic fish also
stores of glycogen mean the less efficient gly- have an extensive mitochondrial reticulum, but in
colytic pathway quickly runs out of fuel. Thus, these animals the reticulum may improve the effi-
the cheetah must capture its prey within a short ciency of oxygen delivery into the cell. Since oxygen
period or its muscle will run out of the carbohy- dissolves more readily into lipid than water, the in-
drate fuels necessary to support sprinting. terconnected mitochondrial membranes facilitate
3. Dependence on oxygen. In the absence of oxy- oxygen delivery into the depths of the cell. This may
gen, glycolysis is the only option to produce be an important mechanism to facilitate oxygen
ATP. During high-intensity activity, oxygen can- delivery into the cell, since many of these animals
not be delivered to muscle fast enough to meet lack the oxygen-carrying proteins hemoglobin and
ATP demands by mitochondrial metabolism myoglobin.
and the tissue becomes functionally hypoxic. The mitochondrial inner membrane structure
Hypoxic muscle relies on internal glycogen also reflects the premium on intracellular space.
stores and produces lactate, metabolic distur- The cristae, which possess the enzymes of oxidative
bances that must be rectified during recovery. phosphorylation, are densely packed to compress a
high catalytic potential into a small space. Each mil-
4. Fuel diversity. Glycolysis relies exclusively on
liliter of mitochondria possesses 20–40 m2 of inner
carbohydrate, whereas mitochondria can gen-
membrane. Imagine 400–800 pages of this textbook
erate energy from oxidation of carbohydrates,
folded into a space the size of the end of your thumb.
lipids (fatty acids), and amino acids. Fuels for
Some “athletic” species possess more densely
muscle activity can be derived directly from
packed cristae, sometimes approaching 70 m2/ml of
the diet or mobilized from intramuscular
mitochondria. At this high cristae density there is
stores or extramuscular storage depots.
barely enough space between cristae to fit two mol-
5. Rate of mobilization. Muscles possess low lev- ecules of an average mitochondrial matrix enzyme.
els of fuels that can be oxidized immediately
Mitochondrial content varies widely among
(glucose, fatty acids, glycerol, free amino acids).
muscle types and species. The sparse mitochon-
Muscles consume these fuels rapidly, so ani-
mals must mobilize stored fuels to sustain mus- dria in glycolytic muscle fibers typically occupy
cle activity. Each type of metabolic fuel can be less than 2% of the muscle intracellular space. The
mobilized at a characteristic rate. When muscle mitochondrial content of oxidative muscles is usu-
activity begins, glycogen hydrolysis begins ally 3- to 10-fold greater than that of glycolytic
within a fraction of a second. If muscle activity muscles in the same animal. In the flight muscles
continues, other fuel depots are mobilized. of insects and hummingbirds, which contract at
very high frequencies, almost half of the muscle
intracellular volume is occupied by mitochondria.
Mitochondrial content influences Furthermore, the mitochondria in these animals
muscle aerobic capacity also possess a very high cristae packing density.
Oxidative phosphorylation is central to the energet-
ics of most muscles, and mitochondrial content is an
important determinant of muscle aerobic capacity. Muscle must recover from
Muscle mitochondria are constructed in ways that high-intensity activity
pack maximal metabolic capacity into minimal High-intensity activity is fueled by intramuscular
space. Many aspects of muscle mitochondrial struc- stores of glycogen. As fast-twitch muscles undergo
ture and function are similar across the animal king- glycolysis, lactate is produced. The muscle becomes
dom. Although the mitochondrial content of muscles exhausted from the combination of energetic short-
may vary widely across muscle fiber types, muscle falls, ion disturbances, and pH imbalance. To re-
mitochondrial properties are similar across species. cover from burst exercise, muscles must replenish
However, some exceptional species show specializa- energy stores, including glycogen, ATP, and phos-
tions that reflect the limits of mitochondrial function phocreatine. They must also reestablish ion gradi-
616
Locomotion
ents, Ca2+ stores, and pH. An important element of flip its tail. With just a few tail flips, the pike acceler-
recovery is removal of the lactate that results from ates up to 5 g, roughly the equivalent of the acceler-
anaerobic glycolysis. At the end of exercise, lactate ation of a jet fighter. If the pike misses its target with
can have many different fates (Figure 11). Some the initial thrust, the prey can escape because the
muscles use lactate as a fuel to rebuild glycogen pike cannot immediately mount a second attack. In-
stores. Other muscles export the lactate for process- stead, it returns to its hiding spot and begins the
ing by other tissues. Some bloodborne lactate is ox- long, slow process of metabolic recovery. The north-
idized by other aerobic tissues, such as the heart. If ern pike, for example, requires many hours for its
muscles release lactate into the blood, they must im- muscle to return to the preexercise metabolic state.
port glucose from the blood to rebuild muscle glyco- Recovery following intense muscle activity re-
gen stores. Many animals use the Cori cycle to quires both metabolic and cellular corrections,
replenish muscle glycogen. In this pathway, muscle- each of which requires energy investment. Resyn-
derived lactate is imported by the liver, which uses it thesis of ATP, phosphocreatine, and glycogen re-
to resynthesize glucose. Liver glucose is then requires oxidative phosphorylation. Energy is also
leased into the blood and taken up by muscle, which required to reestablish ion distributions across
can use it to produce glycogen. The relative impor- membranes (H+, Ca2+, K+, and Na+). Muscle activity
tance of each pathway depends on muscle type and can also cause physical damage to the muscle,
species. which must be repaired during recovery. The en-
Consider the example of the northern pike, a ergy for these processes is provided by mitochon-
fish that lives in northern temperate waters. It drial oxidative phosphorylation. Recovering animals
spends most of its time hiding in the weeds waiting often show elevated rates of oxygen consumption
for unsuspecting prey to approach. When it sees a (EPOC) long after exercise has ceased, a phenome-
small fish or frog, the pike uses its white muscle to non call oxygen debt (Figure 12).
Glycolytic muscle Metabolic transitions accompany

prolonged exercise
Glycogen
Cori cycle Locomotor activity poses unique challenges for
animals. During activity, muscle cells must pro-
duce ATP at high rates. Metabolic fuels, primarily
Lactate
O2 consumption
Lactate Lactate
Elevated
postexercise
O2 consumption
CO2 Glucose
Resting
Heart, red muscles Liver
(oxidation) (gluconeogenesis) Exercise Recovery
Time
Figure 11 Lactate metabolism during recovery
from activity High-intensity exercise in glycolytic muscles Figure 12 Elevated postexercise oxygen
causes buildup of lactate. When exercise ceases, lactate is consumption Exercise causes a rapid increase in the
removed by many different pathways. Some lactate is used to rate of oxygen consumption. Once exercise ceases,
resynthesize glycogen in the glycolytic muscle. Lactate can also respiration declines but remains elevated above the resting
be released into the blood and taken up by the liver, which uses rate for extended periods. The duration of this elevated
it to produce glucose. Oxidative tissues, such as heart and red postexercise oxygen consumption, or oxygen debt, depends
muscle, can oxidize lactate as a fuel. on the intensity of exercise and varies among species.
617
Locomotion
carbohydrate and lipid, must be mobilized from

1.2
intracellular stores or storage tissues. These
metabolic processes must be precisely coordi-
nated to ensure that ATP synthesis matches ATP 1.1
demand. Consider the following two examples.
Respiratory quotient
The hovering hummingbird has one of the 1.0
highest mass-specific metabolic rates in the ani- Hovering
flight
mal kingdom. It must fly to feed, and it must eat 0.9
in order to fly. It is an extreme example of the sort
of metabolic transitions most animals face in inte- 0.8
grating nutrient consumption with activity. Each
summer morning the hummingbird wakes and Rest
0.7
flies from flower to flower, drinking nectar. Occa-
sionally, it eats an insect. Most of its waking hours
0.6
are spent perching. Its nectar diet is almost exclu- 0 5 10 15 20 25
sively sucrose, so you might assume that its meta- Time in flight (min)
bolic regulation is simple. Looking closer, however, Figure 13 Hummingbird flight metabolism
you will discover that complex metabolic control is Hummingbird respiration was monitored by oxygen and CO2
needed to accommodate the daily changes in feed- sensors incorporated into a feeder. The metabolic fuel being
ing, flying, and sleeping. When the hummingbird oxidized is reflected in the respiratory quotient (RQ), which is
the ratio of CO2 produced to O2 consumed. At rest, birds
is actively feeding on summer flowers, it uses di-
oxidize lipid fuels, as indicated by the RQ of 0.7. Once flight
etary carbohydrate to fuel flight muscle metabo- begins and feeding commences, the RQ rapidly rises to a
lism. It stores any extra dietary sucrose as value near 1, an indication of carbohydrate oxidation.
glycogen and lipid. In the evening, the humming- (Source: Adapted from Suarez et al., 1990)
bird cannot feed and must rely on energy reserves
to sustain its resting metabolic demands. It also
becomes hypometabolic, allowing its body tem- sockeye salmon, may travel more than 1000 kilo-
perature to fall to reduce metabolic demands. In meters through stretches of swift currents
the morning, the hummingbird supports its first (Figure 14). During their migration salmon don’t
flight by oxidizing fatty acids mobilized from tis- eat, and must rely on internal energy stores.
sue stores. As soon as it obtains its first nectar Large fat stores fuel the earliest stage of migra-
meal, its metabolism switches to carbohydrate tion but become depleted later in the migration.
utilization and lipid storage. The transitions in With most of its major fuel stores reduced, the
fuel selection can be monitored by measuring the salmon has no choice but to start breaking down
ratio of CO2 production to O2 consumption, known endogenous proteins. The fish then starts to
as the respiratory quotient, or RQ (Figure 13). break down its muscles and intestinal tract, re-
Each metabolic fuel generates a characteristic RQ: leasing the chemical energy stored within the tis-
0.7 for lipids, 1.0 for carbohydrates. This daily cy- sues. The salmon first breaks down the white
cle continues throughout the feeding season, but muscle that is no longer needed for high-inten-
as winter approaches many species of humming- sity swimming, but it spares the red muscle it
birds reorganize metabolism to prepare for mi- uses for slow, steady-state swimming. Some
gration. An important step is an increase in their amino acids are oxidized within muscle, but
lipid stores. A 3-g hummingbird may put on 2 g of many are converted to glucose in the liver. Late
fat prior to its migration. in the migration, glycogen and glucose support
The migration of the Pacific salmon provides the vigorous spawning activity. During this entire
another good example of metabolic transitions. trip the salmon coordinates its whole body me-
Salmon live several years in the open ocean, vig- tabolism to make fuels available to working mus-
orously feeding, growing, and preparing energy cle while sparing the reproductive tissues needed
stores for a final reproductive migration. When for gamete production. By the time the salmon
mature, Pacific salmon migrate from the ocean spawns, it has depleted energy stores and di-
into rivers to reproduce in their natal spawning gested its own tissue. Shortly thereafter, the
beds. Some populations, such as the Fraser River salmon dies.
618
Locomotion
Glycogen
Fat Fat
Protein
Fr
as Glycogen
er
Ri
ve
Protein r
British
Columbia Glycogen
Fat Protein
Direction of
migration Glycogen
Protein
Fat
Glycogen
Protein
Fat
Energy expenditure
Figure 14 Salmon migration During their time at sea, salmon bolster their energy
reserves in preparation for migration. Those that spawn in the upper reaches of the Fraser
River in western Canada utilize stored lipids prior to digesting their own tissues for energy.
Throughout the migration glycogen is spared, or replenished, being reserved for the high-
intensity exercise required for spawning.
Hormones control fuel oxidation in muscle steady-state activity, muscles are promiscuous in
The salmon life history is an extreme version of their fuel preferences, utilizing whichever fuels
metabolic transitions, but all forms of muscle ac- are abundant. The levels of metabolic fuels in the
tivity require complex control of metabolic fuel uti- blood are determined by the balance of actions of
lization. Most animals rely on a combination of many different hormones, such as insulin,
carbohydrate and lipid for muscle ATP production. glucagon, catecholamines, and glucocorticoids.
The carbohydrate can be derived from muscle Each hormone has effects on storage tissues that
stores, mainly glycogen particles, but circulatory influence production or release of fuels. These
glucose is also an important fuel. Muscle main- hormones can also alter the ability of locomotor
tains a store of lipid in the form of triglyceride muscles to use the fuels by altering the levels of
droplets. The blood also provides lipids from transporters and the activities of metabolic en-
breakdown of lipoproteins. Most of the energy for zymes. During low to moderate activity, glucose
muscle activity is produced when mitochondria remains an important metabolic fuel. Glycogen
oxidize pyruvate, from carbohydrate, and fatty breakdown is stimulated in muscle and liver. In-
acids, from lipid breakdown. The pathway for sulin and cortisol act together to promote liver
muscle metabolic fuel consumption is summarized glycogen breakdown and glucose export into the
in Figure 15. blood. Insulin enhances glucose uptake by the
Many of the steps in fuel breakdown change in muscle by stimulating the movement of glucose
response to activity level. These metabolic transi- transporters from intracellular vesicles to the sar-
tions are orchestrated by hormones that act on colemma. Whereas glycogen stores in the liver
skeletal muscle and fuel storage tissues. During and muscle can be mobilized quickly, lipid fuels
619
Locomotion
Lipoprotein
Glucose (with triglyceride) Fatty acid
Endothelium Blood flow
cell of blood
vessel
Lipoprotein lipase
Glucose
transporter Fatty acid translocase
(GLUT-1) (FAT/CD36)
Muscle
plasma Triglyceride
membrane Glucose Fatty acid
Glycogen Hormone-
sensitive
Vesicle lipase
Pyruvate Fatty acyl CoA
Glucose transporter
(GLUT-4) Carnitine palmitoyl
transferase 1 (CPT-1)
Mitochondria
Carnitine acyl
carnitine exchanger
Carnitine palmitoyl
transferase 2 (CPT-2)
Monocarboxylate
transporter Fatty acyl CoA
(MCT)
Pyruvate
β - oxidation
Pyruvate
Acetyl CoA
dehydrogenase
Figure 15 Metabolic fuels and exercise. Exercise is fueled by a combination of

carbohydrate and lipid. Some carbohydrate is stored within the muscle in the form of glycogen.
Muscles also use glucose from the blood, arising from digestion or glycogen stores in the liver.
The main source of lipid for exercise is fatty acids arising from triglyceride breakdown. The
muscle has substantial triglyceride stores in the form of lipid droplets. Triglyceride is also
delivered to the muscle by the blood in the form of lipoprotein complexes.
are mobilized more slowly. If activity levels are

sustained, lipid fuels become increasingly impor-
Perfusion and Oxygen
tant. Triglyceride mobilization in skeletal muscle
Delivery to Muscle
and adipose tissue is governed by lipases. In adi- During locomotion, muscles must be supplied with
pose tissue, hormone-sensitive lipase is controlled fuels and cleansed of end products. Muscle meta-
by corticotropin, epinephrine, norepinephrine, bolic rates of some animals are so low that simple
and glucagon. These hormones act through cAMP diffusion is sufficient to ensure adequate move-
signaling cascades to activate protein kinase A, ment of metabolites and gases in and out of the
which phosphorylates the lipase. Muscle also pos- muscle. For example, nematodes and flatworms
sesses hormone-sensitive lipase activity to trigger are able to obtain adequate gas diffusion across
release of fatty acids directly within muscle. By us- the integument and no specialized circulatory sys-
ing hormones that act at the locomotor muscle and tems are necessary. Active animals use cardiovas-
at extramuscular storage sites, animals are able to cular systems to service muscles, removing
control the flow of metabolic substrates to the metabolic end products and CO2, and delivering
ATP-producing machinery. O2, fuels, and hormones to the muscle. Active in-
620
Locomotion
sects, such as bees and locusts, use tracheae to de-

liver oxygen directly to flight muscle, and a muscu-
Krogh
lar heart to push hemolymph through circulatory distance
systems to provide metabolic fuels. Vertebrate
skeletal muscle is perfused by much more compli- Flow direction
cated circulatory networks. In these muscles, arter- Capillary
ies branch into successively smaller arterioles, Diffusion
of oxygen
which divide into thin-walled capillaries. Perfusion
of muscle depends upon the structure of the capil-
Muscle tissue
lary networks and the amount of blood that reaches
the capillaries. (a)
Capillary networks bring oxygen

to the vertebrate muscle fibers Krogh
distance
Oxygen delivery to muscle is controlled by struc-
tural features, such as capillary density, and func- Flow direction
tional parameters, such as vascular tone and the Capillary
oxygen affinity of hemoglobin. Acting in combina- Diffusion
of oxygen
tion with the respiratory and cardiovascular sys-
tems, the muscle controls how much blood reaches
Muscle tissue
the intramuscular capillary beds and how much
Hypoxia zone
oxygen is extracted from the blood.
Once blood enters the vascular beds of muscle, (b)
oxygen may be released from hemoglobin. Oxygen Figure 16 Krogh model of perfusion
is released when the PO2 is low or when physio- (a) The Krogh model of diffusion suggests that each capillary
chemical conditions alter the oxygen affinity of he- is able to provide adequate oxygen to a volume of
surrounding tissue, represented by a cylinder. (b) In many
moglobin. Muscle activity influences oxygen situations, the oxygen levels decline along the length of a
extraction from the blood in several ways. Aerobic capillary. This reduces the volume of muscle that can obtain
metabolism consumes O2, reducing PO2. Changes adequate oxygen. Some areas become hypoxic unless other
in erythrocyte pH or the levels of regulatory capillaries are close enough to provide oxygen.
metabolites, such as diphosphoglycerate (DPG)
and nucleotides, can cause hemoglobin to release
oxygen to the muscle. Once O2 is released from he- from the capillary, and (5) consumption is uniform
moglobin, the rate of diffusion from the erythro- in the tissue. The Krogh distance reflects the dis-
cyte to the muscle mitochondria depends on the tance that oxygen can diffuse into surrounding tis-
steepness of the gradient and the diffusion dis- sue. Using this model, he calculated the dynamics
tance. The diffusion distance is determined largely of oxygen diffusion under various myofiber
by capillary geometry. Diffusion distances are geometries and physiological conditions.
short in aerobic muscles, which have small diam- The Krogh model and the more recent varia-
eters and abundant capillaries. Diffusion distances tions allow researchers to predict oxygen delivery
are greater in glycolytic muscles, which are larger in relation to fiber geometry and metabolic rate.
and possess fewer capillaries. Many of the constants in the original Krogh model
August Krogh first modeled capillary geometry are treated as variables in more recent models. We
as a cylinder within a cylinder (Figure 16a). The now know that oxygen levels can decline along the
inner cylinder represents the capillary that serv- length of the capillary, causing some regions of the
ices a volume of muscle, represented by the outer muscle to become hypoxic (Figure 16b). Capillar-
cylinder. His model assumed that (1) each capil- ies weave back and forth across the muscle; the
lary is the only oxygen supply for a surrounding degree of weaving, or tortuosity, increases the
cylinder of tissue, (2) the PO2 at the vessel wall is transit time for blood cells, allowing longer periods
equal to that of the blood, (3) there is no decline of for oxygen to unload from the cell (Figure 17). Fur-
PO2 along a capillary, (4) oxygen diffuses radially thermore, a specific region of muscle may be
621
Locomotion
capillary beds. The arteriole diameter is deter-

mined by balance between vasoconstricting and va-
sodilating agents. Although we focus on the
changes in perfusion that arise in response to activ-
ity, muscle blood flow is also altered in response to
nutrient status. Muscle is a major sink for glucose
after a high-glucose meal. Insulin causes increases
in muscle blood flow as part of a mechanism to en-
hance muscle glucose uptake and glycogen storage.
Muscles also alter their perfusion by inducing
the pathways of angiogenesis, which lead to syn-
thesis of additional blood vessels. Angiogenesis is
triggered in response to the persistent regional hy-
poxia that arises when oxygen demands exceed
oxygen delivery. When endothelial cells experi-
Figure 17 Capillary tortuosity Individual muscle fibers ence hypoxia, levels of the protein hypoxia-
are surrounded by capillary networks that weave back and forth inducible factor (HIF) increase. This transcription
across the surface of the myofiber. The image shown here is the factor triggers the release of the hormone vascular
capillary structure from a frog muscle. The capillaries are endothelial growth factor (VEGF) into the wall of
preserved while the muscle is corroded away from the preparation.
(Photo courtesy of Nicholas Hudson and Craig Franklin, University of
the blood vessels. When receptors on the vascular
Queensland) smooth muscle cells bind VEGF, the cells prolifer-
ate and penetrate the surrounding tissue. The
growth of blood vessels into hypoxic regions in-
served by more than one capillary or even minor creases the perfusion of active muscle. The same
arterioles. In a living animal, the organization of pathway is used to increase perfusion of muscle
the capillaries and the regulation of blood flow are regions with damaged or blocked blood vessels.
necessary to match oxygen delivery to muscle ac-
tivity.
Myoglobin aids in oxygen delivery
and utilization
Vasoactive agents regulate blood vessel Myoglobin is an oxygen-binding heme protein
diameter found in aerobic muscles. The myoglobin gene
While capillaries deliver oxygen to the muscle cell, arose early in metazoan evolution and occurs in
the arterioles control which capillaries receive most metazoan taxa. Myoglobin has two major
blood. When an animal is at rest, not all muscle roles within muscle cells: intracellular oxygen stor-
capillaries are perfused. The arterioles that feed age and oxygen transport.
the capillaries undergo vasomotion, regularly cy- Many muscles use myoglobin as an oxygen
cling between constriction and dilation. When store. When tissue oxygen levels decrease, myo-
conditions demand an increase in blood flow to globin releases its oxygen for use by muscle mito-
the muscle, arterioles remain open for longer pe- chondria. Myoglobin concentrations are high in
riods and total blood flow to the capillaries within muscles of animals that regularly experience hy-
that muscle increases. poxic conditions. For instance, diving mammals,
Vasoactive agents alter the contractility of the such as whales and seals, prepare for a dive by
smooth muscle that lines the arterioles, and saturating myoglobin stores with oxygen. During
thereby determine perfusion through capillaries. the dive, oxygen is released from the myoglobin to
Some vasoactive agents, such as insulin, are en- support muscle activity.
docrine hormones produced at distant sites and re- Once oxygen crosses the muscle cell mem-
leased into the circulation. Other neurohormonal brane, it is rapidly bound by myoglobin. By reduc-
factors are produced locally, arising from nerves, ing the concentration of free oxygen within cells,
vascular smooth muscle, endothelium, or the mus- myoglobin helps maintain the oxygen gradient
cle itself. The end products of muscle metabolism, necessary for oxygen diffusion. Oxygen bound to
such as pH, oxygen, and CO2, also exert effects on one myoglobin molecule can be transferred from
622
Locomotion
myoglobin to another molecule to facilitate oxygen Imagine an isolated muscle contracting on a bench
diffusion to the mitochondria. Because of this role top. It is free to contract and relax, but without
in facilitating oxygen delivery, muscle myoglobin connections to some form of skeleton the muscle
concentration often parallels muscle mitochondrial contraction is reduced to a shape change. Earlier
content. in this chapter we discussed how invertebrates
The importance of myoglobin in facilitating such as worms are able to crawl using muscles
oxygen delivery remains controversial. Re- that act on fluid-filled chambers that constitute a
searchers using mathematical modeling of molecu- hydrostatic skeleton. Their muscles contract to
lar movements of myoglobin maintain that oxygen cause a change in the distribution of fluids to move
diffusion is improved by only a small percentage. In the body. Hydrostatic skeletons are also important
an effort to explore the importance of myoglobin in in other animals. A few species of spiders use a hy-
muscle, researchers in the 1990s engineered lines drostatic skeleton as a substitute for an antagonis-
of transgenic mice with the myoglobin gene tic muscle group. They extend their legs with an
knocked out. Much to their surprise, they found that infusion of hydrostatic fluid, functionally replacing
these myoglobinless mice were able to exercise as an extensor muscle group.
well as wild-type mice. At first, these results seemed A solid skeleton is important in the locomotion
to argue against a role for myoglobin in support of of all chordates and many invertebrates, such as
muscle activity. Subsequent studies revealed that echinoderms, arthropods, and molluscs. The inver-
myoglobinless mice had extensive changes in the tebrate external skeletons, or exoskeletons, can
vasculature of muscles. Without myoglobin to facil- cover the animal completely, as in insects, or only
itate oxygen delivery, the muscles adapted by in- partially, as in molluscs. Internal skeletons, or en-
creasing muscle capillarity. From an evolutionary doskeletons, are most common among vertebrates.
perspective, animals produce myoglobin to reduce The endoskeletons found among some groups of in-
the costs of building and maintaining vasculature. vertebrates, such as sponges and echinoderms, are
This trade-off is best illustrated by the Antarctic fish used for protection and support, not locomotion. The
that lack myoglobin altogether. The absence of endoskeletons of vertebrates are made of cartilage or
myoglobin is tolerated in these species because of bone produced by specialized cells. Hard skeletons
their low metabolic rate and the high oxygen con- are central to locomotor strategies of animals, acting
tent of cold polar waters. This trait has arisen sev- as structural support for appendages, elastic storage
eral times in distantly related taxa and by different devices, or biomechanical levers.
mechanisms. In some species the myoglobin gene is
not transcribed, whereas other species express the
gene but do not translate the mRNA into protein. Hard skeletons are made
from cellular secretions
Most cells secrete suites of macromolecules that
make up the extracellular matrix. In soft tissues,
2 CO NC E P T C HE C K the extracellular matrix is the glue that holds cells
1. What are muscle fiber types, and how do
together. Skeletons are derived from a specialized
animals use them to support diverse activity extracellular matrix produced by secretory cells.
levels? They can be made of diverse materials that vary in
2. What are the costs and benefits to using biophysical properties such as rigidity, flexibility,
oxidative phosphorylation versus glycolysis to durability, and inertness.
support muscle activity? Most invertebrates possess an external surface
3. How does myoglobin aid oxygen utilization in layer that helps protect the animal from the environ-
muscle? ment. The exoskeleton of insects, known as the
cuticle, is composed of the carbohydrate chitin,
proteins such as sclerotin, water molecules, and
phenolic compounds. The cuticle is produced from
Skeletal Systems secretions of a layer of cells that lie beneath the cu-
Muscle contraction may provide the force for loco- ticle mounted on the basement membrane. These
motion, but locomotion requires some form of hypodermal cells secrete long strands of chitin that
skeleton to move various forms of appendages. become embedded in a complex protein matrix.
623
Locomotion
Hypodermis and relaxation follows when Ca2+ is resequestered

in the sarcoplasmic reticulum. Direct muscles are
Cuticle found in primitive insects, such as orthopterans
(locusts), coleopterans (beetles), and odonatans
Basement (dragonflies). Some insects have another arrange-
membrane
ment of flight muscles. They are called indirect
Gland cell Myotendon Muscle muscles because of the way contraction is coupled
junction to wing movement, or asynchronous wing muscles
Figure 18 Insect cuticle The insect exoskeleton is a because of the mode of excitation-contraction cou-
modified extracellular matrix of underlying hypodermal cells. pling. Indirect muscle does not attach directly to
Muscles are attached to the exoskeleton at myotendon the wing, but rather changes the position of the
junctions.
wing by altering the shape of the thoracic exoskele-
ton. Both the wings and the flight muscles attach to
After the chitin and protein secretions are assem- the upper region of the thorax known as the
bled, the cuticle incorporates oxidized phenolic tergum. When the elevator muscles contract, the
compounds. This final step of exoskeleton assembly, tergum is pulled down, a distortion that pulls the
called sclerotization, makes the cuticle more rigid. wings up and also stretches the antagonistic de-
Insect muscles are connected to the exoskeleton via pressor muscles. After the wing is elevated, the el-
myotendon junctions (Figure 18). Muscle cells in the evator muscles relax, the depressor muscles are
flight musculature come into contact with epithelial activated, and the tergum pops up, pulling the
cells that produce the cuticle. The two cell types link wings down. More derived insects, such as dipter-
together via cell membrane receptors such as inte- ans (flies) and hymenopterans (bees), use indirect
grins. As the cellular connections mature, the region flight muscles to power flight, although they use
forms the myotendon junction. direct muscles to control the fine movements of
Locomotor strategies are quite complex in in- the wing that allow maneuverability.
sects, and the exoskeleton is used in many differ-
ent ways to allow these animals
to jump, walk, and fly. The in-
sect wing is composed of cuticle,
although it has a different com-
Muscle
position than the cuticle of the relaxed Muscle
exoskeleton. The insect leg is a contracted
series of hollow tubes of exo- Muscle Muscle
contracted relaxed
skeleton. Internal muscles act
across joints to cause the leg to
bend. Insect flight is controlled (a) Direct muscles
by a series of thoracic flight
muscles, either direct, indirect,
Muscle Muscle
or both. Direct flight muscles relaxed contracted
attach via ligaments to the base
of the wing. Activation of one
muscle group (elevators) moves
the wing up, whereas activation
Muscle Muscle
of the antagonistic muscle contracted relaxed
group (depressors) moves the
wing down (Figure 19). These
(b) Indirect muscles
muscles are also called syn-
chronous muscles because Figure 19 Direct and indirect flight muscles Direct muscles attach to
the base of the wing, whereas indirect muscles attach to the thorax. Primitive insects,
muscle activation arises from a
such as the locust, have only direct muscles. More advanced insects, such as the
neuronal stimulus. Contraction blowfly, use indirect muscles to power flight, although direct muscles may be used for
occurs when Ca2+ levels rise, the fine-scale wing movements needed for maneuverability.
624
Locomotion
Vertebrate skeletons are composed

of mineralized calcium Osteocytes
Most vertebrates possess endoskeletons com- Osteoclasts

posed of combinations of bone and cartilage. Car-
tilaginous skeletons are found in the ancient fish, Capillary
including agnathans (lamprey, hagfish) and chon-
drichthians (sharks, rays). More recent fish and all
tetrapods possess skeletons of bone and cartilage. Osteoblasts
Skeletal changes were essential when early
New bone
vertebrates began the transition to land. Without (not ossified)
the support of water, early land animals needed
Newly
more robust skeletons and specialized muscula- ossified
ture to support them against the force of gravity. bone
Birds and bats have secondarily reduced their Figure 20 Cellular basis of bone Bone is composed of
skeletons to facilitate flight. The properties of the an ossified extracellular matrix of bone-producing cells:
endoskeleton are controlled by chondrocytes, osteoblasts and osteocytes. Osteoclasts secrete digestive
enzymes that break down bone. This allows vasculature and
the cells that produce cartilage, and osteoblasts, osteoblasts to invade the bone. The osteoblasts secrete their
the cells that produce bone. extracellular matrix. Gradually, the new bone becomes ossified.
Chondrocytes begin the process of cartilage
synthesis early in embryological development. ing is part of the process of bone growth and re-
They secrete proteins and proteoglycans, such as pair. By regulating bone growth and ossification,
chondroitin sulfate, into the extracellular space. animals can control the physical properties of
These macromolecules make up the extracellular bone, such as dimensions and density. For exam-
matrix of the chondrocyte. Many different chon- ple, these cells build the lighter bones required by
drocytes combine their extracellular matrices to flying animals, as well as the heavier bones of
produce cartilage. Most vertebrate bones begin large herbivorous land mammals.
as cartilage. As the animal grows and matures, Ligaments and tendons hold the muscu-
cartilage is broken down and replaced with bone. loskeletal system together. Ligaments hold one
Mature animals retain cartilage in a few locations bone to another. They are a type of connective tis-
within the skeleton, mostly near the ends of long sue produced when the fibroblasts near the ends
bones where the soft cartilage helps improve the of bones secrete long, parallel fibers of collagen
performance of joints. linked to proteoglycan. Tendons attach muscles to
Mature bone is a living tissue, constantly un- the skeleton. They are composed of connective tis-
dergoing remodeling. Bone itself is a collection of sue similar in structure to ligaments. At one end of
multiple cells, cellular secretions, and mineral the tendon, the connective tissue binds to the
salts, all enveloped in a fibrous sheath called the bone. At the other end, the tendon binds at vari-
periosteum. Osteoclasts secrete hydrolytic en- ous points along the belly of the muscle. Tendons
zymes to create tunnels into the bone or cartilage connect both ends of the muscle to bones.
(Figure 20). These tunnels allow blood vessels to Ligaments and tendons have important roles in
penetrate the extracellular matrix. When os- locomotion. They interconnect the different ele-
teoblasts invade the tunnel, they secrete collagen ments of the musculoskeletal system. They ensure
fibers that will eventually serve as framework for that muscles are correctly positioned and stretched
bone. These collagen fibers help organize the dep- to the appropriate sarcomere length. They also help
osition of minerals, mainly calcium phosphate ap- transmit forces between musculoskeletal elements.
atite, beginning the process of ossification. Once
an osteoblast is surrounded by an ossified extra-
cellular matrix, it can no longer divide and is
Skeletal components act
called an osteocyte. Throughout the lifetime of the
as mechanical levers
animal, osteoclasts continue to digest away re- The individual long bones in locomotor ap-
gions of bone, creating tunnels that are repaired pendages of vertebrates meet and articulate at
by osteoblasts. This ongoing capacity for remodel- joints. The joints are often bathed in synovial fluid
625
Locomotion
to reduce the degree of friction between two oppos-

ing bones. Joints differ in structure in ways that de-
termine the range of movement. For example, the Force Fulcrum LWA Weight
hip and shoulder are ball-and-socket joints: the
end of one bone is rounded or convex, and the op-
posing bone is concave. These joints provide the LFA
greatest range of motion. The knee and elbow are
(a) Class I lever
hinge joints and allow movement in only one plane.
Muscles work in combination with bones to
create levers. When an untethered muscle con-
tracts, it pulls its end toward its middle to gener-
ate a linearly compressed movement. When the
muscle is attached to a bone, the geometry of
the bone and the position of the joint constrain the
LWA
muscle from its natural range of movement. The
contracting muscle pulls the bone, causing it to ro- LFA
tate through an arc. This movement allows the (b) Class II lever
bone to be used as a lever. All mechanical and bi-
ological levers have three elements: a fulcrum, a
weight, and a force. The fulcrum is the point of ro-
tation, which in the context of locomotion is the
joint. The weight is the force exerted by the object
to be moved. The force is generated by muscle
contraction. If you are bending your arm to pick LFA
up a rock, the fulcrum is the elbow, the rock is the
LWA
weight, and the biceps muscle generates the force.
The mechanics of lever action depend on the (c) Class III lever
relative position of the three elements, as well as Figure 21 Levers Three classes of levers are
the distances between the elements. The distance distinguished by the relative positions of three elements: the
between the force and the fulcrum is the force fulcrum, the weight to be lifted, and the point at which force
is applied. The part of the lever between the fulcrum and the
arm. In the example of your arm, the force arm is
weight is the weight arm. The force arm is the part of the
the distance between the elbow and point of inser- lever between the fulcrum and the point at which force is
tion of the biceps muscle. The region between the applied. The ratio of the length of the force arm (LFA) to that
fulcrum and the weight is the weight arm. The me- of the weight arm (LWA) is the mechanical advantage.
chanical advantage (MA) of a lever is expressed as
the ratio of the length of the force arm (LFA) to the lever has no mechanical advantage because LFA is
length of the weight arm (LWA). always less than LWA. Consequently, class III levers
Levers are distinguished based on the relative are the least effective in translating muscle force
position of the three elements (Figure 21). A crow- into leverage. These levers are valuable not because
bar is an example of a class I lever. The lever is long of a mechanical advantage but because they can in-
(large LFA) and the fulcrum is close to the weight crease the range and velocity of movement. A mod-
(small LWA). Thus, this type of lever has a large me- est amount of force exerted at a short distance from
chanical advantage; a minimal amount of force can near the fulcrum causes the mobile end of the lever
be used to lift a large weight. A wheelbarrow is an to move quickly through a much greater distance. In
example of a class II lever. The weight is between terms of your arm, when the bicep shortens only
the fulcrum and the force. We can lift quite a bit of about 2 cm, it causes the hand to rotate through a
weight using a wheelbarrow, but a class II lever does 50-cm arc.
not have as great a mechanical advantage as a class The position of the muscle insertion on the bone,
I lever. Most levers in animal locomotion are class III relative to the joint, has important biomechanical
levers. In our arm example, the biceps (force) in- ramifications. The relative lengths of the force arm
serts between the elbow (fulcrum) and hand and weight arm determine how efficiently muscle
(weight). Unlike the other types of lever, a class III force can translate into leverage and movement.
626
Locomotion
The importance of these relationships

is best illustrated by considering the
morphometry of the legs of animals
specialized for different lifestyles. A
cheetah is built for speed, whereas a
lion is slower but stronger. When the
forelegs are drawn to a similar scale,
the differences in leg morphometry
are more obvious (Figure 23). The
Teres LFA
teres major is the muscle that pulls LFA major
Teres
major
the foreleg backward, a movement
that is used in running and also in
prey capture. The teres major at- LWA
taches much closer to the shoulder LWA
joint in a cheetah than in the lion. As
a result of these differences in me-
chanical advantage, the cheetah can
move its foreleg faster whereas the Cheetah Lion
lion moves its foreleg with more force.
(a)
Skeletons can store Shoulder Shoulder

elastic energy (fulcrum) (fulcrum)
Relaxed
Another way that animals use the Relaxed
skeleton in movement is through Contracted
elastic storage energy. When the LFA Contracted

LFA
muscle shortens, some of the force
that is used to stretch the connective
tissue and bend the bones is stored
Humerus
as elastic storage energy. When the LWA (lever) Humerus
muscle relaxes, the elastic storage LWA (lever)
energy can help the muscle stretch.
Vertebrates benefit from elastic stor-
age energy in locomotion, although Cheetah Lion
some animals benefit more than oth-
ers. The kangaroo uses elastic stor- (b)
age energy to improve the efficiency Figure 22 Muscle position on the bone The geometry of muscles and
of locomotion. When the kangaroo bones determines the relationship between the force generated by the muscle and the
first begins to hop, extensor mus- type of movement that results. (a) In the cheetah foreleg, the muscle is inserted closer
cles are used to lift the animal off to the joint than in the lion foreleg, when drawn to the same scale. (b) When modeled
as a lever, the cheetah foreleg can move faster, through a longer arc, but the lion
the ground. When it lands, some of foreleg can generate more forceful movements.
the force is used to distend the mus-
cle and connective tissue, creating a short-term
store of elastic energy. Upon recoil, these elastic cles altogether. For example, many spiders have
elements generate force that can be applied to- leg joints that lack extensor muscles. Portions of
ward the next jump. Later in this chapter we dis- the exoskeletal plates called sclerites span the
cuss how animals use the muscles of the back as joint (Figure 23). Muscle contraction deforms the
elastic energy stores during running. sclerites during flexion. When the muscles relax,
The importance of elastic storage energy is the sclerites recoil to extend the leg.
much more obvious in arthropod locomotion, par- Such elastic structures were an important
ticularly jumping and flight. In some cases, elastic evolutionary innovation in arthropods. Most in-
structures functionally replace antagonistic mus- vertebrates move with the help of hydrostatic
627
Locomotion
Palella In this section, we have discussed how loco-

Extensor motor systems are the products of the combina-
tion of muscle, metabolism, perfusion, and the
Tibia skeleton. The interdependence of the systems is
Femur perhaps most clearly demonstrated by those
species that move in a way that is markedly differ-
ent from that of their close relatives. Researchers
Contraction of are drawn to animals that run, fly, or swim faster
extensor
straightens leg than all others. In the accompanying feature
(Box 1, Methods and Model Systems: Animal Ath-
(a) Heterometrus (Asian forest spider)
letes), we explore the physiology of these animal
athletes to understand the nature of the complex
anatomical specializations that allow these ani-
mals to move faster than their relatives.
Translating Contraction
into Movement
Muscle function in animal locomotion varies
Elastic hugely, and all levels of biological organization
sclerite
contribute to this diversity. Recall from what
you've learned, the many ways that variations in
the molecular and cellular properties of the stri-
(b) Eremopus (sun spider) ated muscles contribute to muscle diversity: mo-
Figure 23 Spider legs Leg extension occurs in spiders tor neuron properties, contraction frequency,
by several mechanisms. Some use movement of hydrostatic motor end plate organization, T-tubules and ac-
fluids to extend the leg (not shown). More commonly, spiders tion potential propagation, SR structure, Ca2⫹
use either (a) extensor muscles or
buffering, thin and thick filament protein iso-
(b) elastic storage structures that span the leg joint. When leg
joints are flexed, the elastic sclerite is deformed. When the forms, the arrangement of myofibers into a mus-
muscle relaxes, the sclerite recoils to extend the leg forward. cle, and the material properties of the connective
(Source: Sensenig and Shultz, 2003) tissue and skeleton. Each of these factors affects
the muscle dynamics, but we must also consider
skeletons. As mentioned earlier in this chapter, how the muscles are integrated into the anatomy
many extant spiders use fluid movements and hy- of the whole animal, and how this affects the con-
drostatic pressure to aid in leg extension, aug- version of muscle contraction to movement.
menting elastic storage energy. However, a
strategy that relies on hydrostatic pressure for lo-
comotion has several limitations in rapidly mov-
Muscles are specialized for force
ing animals. The mass of elastic structures is
generation or shortening velocity
small relative to the mass of the hydrostatic fluid Within a complex animal, locomotor muscles
that would be needed to extend a leg. Thus, if legs serve many purposes. Let’s consider two alternate
rely on elastic structures they can be smaller, muscles of equal mass that differ in shape. One
which saves energy for a moving animal. It also muscle is short and thick, and the other is long and
costs the animal metabolic energy to push hydro- thin. The short, thick muscle has its sarcomeres
static fluids into the leg. Using an extracellular arranged in parallel, whereas the other has its sar-
fluid to generate hydrostatic pressure may also comeres arranged in series. Because of its larger
compromise the diffusion of metabolites and res- cross-sectional area, the short, thick muscle can
piratory gases in the circulatory system. Thus, generate a great deal of force with relatively little
structures that rely on elastic storage energy al- shortening. In contrast, the long, thin muscle will
low arthropods to escape some of the constraints shorten faster (and further) but generate less
imposed by hydrostatic skeletons.
628
Locomotion

Animal Athletes
One of the basic tenets of comparative an- The tuna meets the energetic demands of rapid swim-
imal physiology is the August Krogh principle: For ming with specializations of the respiratory, cardiovascu-
every biological problem there is an organism on which it can lar, and locomotor systems. The gills have a large surface
be most conveniently studied. In this chapter, we have dis- area and thin gill epithelia, structural features that en-
cussed several models with properties that are conducive hance the rate of oxygen exchange. The blood has a high
to experimentation, such as fish muscle fibers with their oxygen-carrying capacity, due to higher hematocrit and
homogeneous fiber types and the frog jumping muscle. higher hemoglobin concentrations. Tuna have an extensive
When studying integrative locomotor physiology, animal coronary circulation that delivers oxygenated arterial
athletes are useful models for studying the limits to aer- blood to the heart, unlike most fish hearts, which must ex-
obic activity. Each animal taxon has a few species that tract oxygen from the venous blood passing through the
epitomize some aspect of aerobic locomotor perfor- cardiac chamber. The capillarity density of the red muscle
mance. Bumblebees and hummingbirds flap wings at ex- can be as much as four times greater than in other fish.
ceptionally high frequencies, allowing these animals to Muscle myoglobin content is also high in tuna. Each of
hover. Thoroughbred horses and pronghorn antelope run these features would seem to enhance the capacity of the
faster than most land animals. Tunas and lamnid sharks fish to extract oxygen from water and deliver it to the mi-
swim faster than other fish. To explore the physiological tochondria of the working muscle. The muscle itself has
features that accompany exceptional aerobic locomotor a high aerobic capacity. Although the mitochondrial con-
performance, we will consider the physiology of tuna. tent is similar to that of other species (about 35% of cell
Body shape is very important for aquatic animals. The volume), the mitochondrial cristae are two to three times
streamlined, fusiform body of tuna is built to move effi- more densely packed than other species. Thus, mito-
ciently through water. Many other fish have a general chondrial enzymes required for energy production occur
streamlined shape, but the tuna is as close to a perfect at high activities. This high mitochondrial capacity is
teardrop as any fish. The shape of the caudal fin is characteristic of all animal athletes, which may possess
also unusual, with its narrow caudal peduncle and thin, exceptional mitochondrial volume density and cristae
crescent-shaped (lunate) caudal fin. Tuna also show an packing density. Tuna are also unlike most fish in their
unusual swimming style. Even at high speed there is little thermal physiology. These fish are regional endotherms;
movement in the trunk. The caudal fin merely bends back they are able to retain muscle heat within the body core.
and forth at the caudal peduncle. Although the trunk These elevated temperatures increase the kinetics of
doesn’t move during swimming, the muscles within the both contraction and energy metabolism.
entire trunk contribute to force generation for the caudal Tuna are remarkable animals that have provided im-
fin. Force is transferred from the muscle to the caudal fin portant information about the structural and physiologi-
through the myosepta, skin, and tendons. cal constraints on locomotor activity. The evolutionary
The red muscle of tuna is unusual in two important re- and developmental origins of these specializations re-
spects that influence force generation. Most species of main to be explored. Interestingly, the lamnid sharks,
fish have a thin wedge of red muscle that runs the length which include the mako and great white sharks, demon-
of the fish, just beneath the lateral line. Tuna red muscle, strate many similarities with tunas. Since these species
however, is not homogenously distributed but rather is are only distantly related, the striking similarities be-
concentrated midway along the length of the fish. It is also tween tuna and lamnid sharks are examples of conver-
located deep within the body, close to the spine. In this gent evolution.
chapter we discussed how the superficial location of red
muscle of fish is ideal for force generation. In this position,
References
it has leverage to bend the body wall. How then does the
q Bernal, D., K. A. Dickson, R. E. Shadwick, and J. B. Graham. 2001.
deep red muscle of tuna power its high-velocity swim-
Analysis of the evolutionary convergence for high performance
ming? Recent studies have shown that the core of deep
swimming in lamnid sharks and tunas. Comparative Biochemistry
red muscle is able to shorten more than the surrounding and Physiology, Part A: Molecular and Integrative Physiology 129:
white muscle. The red muscle tendons connect directly to 695–726.
the caudal fin, allowing more effective force transmission. q Donley, J. M., C. A. Sepulveda, P. Konstantinidis, S. Gemballa, and
Because of these efficient tendons, the anterior red mus- R. E. Shadwick. 2004. Convergent evolution in mechanical design
cle can make important contributions to the power of tail of lamnid sharks and tunas. Nature 429: 61–65.
movements, even though the anterior part of the fish does
not bend during swimming.
629
Locomotion
force. Mechanical power (P) is the mathematical when contraction velocity is 30–40% of the maxi-
product of force (F) and shortening velocity (V): mal shortening velocity.
P⫽F⫻V Mechanical power is the most important pa-
rameter in most forms of locomotion. Animals ap-
Though the thick muscle generates lots of force but ply the power generated by a muscle to the
at low shortening velocities and the thin muscle environment to generate movement. The arm
generates rapid shortening but little force, the two throws a ball by transferring the power generated
muscles have a similar power output. in contraction to forward movement of the ball.
An animal can alter the power output of a The power you generate with a leg contraction al-
muscle by changing either the force generation or lows you to jump. The contraction must be force-
the velocity of shortening. Consider the following ful and rapid, or you will not leave the ground.
example to understand the trade-offs between Many muscles are built, arranged, and used in
these parameters and how they affect power. You ways that maximize power output.
can throw a ball by contracting your triceps mus-
cle in the back of your arm. You can maximize
force by trying to throw a very heavy ball. Your Work loops show the balance between
arm might generate a great deal of force, but the positive and negative work
ball is so heavy that you can barely move your arm
Power can also be expressed in relation to work
(your triceps has high force but little shortening).
(W). Recall that P ⫽ F ⫻ V. Since V equals distance
Alternatively, you can maximize shortening veloc-
(D) per unit time (t), then
ity. The way to move your arm the fastest is by
choosing a very light ball; very little force is gener- P ⫽ F ⫻ D/t
ated but you can move your arm very quickly. Nei- Work (W) is the product of force (F) and distance
ther of these situations generates significant power (D). Expressing force in terms of work, we get F ⫽
because in each situation one of the parameters— W/D. Thus, power can also be expressed as work
force or shortening velocity—approaches zero. per unit time (P ⫽ W/t). This rearrangement also
Power is greatest at an intermediate velocity (Fig- emphasizes the important difference between
ure 24). Most muscles generate maximal power work and power. It requires about the same
amount of work to lift an object slowly versus
quickly. Thus, the metabolic energy demands are
1.0
similar. However, much more power is required to
Relative power (force • distance/sec)
lift the same weight in a shorter period of time.

Researchers can calculate the amount of work
done by a muscle by measuring force and length
during cycles of contraction and relaxation (Fig-
0.5 ure 25). Upon activation, the muscle shortens and
force declines until the muscle reaches its shortest
length. The area under this descending curve re-
flects the work done by the muscle during contrac-
tion and is called positive work. During relaxation,
the muscle lengthens. Although the lengthening
0 muscle still exerts some force, it is usually less than
Contraction velocity (distance/sec)
the force exerted at the same muscle length during
Figure 24 Power versus velocity of shortening The contraction. The area under this ascending curve
ability of a muscle to generate power depends on the force is the negative work. The net work done by the
generated by the muscle and the velocity at which the muscle
muscle is the difference between the positive work
shortens (here, distance per second). Power approaches zero
when the velocity of shortening (V) is either minimal or and the negative work. Graphically, this is re-
maximal. V is very low when the muscle is heavily loaded and flected in the area enclosed by the two curves,
cannot shorten. V is maximal when there is no load. Without a known as the work loop. In most cases, the de-
load, all of the energy released in the cross-bridge cycle is used
scending curve (during contraction) lies above the
to shorten the muscle and no force is generated. Power is at its
greatest when the muscle is loaded in such a way that it ascending curve (during relaxation). If you fol-
shortens at about one-third its maximal velocity. lowed the coordinates of force and length around
630
Locomotion
muscle generates positive or negative work de-

pends on when it is activated during limb move-
ment. If, for example, external forces cause a
muscle to compress at a time when it is shorten-
Shortening ing, the muscle generates much less force than is
possible. Many of the muscles that control the fine
Relative force
movements of flying insects produce negative net

work. They exert their effects by using contraction
to change their mechanical properties, altering
how other muscles and the exoskeleton affect the
Lengthening
flight system.
Relative length 4. What are the components of a vertebrate skeletal

system? What is the chemical composition of
Figure 25 Work loops The work loop plot is each element, and how is it made?
generated when the force and length of a muscle are
5. What are the different types of levers, and how
monitored during a shortening and lengthening cycle. As the
muscle shortens, force decreases to a minimum. The area do they work?
under the descending curve depicting force versus length 6. What is the relationship between force, power,
reflects the positive work done by the muscle. When the and work?
muscle relaxes, it lengthens producing an ascending curve
with relatively low force. The area under the ascending curve
is negative work. The difference between the positive and
negative work, depicted by the area within the loop, is the net
work. The direction of the loop reflects whether positive net
work was performed (counterclockwise) or negative net work
Moving in the Environment
(clockwise).
The musculoskeletal system allows an animal to
generate force to move its body and appendages.
the graph during such an experiment, you would Whether or not this activity translates into loco-
move around the work loop in a counterclockwise motion depends on how the animal interacts
direction. This signifies that a cycle of contraction with the physical environment. The two domi-
and relaxation generates net positive work. nant environmental factors that influence loco-
Not all myofibers generate positive work. Iso- motion are gravity and fluid properties. In the
metric muscles do not change in length, generate following section we discuss the constraints on
no power, and therefore perform no net work dur- animal locomotion in terms of these environ-
ing contraction. It is also possible to have a situa- mental factors. We use this approach rather than
tion where a muscle does change in length but describing locomotion in terms of style of move-
produces negative net work. More work is per- ment, such as swimming, jumping, running,
formed during extension than shortening, or put walking, and flying. The physiology of locomo-
another way, the muscle actually absorbs energy tion has much more to do with the physical envi-
during contraction. These muscles are not acting ronment than with the pattern of movement of
as power generators but rather as shock ab- appendages. For example, fleas, frogs, and kan-
sorbers, or dampers. Experimentally, a muscle garoos each jump, but the forces that govern
acting as a damper shows a work loop that runs their movement are completely different because
clockwise, signifying negative net work. There is of their size and the effects of gravity. Conversely,
nothing unusual about the cellular properties of the biomechanics of swimming and flying are
the muscle that causes this relationship. Rather, quite similar. Both air and water are fluids and
negative net work arises because of the way the obey the same laws of fluid dynamics. Locomo-
muscle is arranged into the musculoskeletal sys- tor systems allow animals to move from place to
tem and the nature of the anatomical relationships place, overcoming the physical constraints im-
with other muscles during movement. Whether a posed by the environment.
631
Locomotion
Gravity and Buoyancy air. The subtle differences in body composition

that affect our buoyancy also affect the buoyancy
Gravity is the element of the physical environment of aquatic animals and influence the energetics of
that has the greatest consequences for locomotor movement in aquatic systems. But not all animals
strategies. No animals can escape gravity, but some need to be buoyant. Benthic animals—those that
are less affected by it than others. Gravity exerts its live on the bottom of aquatic ecosystems—tend to
greatest effects on terrestrial animals, which use be denser than the surrounding water. This allows
muscles to solve the biomechanical problems asso- them to maintain contact with the bottom without
ciated with movement on land under the full weight expending energy. However, most aquatic animals
of gravity. Gravity has much less effect on an animal possess a body composition that induces either
with a body density that approximates that of the en- neutral buoyancy or positive buoyancy, allowing
vironment. Aquatic animals can reduce the effects of them to move through the water column. These
gravity by manipulating their body composition. animals reduce their overall density by increasing
the proportion of less dense constituents, typically
lipids or gases.
Body composition influences
buoyant density
An object immersed in water tends to float if it is less
Lipid stores increase the buoyancy
dense than the water. The tendency to float is buoy-
of zooplankton and sharks
ancy, an upward force that counteracts the effects of Although all animals possess some lipids in mem-
gravity. The body density is determined by the body branes and energy stores, some aquatic animals
composition. Each component has a characteristic accumulate high concentrations of lipids, which
density, measured as specific gravity (Table 1). Wa- increase buoyancy. Many species of zooplankton
ter is the most abundant molecule in most animals, possess large droplets of lipid, typically in the form
and therefore body density usually approximates of wax esters. A wax ester, which is a long chain
the density of water. Bones and cartilage have the fatty acid esterified to a long chain fatty alcohol, is
highest density in animals. Proteins are slightly metabolically active. Zooplankton can alter their
denser than water, whereas lipids are slightly less buoyant density by synthesizing or degrading the
dense than water. Gases have the lowest density. wax esters, allowing these animals to slowly alter
A visit to the local swimming pool reveals how their buoyancy to change their position in the wa-
body composition influences the effects of gravity. ter column (Figure 26).
“Sinkers” complain that swimming is exhausting
because they spend considerable energy just to
keep afloat. “Floaters” gleefully drift around on the
surface, apparently expending no energy at all. It
is much easier to float when your lungs are full of
Table 1 Specific density of biomaterials.
Biomaterial Specific gravity (g/ml)

Bone 3
Cartilage 2
Protein 1.6
Seawater 1.024
Pure water 1.0
Triglyceride 0.90 Figure 26 Lipid droplets in zooplankton Many
species of planktonic animals, such as the calanoid copepod
Squalene 0.86 shown here, possess lipid droplets that aid in buoyancy.
Oxygen 0.00143 (Photo courtesy of Rob Campbell and John Dower, University of
Victoria)
632
Locomotion
Chondrichthians (sharks and rays) also use

lipid to increase their buoyancy. They accumulate
high levels of the steroid compound squalene in
their livers. The amount of lipid is highest in
pelagic sharks, which can be neutrally buoyant,
and lowest in benthic rays, which are slightly neg-
atively buoyant. Other aquatic animals with high Gas gland Oval
levels of lipid in their tissues benefit from their (a) Physoclist swim bladder
buoyancy, although they are accumulated for
other purposes. The triglyceride accumulations in
fish livers are primarily important in energy me-
tabolism. The lipid found in the thick blubber layer
of marine mammals serves as insulation. How-
ever, these substantial lipid depots also contribute Pneumatic duct
to buoyancy, thereby reducing the amount of en-
ergy needed to remain in the water column. Esophagus
(b) Physostome swim bladder

Swim bladders are gas-filled sacs
that increase buoyancy Figure 27 Swim bladders (a) Physoclist fish inflate
the swim bladder by injecting oxygen from the blood into the
Recall what you know about the fish swim bladder. bladder at a region called the gas gland. Gases can escape
It is not yet certain whether the swim bladder the bladder at another vascularized region, called the oval.
(b) Physostome fish inflate and deflate their swim bladder
arose first as a primitive lung or as a buoyancy or- through a direct connection between the gastrointestinal
gan. Whereas the fish that use the swim bladder tract and the swim bladder, called the pneumatic duct.
as a lung occur in many fish taxa, the buoyancy
function occurs only in actinopterygian fish. This
suggests that swim bladders likely arose first as a
primitive lung, and only secondarily as a buoyancy These fish inflate the swim bladder at a vascular-
organ. ized region of the organ called the gas gland.
The swim bladder (Figure 27) is derived from Blood arrives at the gas gland with oxygen loaded
an outgrowth of the gastrointestinal tract that ap- onto hemoglobin. When a fish needs to increase
pears early in fish development. The gas accumu- the volume of the bladder, the gas gland induces a
lated in these internal balloons is sufficient to local acidification, causing hemoglobin to release
compensate for the negative buoyancy of the re- oxygen. Oxygen unloading is maximized by the
mainder of the body. The walls of the swim blad- countercurrent arrangement of the blood vessels.
der are flexible, allowing the organ to contract and When a fish needs to reduce the volume of the swim
expand. Guanine crystals embedded in the swim bladder, oxygen is allowed to flow into the blood at
bladder reduce the permeability of the swim blad- a separate vascularized region called the oval.
der to gases. For a fish to be able to use a swim Physostome fish may also have a gas gland and an
bladder as a buoyancy organ, it must be able to oval, but they are generally reduced in size and less
control the volume of gas within the organ. important for gas exchange than the structures in
Physostome fish have a connection between the physoclists.
gastrointestinal tract and the swim bladder. They Gas-filled swim bladders reduce the costs of
increase the volume of the swim bladder by gulp- swimming, but they do have functional limita-
ing atmospheric air and pushing it through the tions. The volume of the swim bladder changes in
pneumatic duct that connects the gut to the swim response to hydrostatic pressure. As hydrostatic
bladder. Similarly, they reduce the swim bladder pressure increases, the volume of a swim bladder
volume by contracting the smooth muscle that sur- shrinks. When the pressure is relieved, the swim
rounds the bladder and opening the pneumatic bladder expands. Swim bladders are most useful
duct to release air into the gut, where it is burped for fish that remain within a narrow range of
out of the animal. Physoclist fish have lost the di- depths, but they would impair pelagic fish from
rect connection between gut and swim bladder. moving rapidly up and down in the water column.
633
Locomotion
If a deepwater fish comes to the surface too

quickly, the volume of its swim bladder can in- Paddle
crease so fast that the fish is incapacitated. Many
active fish have lost their swim bladders, and in-
stead expend muscle energy to maintain their po- Water
sition in the water column. Although this is more
expensive energetically than a swim bladder, it al-
lows the fish to rapidly change depth without suf-
fering a rapid change in swim bladder volume.
Fluid Mechanics Slow flow

An object moving through a fluid creates a com-
plex pattern of flow. The rules that describe the
movement of a fluid, called fluid mechanics, ap-
ply to both air and water. Animals are able to
move through fluids by governing the path of the
fluids around them. Some animals are most con- (a) Laminar flow
cerned with moving fluids out of the way to allow
efficient movement. The fluids impede forward
movement. Other animals control fluid move- Fast flow
ments to aid in locomotion. In this situation, the

movement of fluids pushes the animal forward or
lifts it upward.
Reynolds numbers determine turbulent

or laminar flow (b) Turbulent flow
A simple way to begin our discussion of fluid me- Figure 28 Laminar and turbulent flow As an
chanics is to consider the forces that act on an ob- object such as a canoe paddle moves through water, the fluid
is forced around the blade. (a) The flow remains laminar at
ject, such as a canoe paddle, moving through water
low velocities. (b) At greater velocities the flow can become
at different speeds and orientations (Figure 28). chaotic, resulting in turbulence in the wake of the object. This
When you move the paddle through water very increases the cost of movement.
slowly, the fluid flows over the surface of the blade
in smooth layers, a condition called laminar flow.
If you were to repeat this movement at increasing things as how easily an object can glide through a
velocities, you would reach a point where the pat- fluid or when movement through a fluid is likely to
tern of flow would become less ordered, resulting in be turbulent. Our intuitive appreciation of the bio-
more turbulent flow. The costs of locomotion are logical factors that influence locomotion can be
greatly increased under turbulent flow conditions. traced back to the parameters of the Reynolds
The transition from laminar flow to turbulent flow equation.
depends upon properties of the fluid (viscosity, den- In our example of moving the canoe paddle
sity), the object (size, shape), and the movement (ve- through water at different velocities, the mathe-
locity, direction). The relationship between these matical explanation for the increase in turbulence
parameters is described by the Reynolds equation. is related to the effect of V on Re. The influence of L
The Reynolds number (Re) is calculated as follows: on Re can be illustrated by changing the orientation
of the paddle. Moving it through the water edge first
Re ⫽ VLρ/µ
is easier than when the paddle moves face first. In
where V is velocity of movement, L is a linear di- the face-first orientation, the surface of the paddle
mension of the object, ρ is the density of the fluid, that first encounters the fluid is much wider. In the
and µ is the viscosity of the fluid. The Reynolds calculation of Re, this difference is reflected in val-
number enables researchers to predict such ues of L (Figure 29). To appreciate the impact of
634
Locomotion
(a) Low viscosity

(a)
Boundary
L layer
(b) High viscosity
Figure 30 Boundary layers (a) When an object

(b) moves through a solution of low viscosity, each layer of
laminar flow moves at the same velocity, as indicated by
Figure 29 Orientation and turbulent flow The
vectors of equal length. (b) In solutions of higher viscosity,
orientation of objects can influence the formation of
the layer of laminar flow in contact with the object moves
turbulence. As the linear dimension encountering the fluid (L)
more slowly because of interactions with the object. The
increases, the turbulence also increases. (a) When the canoe
impact of the object is reduced further from the object. The
paddle moves edge first, the lower L value results in less
boundary layer is the microscopic layer of fluid that is
turbulence. (b) Moving the paddle blade first increases L and
retarded by the object.
enhances turbulence.
density, compare the effort of paddling through air tra energy to carry that layer of honey through the
versus water. An object moving through air has a remainder of the honey, known as the bulk phase.
lower Re because air has a lower density (ρ). Note that fluid viscosity affects animal locomotion,
The last parameter in the Reynolds equation, but animals do not have to cope with changes in
viscosity (µ), requires more explanation. Fluids environmental viscosity. The viscosity of water or
differ in their ability to flow around an object. air varies little under most conditions. Thus, for
When a solution moves across a surface, the mo- the Re of an animal in its environment, the most
lecular layer closest to the surface adheres to the important factors are V and L.
surface and moves with it. The next layer of fluid
interacts with the layer of fluid in contact with the
surface. The further the distance from the surface,
The relative importance of viscous
the less the fluid movement is influenced by the
and inertial effects determine Re
surface. The boundary layer is the molecular layer The thickness of the boundary layer is a property
of fluid that is influenced by the surface of the ob- of the fluid, not the moving object. The boundary
ject around which it moves (Figure 30). Some flu- layer of water is just as thick on a whale as on a
ids are more viscous than others, a physical small aquatic invertebrate, such as a copepod. The
property that we recognize as the “thickness” of a whale expends relatively little energy to carry
solution. For example, we perceive honey to be around the added water because the water layer is
thicker than water. Viscosity influences the move- trivial in comparison to the size of the whale. How-
ment of an object through a fluid because of the ever, the costs to the copepod are significant.
way the fluid interacts with the object to create a These fluid layers exert the greatest effects on lo-
boundary layer. If you remove your finger from a comotion of small, slow animals. The magnitude
bowl of water, it will have a thin coating of water. of these viscous effects depends on the viscosity of
If you remove your finger from a bowl of honey, a the fluid, the velocity of movement, and the prop-
much thicker layer sticks to your finger. Any time erties of the surface of the animal that interacts
you move your finger through a liquid, you carry with the fluid. These properties include body
that layer of fluid along for the ride. It costs you ex- shape and surface area, the physical composition
635
Locomotion
of these shapes has the same height

103 (L). The broad, flat plate redirects the
flow of almost all of the fluid it encoun-
ters. As the fluid is forced around the
100 Birds Large object, a region of turbulence develops
Velocity (m/sec)
Larger fliers swimmers

in its wake. Under these conditions,
10 -3 there is a great deal of pressure drag.
Small However, there is not much friction
fliers drag because the surface area that en-
Small
swimmers counters the fluid is reasonably small.
10-6
Protists When a sphere moves through the
Bacteria fluid, it has a less disruptive effect on
laminar flow (less pressure drag), al-
10-6 10-3 100 103 106 though the surface area in contact
Reynolds number
with the fluid is greater (more friction
Viscosity Both effects Inertia drag). However, the total drag is lower
dominates important dominates for the sphere than for the plate. The
Figure 31 Influence of Reynolds number on animal locomotion streamlined shape of the teardrop has
The Reynolds number reflects the properties of a fluid and the size and shape of the the least effect on laminar flow, caus-
animal. Larger animals have a higher Reynolds number than smaller animals.
ing the lowest amount of pressure
Swimmers have a larger Reynolds number than fliers of similar size. The larger the
Reynolds number, the more important are inertial effects on locomotion. Viscous drag. Although additional friction
effects dominate at low Reynolds numbers. drag is associated with the stream-
(Source: Adapted from Nachtigall, 1977) lined shape, the total drag is the low-
est of all three shapes.
of the surface, and the nature of appendages. Larger, Streamlining reduces the amount of energy
faster animals are less influenced by viscous effects animals require to overcome pressure drag. Al-
because of much lower ratios of surface area to mass though each of the objects shown in Figure 32 has
(Figure 31). When a copepod stops swimming, the a similar value of L, they have very different
viscous effects stop forward progression. When a masses. That means that the cost of overcoming
whale stops moving its tail, it has enough momen- drag in a large, streamlined animal is similar to
tum to overcome viscous effects. These inertial ef- the cost for a much smaller, nonstreamlined ani-
fects, which are dependent on body mass, dominate mal. Most larger swimmers and fliers have
the movement of larger animals in air and water. streamlined body shapes that reduce drag.
The high Re in large animals, however, creates an- In addition to streamlining, many of the
other potential problem: turbulence. fastest swimmers and fliers also have modified
body surfaces that further reduce friction drag.
This increased efficiency is critical for an animal
Streamlining reduces drag like the dolphin, which can swim through the wa-
For an object to move through a fluid, it must over- ter at 40 km/h. The surface of the dolphin is
come the forces that oppose forward movement. mounted on a layer of tiny pillars that readily
These forces are collectively called drag. Two change shape when water moves over the sur-
types of drag are encountered by moving objects. face. When the skin compresses in response to
Friction drag arises from the interaction between small, localized turbulence, friction drag is mini-
the surface and the fluid. It is dependent on the mized as fluids move smoothly over the surface.
area of the surface that interacts with the fluid, as Another property of dolphin skin allows this ani-
well as the viscosity of the fluid. Pressure drag is mal to avoid a problem that plagues recreational
the force required to redirect a fluid around a sailors and the navy. Barnacles readily attach to
moving object. The more dense the fluid, the the surface of manufactured vessels, drastically
greater the pressure drag. reducing the efficiency of movement through the
The shape of the object is an important determi- water. Barnacles cannot attach to the skin of dol-
nant of pressure drag. Consider how three different phins because of microscopic contours over the
shapes influence the flow of fluids (Figure 32). Each surface. This nanoscale terrain prevents the bar-
636
Locomotion
and fliers must overcome the force of gravity to

maintain their vertical position. Their locomotor
strategies must be consistent with the physical
L properties of the fluid, particularly density. Swim-
mers and fliers both benefit from streamlining and
use appendages to control the movement of fluids
over the body.
Aerofoils and hydrofoils generate lift

When an object moves through a fluid, the fluid is
L diverted around the object. This movement, and
the changes in pressure that result, are responsible
for both defying gravity and generating forward
movement, or propulsion. Wings and fins are struc-
tures used by animals to control the path of move-
ment of the fluid. Most of these structures have a
cross-sectional structure similar to that shown in
Figure 33. This is the general shape of an aero-foil,
L or in water, a hydrofoil. The upper surface is
curved. The lower surface is flattened, the front is
rounded, and the back tapered. The shape is criti-
cal in producing the force required to generate an
(a)
upward force called lift. We will discuss how lift
works using an aerofoil as an example, but the
Pressure drag
same principles apply to hydrofoils.
Friction drag
When the aerofoil moves forward, air collides
with the leading edge and causes an increase in
Drag
air pressure. The air slides upward and is com-

pressed into the air on top of the aerofoil. The
airstream continues to flow backward. The upper
surface of the aerofoil curves downward, away
Plate Sphere Teardrop
(b)
from the airstream. This causes a region of low air
pressure. On the bottom of the aerofoil, the air
Figure 32 Streamlining and drag Three objects continues smoothly along the surface. Because of
move through a fluid at the same velocity. They have the
same cross-sectional profiles, as indicated by a constant the differences in the airflow, there is a difference
value of L. The Reynolds number for each object is identical.
The shape of the objects influences the amount of pressure Lift Bird wing
and friction drag. The streamlined object has the lowest Longer
amount of pressure drag, despite its much greater mass. surface
Although the streamlined object has a larger friction drag,
due to its larger surface area, the total drag is much less Faster flow
than that with the plate or the sphere.
nacle from forming a tight seal on the surface,

and keeps the dolphin barnacle-free throughout Shorter Slower
surface flow
its life.
Figure 33 Aerofoils and hydrofoils Many wings
and fins possess the shape of an aerofoil or hydrofoil. Shown
Aerodynamics and Hydrodynamics in cross-section, the upper surface of the aerofoil is curved
and tapered downward, whereas the lower surface is flat. The
Because air and water share similar fluid proper-
fluid must move faster as it moves over the longer upper
ties, swimmers and fliers face similar challenges surface. This results in an area of low pressure, causing a net
in moving through the environment. Swimmers upward force known as lift.
637
Locomotion
in the air pressures over the surfaces of the aero- evitably descends toward the ground. Gliding is
foil. This pressure differential equates to a force. much more widespread in animals because it re-
Some of the force lifts the aerofoil upward. Some quires much less anatomical and physiological
of the force is lost as drag. specialization than does true flight. Any structure
The balance between the lift component and that increases surface area can improve the ability
the drag component depends on many factors: air to glide. There are many examples of mammals
speed, air density, wing area, and a coefficient that (squirrels, primates) and reptiles (snakes, lizards)
is specific to each aerofoil. Both the lift coefficient that extend flaps of skin from the body to glide
(Cl) and drag coefficient (Cd) are determined by di- (Figure 35). Flying squid and flying fish, which
rect measurement. They are properties of the ob- don’t actually fly, use fins to glide over the surface
ject size and dimension. Another parameter that of water. In each case, the shape or orientation of
affects lift and drag is the angle of attack, which is the gliding structure produces some lift, just not
the angle the aerofoil faces relative to the oncoming enough to remain aloft indefinitely.
airflow (Figure 34). Of all the flying animals, only birds soar. In some
large birds, such as the albatross and condor, wing
structure is much better suited to soaring flight than
Soaring uses lift from natural air currents flapping flight. The efficiency of soaring is enhanced
to overcome gravity by strategies that capitalize on natural air move-
When discussing movement through the air, it is im- ments. Many birds undertake slope soaring, riding
portant to distinguish true flight from gliding. In on the air currents deflected upward along the to-
true flight, animals use wings to lift off the ground pography of the surface. Many sea birds, such as
and remain airborne for long periods. True flight in-
cludes flapping flight and hovering flight, where
wing movements generate fluid movements that al-
low the animal to control altitude and velocity. True
flight also includes soaring, where the animal uses
stationary wings to generate lift to keep it airborne.
True flight appears to have arisen only four times
throughout animal evolution (Box 2, Evolution and
Diversity: The Origins of Flight). Gliding, like soar-
ing, relies on stationary structures to alter fluid
movements, but unlike soaring, the animal in-
High lift
Low lift
(a) Aerofoil shape
Low lift High lift

(b) Angle of attack
Figure 34 Aerofoil shape and angle of attack

(a) The amount of lift generated by an aerofoil is influenced
by the shape of the aerofoil. The longer the curved surface,
the greater the lift. This high-lift aerofoil also has high drag
because of the greater surface area. (b) The angle of the Figure 35 Gliding animals (a) Flying squirrels and
aerofoil relative to horizontal, known as the angle of attack, (b) flying fish are two of the many nonbird species that can
influences the pattern of fluid flow and consequently lift. glide.
638
Locomotion

The Origins of Flight
True flight has arisen at least four times other purposes, but evolution has allowed them to be-
since the origins of metazoans. The earliest fliers come fine-tuned for flight performance.
were insects derived from a single common terrestrial Vertebrate wings are modifications of forelimbs and
ancestor that first took flight about 350 million years ago. hands, but the origins of insect wings are less obvious.
By 290 million years ago, this group had diversified to At one point in evolutionary time, prior to the emergence
more than 15 orders of insects. Pterosaurs, or flying di- of flight, insects and crustaceans shared a common
nosaurs, arose about 290 million years ago and rapidly arthropod ancestor. This ancestor had extra ap-
diversified. Birds probably arose from small theropod di- pendages that evolved in different ways in each lineage.
nosaurs around 180 million years ago. Bats appeared In the crustacean lineage, the appendages became
about 50 million years ago. The geological record tells us epipods, elongated structures that aid in gas exchange.
that in each of these periods, atmospheric oxygen con- In the insect lineage, the extra appendages became the
centrations were unusually high. A high oxygen level had wings. The same genes that gave rise to insect flight
two effects on animal locomotion. First, the greater avail- 350 million years ago control the development of the
ability of oxygen allowed animals to produce ATP at epipods in modern crustaceans and wings in insects.
higher rates. Second, the increased atmospheric oxygen Insects show many examples of developmental tran-
level increased the density of air. This allowed animals to sitions in wings and flight. Most ant species have winged
generate more lift from the same structures. and wingless individuals of both genders. Flight capa-
Flight is not possible without wings, but the original bility is an important element of social caste and repro-
function of structures that became wings probably had lit- ductive biology of the species. Wingless castes arise
tle to do with flight. The wings of insects, which are struc- when genes required for wing development are re-
turally related to their cuticle, may have arisen to increase pressed in critical developmental windows. The mecha-
the efficiency of gas exchange. Movement of the wings nisms that control these genes within species, and the
would both increase the movement of gases around the reasons for differences between species, have only re-
insect spiracles and induce a form of thoracic pumping to cently been studied using DNA microarray technologies.
increase respiration. The presence of wings in the aquatic Some insect species can change their wing develop-
ancestors of insects may have allowed a type of movement in response to environmental conditions. The life
ment that eventually gave rise to flight. Some modern history strategy of many insects is influenced by compe-
stone flies, for example, use their wings to propel them- tition for food. Food abundance is detected by hormonal
selves across the surface of water. Surface tension keeps cues linked to energy metabolism. When conditions are
them on top of the water, and the wing movement pushes crowded, touch receptors in the insect legs are activated
them along the surface. For the vertebrate fliers there is by neighboring insects. These sensory cues alter the
an ongoing debate about whether they first flew from development of the machinery for flight. Locusts, for ex-
trees (arboreal) or from the ground (cursorial). In the ar- ample, can develop into a brown migratory form when
boreal hypothesis, animals would climb trees or cliffs and food is scarce or a green solitary form when food is
then use their wings to gently glide down to the ground. abundant. A soapberry bug living with too many other
This same strategy is seen in many modern vertebrates. soapberry bugs retains robust flight muscles and long
Flying squirrels and flying lizards extend flaps of skin to wings, enabling it to fly away. When living where food is
increase the ability to soar. In the cursorial hypothesis, abundant, the soapberry bug might break down its flight
animals would use their wings to lift off the ground into apparatus, histolyzing the musculature to reuse the en-
the air. Modern birds such as quail use their wings to ergy for reproduction.
climb trees. They run vertically up trees, flapping their
References
wings in a way that generates reverse lift to push them
q Brodsky, A. K. 1994. The evolution of insect flight. Oxford: Oxford
against the tree for better foot traction.
University Press.
Feathers are very important in bird flight, helping to
q Dudley, R. 2000. The evolutionary physiology of animal flight: Pa-
guide the flow of air across the wing surface. The earli-
leobiological and present perspectives. Annual Review of Physiol-
est bird fossil, the archaeopteryx, had feathers but it is ogy 62: 135–155.
thought that it probably did not fly. Early feathers arose
q Marden, J. H., B. C. O’Donnell, M. A. Thomas, and J. Y. Bye. 2000.
in several birdlike reptilian lineages as insulation. The Surface-skimming stoneflies and mayflies: The taxonomic and
structures necessary for flight in modern animals, such mechanical diversity of two-dimensional aerodynamic locomo-
as wings, muscles, and feathers, may have arisen for tion. Physiological and Biochemical Zoology 73: 751–764.
639
Locomotion
pelicans, use air movements on the surface of water To understand how wings and fins generate
(Figure 36). Land birds use wind currents flowing thrust, let’s begin by considering an analogy. Imag-
up from ridges to reduce the costs of flight. Soaring ine a ball floating stationary in a pool of water. If you
birds can also ride upwellings of warm air called were to move your hand gently over the surface of
thermals. Migratory birds can ride a bubble of air the ball, you would cause the ball to spin. Similarly,
upward to great height, then soar away heading to- when the caudal fin of a fish moves through the wa-
ward the next thermal. Slope soaring and thermal ter, it causes the fluid to swirl into a circular pattern
soaring dramatically reduce the costs of flight. Many called a vortex. Moving the fin in one direction
birds migrate along routes that take advantage of causes a clockwise vortex, and moving the fin in the
the airflows over natural topographic features, cov- opposite direction causes a counterclockwise vor-
ering distances that would not be possible without tex. These vortices of fluid movement are a conse-
the metabolic savings of soaring. quence of the transfer of force from the fin to the
environment. As the fish moves through the water,
the flapping caudal fin leaves a series of interlinked
Fluid movements can generate propulsion vortices in its wake (Figure 37). These fluid move-
Bird wings are of a size, shape, and orientation to ments ultimately provide the force that propels the
generate lift if the animal is moving relative to the fish forward.
air. If the animal is not moving forward through The same vortex ring theory applies to flying an-
the air, no lift results. If movement of the fluid rel- imals, but wing movements are much more compli-
ative to the animal is required to generate lift, then cated than fin movements. Wings must move in a
how do animals take off or hover, behaviors that way that generates both the forward force and the
would seem to preclude the generation of lift? In upward force. Lift is a force that arises from wing
other words, how do animals generate the propul- shape (aerofoil) only when the fluid is flowing over
sive forces necessary for forward movement? the aerofoil. Lift is adequate to keep a soaring bird
Swimmers and fliers move their appendages aloft, but the situation is much more complex when
to generate airflows to produce propulsive force, a wing moves in space. Furthermore, if the animal
or thrust. Whereas lift overcomes body weight and is not moving forward, how can it generate lift to re-
the effects of gravity, thrust overcomes drag. As main aloft? Most insects move their wings in a pat-
with other rules of fluid dynamics, the mecha- tern that cannot easily generate lift. At the top of the
nisms of thrust are similar in swimmers and fliers. stroke, the wing is nearly vertical above the insect.
Thermal soaring
Slope
soaring
Thermal
Figure 36 Soaring on air currents Birds can soar on upwardly directed air currents.
Sloping land such as ridges can direct air upward. Warm bubbles of air, called thermals, rise
upward over land warmed by the sun.
640
Locomotion
in these structures within the animal kingdom re-

flects the effects of biological properties and the
physical environment acting in combination.
Although insects, bats, and birds all fly, their
Swimming forward
wing shapes are markedly different. Insect wings
(a) Lateral view
differ widely in shape and appearance, but they
Each tail movement share many features. Typically, the leading edge of
sheds a vortex the wing is a stiffened structure, whereas most of
of fluid
the wing is a flexible membrane strengthened by
an internal framework. During flight, the insect
wing distorts, creating complex fluid movements
(b) Dorsal view that enable flight. Bat wings, like insect wings, are
membranous, but the bones that act as the frame-
work of the wing are jointed. The fine muscles
within the wing allow the bat to change the wing
shape, which translates into greater maneuver-
(c) Vortex fluid movement ability than is seen in insects. With the elasticity of
the membrane, the bat is able to change the di-
Figure 37 Vortices and movement through fluids
When a fish flaps its caudal fin, it generates a complex circular
mensions of the wing by as much as 20% without
pattern of fluid flow called a vortex. Swimming activity induces incurring a change in the tightness of the mem-
a series of vortices that can be seen in (a) lateral view or brane. The feathers of the bird wing have specific
(b) dorsal view. Each vortex resembles a doughnut. (c) Fluids shapes and positions that allow the wing to better
move from the center of the doughnut outward to the edge and
loop back toward the center. These patterns of fluid movement
control the path of air over the surface of the wing.
reveal how the tail interacts with the water during propulsion. Because the feathers overlap and can slide over
(Source: Adapted from Nauen and Lauder, 2002) each other, birds can change the geometry of the
wing without compromising the ability of the wing
to act as an aerofoil.
The wing moves rapidly downward below a hori- While bird wing geometry is similar overall
zontal plane, twisting as it moves. The combination among species, the subtle differences in shape have
of rapid downstroke and a twisting movement gen- important ramifications for flight. Let’s first con-
erates a large vortex of air movement at the leading sider the relationship between bird wing size and
edge of the wing. These air movements allow the in- body mass. Since air flows over the entire wing sur-
sect to generate both the upward and the forward face, a combination of wing span (b) and surface
force. The situation is fundamentally similar in birds area (S) influences lift. Obviously, larger birds need
and bats. Downward wing movements generate larger wings to generate the lift to remain aloft.
vortices that can be used to remain aloft and propel However, which is more effective, longer wings or
the animal forward. In addition, insects and hum- broader ones? Birds of the order Procellariiformes,
mingbirds can generate favorable fluid movements which includes albatrosses and petrels, differ in
during the upstroke, which allows them to hover. size by 400-fold. They share a similar lifestyle, soar-
Although researchers have many techniques ing long distances over open ocean. When these
to visualize the vortices that develop during flight, birds are drawn scaled to the same wing span, the
the exact forces at play remain unclear. The style importance of wing shape is evident (Figure 38).
of movement, the shape of the appendages, and The larger birds have longer and narrower wings.
the velocity of movement all affect the nature of Mathematically, the shape is described as the as-
the wake and the forces that govern movement. pect ratio (Λ), which is calculated as follows:
Λ⫽ b2/S
Fin and wing shapes influence The shape of fish fins, which are much more
fluid movements variable in shape than bird wings, enable fish to un-
In the previous sections we have described how dertake diverse swimming styles. If we restrict our
the physical attributes of body shape, wing, and comparison to the fastest-swimming fish, we can see
fin shape influence fluid movements. The diversity the importance of fin shape in swimming strategies.
641
Locomotion
Wandering albatross
Homocercal
tail
Black-browed albatross (a) Mako shark
White-chinned petrel
Heterocercal
tail (weak)
Cape pigeon (b) Blue shark
Heterocercal
tail (strong)
Wilson’s storm petrel
Figure 38 Wing aspect ratios The birds shown in

(c) Thresher shark
this image range almost eight-fold in wing span, but are
drawn to the same wing span to illustrate the differences in Figure 39 Caudal fin shapes Sharks’ caudal fins
wing shape. Horizontal bar represents relative wing span. range in shape from nearly symmetrical (homocercal) to
The smallest birds have relatively broad wings. strongly assymetrical (heterocercal).
(Source: Modified from Pennycuick, 1992)
Burst swimmers, such as pirarucu, possess thick brates. Many show vestiges of their aquatic ances-
caudal peduncles with rounded caudal fins of low try in semiaquatic lifestyles and aquatic develop-
aspect ratio. Fast steady-state swimmers, such as mental stages. Each lineage faced its own set of
tuna, possess thin caudal peduncles with crescent- challenges with terrestrial life. In this section we
shaped, or lunate, caudal fins of high aspect ratio. consider how terrestrial animals meet the oppres-
Each of these caudal fins is homocercal, or symmet- sive challenge of gravity.
rical above and below the midline. Many sharks pos-
sess asymmetrical caudal fins. These heterocercal Aquatic animals invaded the land
caudal fins are much taller on the dorsal side than several times
the ventral side (Figure 39). With each stroke, more
thrust is generated dorsally, forcing the shark poste- Invertebrates invaded land many times, but the
rior downward and rotating the anterior upward, most successful group is the arthropods, prima-
causing the nose of the shark to pitch upward. The rily arachnids (e.g., spiders), myriapods (e.g.,
fastest sharks, such as the mako shark, have homo- centipedes), and hexapods (e.g., insects). The
cercal caudal fins, but pronounced heterocercal cau- earliest terrestrial invertebrates were probably
dal fins are found in pelagic cruising sharks. As with detritivores, scrambling over the ground eating
all sharks, the rigid pectoral fins generate lift and partially hydrolyzed plant material. Herbivores
prevent the shark from rolling. and carnivores arose later in invertebrate evolu-
tion. Each lifestyle requires a different type of lo-
comotor apparatus to meet the challenges of the
complex terrestrial world.
Terrestrial Life Vertebrates were once found only in aquatic
Early in the evolutionary history of metazoans, all ecosystems, when large, shallow marshes domi-
animals lived in aquatic ecosystems. The invasion nated the landscape. Then about 370 million years
of land came in at least two waves. Today, the ago the vertebrate invasion of land began. Many
metazoans of terrestrial ecosystems are repre- fish species had already evolved strong fins that en-
sented by diverse taxa of invertebrates and verte- abled them to move through sunken vegetation.
642
Locomotion
These locomotor modifications helped the first am- tadpoles metamorphose into semiaquatic frogs and
phibious fish to move on land, facilitating the tran- terrestrial toads. This developmental transition
sition to a terrestrial world. The coelacanth, a fully from aquatic to terrestrial animals is also common
aquatic fish, is closely related to the early terrestrial in insects. These animals provide vivid examples of
invaders and anatomically similar. Many unrelated the anatomical and physiological differences in lo-
fish have fin structures that facilitate a semiterres- comotor patterns in aquatic and terrestrial animals.
trial life. These early invaders used paired pectoral Amphibians provide many interesting examples
and pelvic fins to pull the body along, but the trunk of how changes in locomotor physiology are inte-
was in direct contact with the ground. Evolution of grated into life history strategies. Some amphibians
the appendicular musculature and skeleton al- remain aquatic animals throughout their lives, us-
lowed animals to become more mobile, as the limbs ing appendages and a tail to swim through the wa-
supported more of the weight of the animal. Im- ter or crawl through vegetation. Many frogs and
provements in leg musculature, changes in pos- toads undergo metamorphosis. Tadpoles are larval
tural muscles, reoriented skeletons, and stronger forms of frogs and toads that undergo indirect de-
bones all contributed to the colonization of land velopment. They swim through the water much like
and the diversification of land animals. The many a fish that uses its tail and trunk to generate thrust.
species of semiaquatic animals illustrate the type of In the late stages of larval development, changes in
physiological modifications that are necessary for a thyroid hormone levels trigger remodeling of the lo-
terrestrial life. comotor apparatus. Limb buds arise from the body
Amphibious animals that must move on both trunk and grow into hindlimbs and forelimbs
land and water face the challenge of using the (Figure 40). At maturity, the hindlimb anatomy
same locomotor apparatus under two different
conditions. Eels and snakes use trunk movements
to swim in water and crawl over land. Ducks and
turtles use their feet to walk on land and paddle in
the water. The same locomotor modules are used
to move in both environments, but an animal may
use the musculature in a way that is specific for
each environment. For example, when ducks and
turtles are in water, they do not need to use leg
muscles to support the body mass. Rather, the leg
musculature can extend and contract at a higher
frequency during swimming. Eels and snakes use
the same undulatory movements both on land and
in the water. However, movement on land requires
more force because of the effects of gravity. Thus,
the undulations of an eel on land may be at the
same frequency as in the water, but the eel uses
the more powerful white muscle on land, and the
more efficient red muscle in the water. Collectively,
amphibious animals use combinations of motor
patterns and recruitment to utilize the same loco-
motor modules to move in two worlds.
Metamorphosis remodels anatomy and

physiology for terrestrial locomotion
Many animals begin their lives in an aquatic world
and then undergo a developmental remodeling of Figure 40 Tadpole metamorphosis Fully aquatic
larval frogs (tadpoles) swim using their tail. Legs begin to grow
anatomy and physiology to specialize for a terres- during metamorphosis: first hindlimbs then forelimbs. Once the
trial life. You are probably most familiar with the detail is resorbed, the mature frog ventures onto land, using its
velopment of local amphibians, where fully aquatic legs to walk and jump.
643
Locomotion
becomes specialized for a type of movement that Flightless birds evolved in the absence
enables both swimming and jumping, although un- of terrestrial predators
like mammals, the limb musculature does not sup-
For many animals, the locomotor machinery
port the entire weight of the animal. In some
must allow movement in more than one environ-
species of frogs, tadpoles can climb onto the back
ment. Although flying is the most efficient mode
of a parent, which carries its offspring between
of transportation for birds, most birds also spend
ponds (Figure 41). Still other species of frogs un-
significant time on the ground. At one extreme
dergo direct development. Miniature frogs, known
are the flightless ratite birds, which include the
as froglets, hatch from eggs laid on vegetation. In
extant ostrich, emu, and kiwi, as well as the ex-
contrast to tadpoles, these juvenile frogs can swim,
tinct moa and elephant bird (standing 2.5 m tall
climb, or jump from place to place. It is not yet
and weighing 450 kg). Although the evolutionary
clear how the basic developmental biology of the
ancestry of these animals remains uncertain, it
amphibians’ locomotor system has evolved to ac-
is likely that the flightless lineages arose about
count for these diverse life history strategies.
40 million years ago. Modern ratites, such as the
The insect orders Orthoptera (dragonflies, dam-
ostrich, use wings for balance during running
selflies), Ephemeroptera (mayflies), Plecoptera
and as part of courtship rituals. These birds pos-
(stone flies), and Diptera (flies, midges, mosquitoes)
sess well-developed leg musculature, allowing
each include species that both lay eggs and undergo
many species to run at high velocities. Other
early development in water. The aquatic juvenile
species of flightless birds appear around the
forms, called nymphs, occupy diverse niches within
world. The wings of penguins may look like shark
the aquatic environment. Dragonflies, mayflies, and
fins or seal flippers, but the penguins use their
stone flies crawl along the bottom of streams and
wings to “fly” through the water.
rivers. These animals possess heavy armored plates
Darwin once commented that there is no
that offer protection against larger predators. Mos-
greater anomaly in nature than a bird that cannot
quito larvae float on the surface of stagnant water,
fly. There may be many reasons for the evolution-
slurping oxygen from the top, oxygenated layer of
ary loss of flight. The two most obvious advantages
water. Chironomids are larval midges that live in the
of flight are avoidance of predators and ability to
sediment of lakes, often in the near absence of oxy-
migrate to more favorable environments. Most
gen. Each of these larval forms has exquisite physi-
flightless birds arose in the absence of major ter-
ological strategies to survive in specific niches.
restrial predators. Populations of flightless birds
However, these aquatic specializations are left be-
exist in the Galapagos Islands, which lack major
hind when the animals undergo their last develop-
terrestrial predators. The ostrich lives in a region
mental transition into flying adults.
with many large predators, but its large size and
powerful kicking legs discourage most predators.
Whether considering macroevolutionary variation
(flightless species), or microevolutionary variation
(flightless populations of one species), the transi-
tion from flight-capable to flightless strategies
must provide energy savings. The energy that
would otherwise be spent building and maintain-
ing wing muscles can be diverted to other systems.
Animals of similar geometry should be

able to jump to the same heights
Jumping is a form of locomotion peculiar to terres-
trial animals, with specialized anatomy. Animals
must use a single muscular contraction to lift the
entire mass off the ground. Good jumpers differ
Figure 41 Unusual mode of locomotion in the
tadpole In some species of tropical frogs, tadpoles can from poor jumpers in the geometry of the legs and
hitch a ride on the back of an adult frog, allowing it to move the strength of the jumping muscles. Higher jumps
between sources of water. are possible with longer legs. Some animals have
644
Locomotion
additional leg segments that participate in jump- paring different species, variations in the animal
ing, like the elongated tarsals of frogs. These morphology, physiology, and composition come
longer legs improve jumping because the bones into play, and contribute to differences in the
move through a greater arc for a given angle of ro- ability to jump.
tation. Jumpers must also be able to contract mus- Fleas are often considered to be exceptional
cles rapidly. The greater the velocity at takeoff, the jumpers because they can jump to heights hun-
further the animal can jump. dreds of times greater than their own height.
Animals of different size but similar geome- Small jumping animals, like the flea, face several
try should be able to jump to the same height. challenges that are less important for larger ani-
Similar geometry means that the overall dimen- mals. First, viscous effects are more important for
sions of legs are similar and the mass of the small animals. A flea jumping through air faces a
jumping muscle is a constant proportion of body drag force similar to what a larger animal might
mass. With a constant proportional muscle face jumping through water. Second, jumping an-
mass, the velocity at takeoff would be similar, imals need to move their legs fast enough to reach
and therefore small and large animals should be takeoff velocity. Flea legs are so small that no con-
able to jump to the same height (Figure 42). The ventional musculoskeletal combination could
reference point when talking about the effects of reach the required contraction velocity. Fleas
gravity is the vertical midpoint of the mass of the avoid this problem by using an unusual mecha-
animal—the center of gravity. Although a small nism. Muscles power the jump of a flea only indi-
animal may not reach the same height as a large rectly. In the first of two steps, a leg muscle pulls
animal, it is able to lift its center of gravity the on an internal spring and locks it into the loaded
same distance. These relationships depend on position. Next, a second muscle releases the
the assumption of similar geometry. When com- spring, causing the leg to rapidly extend and the
flea to jump. The spring returns to its unloaded
position faster than any muscle could induce a
contraction.
Center of Terrestrial animals require strong bones

gravity
and postural musculature
The main challenge in terrestrial locomotion is
gravity. In the aquatic world, the natural density
of the body imparts some degree of buoyancy that
greatly reduces the influence of gravity. However,
terrestrial dwellers are much more dense than
Height air, the surrounding fluid. Amphibians and rep-
tiles typically lie directly on the ground, reducing
the costs of fighting gravity. However, birds and
Height mammals, as well as extinct dinosaurs, use their
limb muscles to lift the body off the ground. This
strategy requires anatomical and physiological
investments. Bones must be thicker to accommo-
date the increased force of gravity. Limb muscu-
lature must be more extensive to support and
move the limbs. Muscle activity is required
throughout the body to actively maintain posture.
Even the process of standing still requires consid-
Figure 42 Jumping antelope Animals of similar erable muscle activity. In the next section we dis-
geometry should be able to lift their center of gravity the cuss the energetic factors that govern animal
same vertical distance in a jump. The larger animal reaches
locomotion. Although these considerations apply
a greater height because its center of mass begins at a
greater distance from the ground. to all animals, they have special relevance for ter-
(Source: Adapted from Pennycuick, 1992) restrial animals.
645
Locomotion
Energetics of Movement gen content of skeletal muscle. For example, the re-
searcher might conclude that flying from one site to
Locomotion is expensive, and many studies in the another costs x joules of energy, on the basis of the
comparative physiology of locomotion focus on the difference in weight and fuel depots.
ways anatomy and physiology are used to minimize A more biomechanically oriented physiologist
the costs of movement (see Box 3, Genetics and Ge- might be most interested in how velocity of move-
nomics: Artificial Selection of House Mice). In addi- ment affects the metabolic costs. Laboratory studies
tion to the long-term costs of building and might involve flying this bird species in a wind tun-
maintaining locomotor tissues, animals incur nel to assess the energetic costs of flying at different
short-term costs when they use that machinery to velocities. Birds may be fitted with gas masks that
move. The costs of locomotion, which depend on provide oxygen and capture CO2. The metabolic de-
many biological and physical factors, can be ex- mands of exercise are discussed in the context of a
pressed in several different terms. The mechanical specific parameter called cost of transport (COT).
costs of work can be expressed in units of joules (or The central question in these studies asks how
calories). The metabolic costs of work are best ex- much energy it costs an animal to move a particu-
pressed as ATP turnover (moles of ATP per minute). lar distance. The total COT (COTtotal) is calculated as
An estimate of ATP turnover can be obtained from the metabolic rate divided by locomotor velocity.
oxygen consumption, but only when the animal is
moving slowly enough to justify the assumption COTtotal ⫽ (ml of O2 per min) / (m per min)
that oxidative phosphorylation is providing the ATP. ⫽ ml of O2 per m
CO2 production, measured relative to oxygen con- The calculation of COTtotal does not take into ac-
sumption, provides important information about count the resting metabolic rate of the animal. The
metabolic fuel selection. Most importantly, these net COT is the difference between the total meta-
different indices of the cost of locomotion are read- bolic rate and the resting metabolic rate. COT cal-
ily interconverted. Oxygen consumption (VO2), the culations allow a researcher to determine the
most easily measured parameter, can be translated velocity at which an animal can move to most eco-
into both metabolic units (ATP) and work units nomically cross a given distance.
(joules). For example, an animal that consumes 1 Each of the previous examples considers the
ml of oxygen generates about 20 J of energy. The energetics of movement of specific animals, but in
costs of movement depend on many factors, both many cases researchers are interested in compar-
environmental and functional. isons between different animals. The most com-
mon type of comparison considers the effects of
body size on the COT. Larger animals use more en-
Energy demands of movement ergy to move, simply because they are larger and
can be expressed as total costs have greater total metabolic demands. When con-
or mass-specific costs sidering the impact of body size, it is common to
There are many ways to assess the energy required standardize locomotor parameters to the body
for locomotion. Each specific parameter takes into size. For example, the metabolic rate measure-
account a different set of concerns that are appro- ments may be expressed relative to body mass to
priate to the situation. Calculation of each param- compare differences in energetics in two animals
eter includes reasonable assumptions that must be of different sizes. Also, studies on fish locomotion
kept in mind to properly interpret experimental often express velocities not in absolute terms (me-
observations. Let’s consider some examples. ters per second) but as body lengths per second.
An ecological physiologist might be interested Each of these energetic parameters is useful
in the energetics of a specific migratory bird. The and important in specific contexts. However, the
primary question is the relationship between stored nuances of each parameter are crucial considera-
energy and the locomotor feat. The experiment may tions. Expressing values per animal versus per
be as simple as weighing birds before and after mi- gram of animal provides very different informa-
gration. Analyses of body tissues may be used to as- tion about the energetics. Similarly, each measure-
sess how specific energy storage depots change as ment has implicit assumptions about the
a result of the activity. These measurements could underlying biochemistry. Although these calcula-
include adipose tissue mass and the lipid and glyco- tions are intended to provide information about
646
Locomotion

Artificial Selection of House Mice
For hundreds of years, humans have though the impetus to run may reflect processes in the
used artificial selection to tailor the locomotor central nervous system, the ability to run is met by the
physiology of animals to suit our needs for agricultural locomotor physiology, in association with other physio-
animals and sports. For instance, thoroughbred horses logical systems.
and greyhounds, both remarkable runners, are the If you examined two closely related species that dif-
products of centuries of artificial selection. Only re- fered in activity levels, it would be reasonable to predict
cently have researchers designed artificial selection ex- differences in indices of exercise performance and mus-
periments specifically to explore the mechanisms by cle metabolism. Surprisingly, the selected and control
which locomotor systems evolve, exploring the links be- mice were indistinguishable in terms of basal metabolic
tween physiological systems. rate, maximal respiratory rate (Vmax), maximal sprint ve-
In the early 1990s, Ted Garland set up a long-term se- locity, or endurance capacity. Selected mice had differ-
lection experiment with house mice, with the goal of ex- ences in some respects: muscle glucose transport, bone
ploring the evolution of aerobic exercise levels. Each dimensions, heat shock protein expression, and liver an-
mouse was given free access to a running wheel, with the tioxidant capacities. Also, the activities of the mitochon-
number of revolutions monitored by computer. Mice that drial enzymes that support muscle energy metabolism
ran the furthest were allowed to become the parents for were somewhat higher in muscles of selected animals.
the next generation. After only 16 generations of such se- One of the most interesting findings from these selec-
lection, the selected mice typically ran about 2.7 times tion studies was the variability among replicate lines.
farther and twice as fast as randomly bred controls. Al- When the experiments began in the early 1990s, the re-
though the initial focus of the experiment was on the res- searchers first divided the mice into eight populations, re-
piratory and musculoskeletal systems, these studies sulting in four selected for high running and four bred
also revealed how other physiological systems coevolved randomly to serve as control lines. While the selected
with activity levels, often in surprising ways. lines evolved similar levels of voluntary wheel running,
The goal of these selection studies was to assess re- the replicate lines differed in several ways. For example,
lationships between locomotor propensity and ability. two of the four lines of selected mice showed a high fre-
The characteristic used as the basis of selection was a quency of small gastrocnemius muscles. These “mighty
behavioral trait: how much mice ran of their own free minimuscles” had the same enzyme capacity of a larger
volition. The reason for the variation in voluntary run- muscle packed into a smaller muscle that is more resis-
ning among individual mice in the original population tant to fatigue. The minimuscle phenotype was rare in all
remains unclear. More active individuals may have a four control lines and two of the selected lines. The
greater sensitivity to the positive, euphoric benefits of gene(s) responsible for this unusual phenotype remain
running or, alternatively, a lower sensitivity to the neg- unknown, but the difference among lines reveals two im-
ative, painful effects of prolonged activity. In any case, portant concepts in evolutionary physiology. First, genetic
several other behavioral traits correlated with the vol- variation within populations represents a pool of alternate
untary activity levels. Mice in the selected lines showed solutions to problems not yet encountered. The minimus-
much greater levels of aggressive predatory behavior cle phenotype was relatively rare in the original popula-
toward crickets. Subsequent studies showed that the tions, and only underwent positive selection in the context
region of the brain that controls predatory behavior, the of this experiment. However, it is not difficult to imagine
lateral hypothalamus, was also more active in the se- how a change in the natural environment could also re-
lected mice. The underlying differences in CNS activity ward this phenotype of a smaller, more fatigue-resistant
were reflected in the response to neuropharmacological muscle. Second, these studies illustrate that genetically
agents. When mice from each of the lines were injected similar (though not identical) animals can solve physio-
with Ritalin, a drug used to reduce hyperactivity in chil- logical challenges in different ways.
dren, the differences between lines greatly diminished.
Although the researchers recognized that the variation
in voluntary activity levels was ultimately attributable to References
the motivation to run, the selection experiments also q Garland T. Jr., and S. A. Kelly. 2006. Phenotypic plasticity and ex-
provide insight into the underlying locomotor physiology perimental evolution. Journal of Experimental Biology 209:
required to support high levels of aerobic activity. Al- 2344–2361.
647
Locomotion
the muscles that underlie locomotor systems, it is Animals change style of movement
important to recognize that other physiological to alter the costs of locomotion
systems, such as respiratory and cardiovascular
Many animals use different styles of movement
systems, also incur a cost during locomotion.
over different ranges of velocity. A famous study
that emerged from the laboratory of the late Dick
Velocity of movement affects Taylor used ponies to illustrate how animals can
locomotor costs change gait to alter the interaction between veloc-
ity and energetics. Like many land animals, ponies
As mentioned in the previous section, the velocity
exhibit distinct styles of moving or gaits. They walk
of movement influences both the metabolic rate
at low speed, trot at intermediate speed, and gallop
(milliliters of O2 per minute) as well as the effi-
at the fastest speed. Taylor’s group measured the
ciency of movement, expressed as COT (milliliters
metabolic rate of ponies as they moved with differ-
of O2 per meter). Experimentally, these relation-
ent gaits at increasing velocity (Figure 43). When
ships are studied by monitoring respiration of an
ponies walked at their preferred velocity of 1–1.5
animal that is moving at different velocities. Such
m/sec, they consumed about 300 J/m. If they were
studies have been performed with aquatic, aerial,
forced to move more slowly or quickly using the
and terrestrial animals. At a low velocity, an ani-
same walking gait, their COT increased. The same
mal consumes oxygen at a rate near its resting
was true of ponies that either trotted or galloped.
metabolic rate. An increase in velocity increases
The energy demands at their chosen velocities were
metabolic demands in a pattern that differs de-
about 300 J/m, regardless of the gait. Forcing them
pending on the animal, the style of movement, and
to move faster or slower than their preferred veloc-
the environment. When these metabolic rate data
ity increased their energy demands. In other
are used to calculate total COT, a U-shaped curve
words, the minimal COT values were the same in
typically results with a minimum COT at a velocity
each gait as long as the animals could move at the
intermediate between the slowest and fastest ve-
preferred velocity. A pony that walks, trots,
locities possible using that style of movement.
or gallops a distance of 1 km will consume about
When given a choice, animals tend to move at
300 kJ of energy. The galloping pony will use the
a specific velocity called the preferred velocity. You
energy faster, but it will cover the distance in a
have probably experienced this yourself if you have
shorter period of time.
walked with someone who is shorter or taller. For
Gait alters energy expenditures by changing
example, a tall person walking with a small child
the way locomotor systems are used. Within each
finds it challenging to walk at the child’s pace. Re-
markably, the preferred velocity is usually close to
the velocity at which the COT is minimal. 500
The relationships between preferred velocity

and minimum COT bring up interesting questions 400
about the evolution of physiology. That animals
Energy cost (J/m)
choose a velocity that is near COT suggests that

300 Gallop
animals are able to detect conditions that result in Walk Trot
maximal efficiency. The sensory feedback mecha-
nisms responsible for the relationship between 200
preferred velocity and COT are not yet clear. Pre-
sumably, there is also an evolutionary advantage
100
to a behavior that leads to an animal moving Walk Trot Gallop
slower than it otherwise could. The immediate
benefits are in energy savings, but there may also 0
1 2 3 4 5 6
be long-term benefits in terms of avoiding muscle Speed (m/sec)
damage. When animals move near the maximal
possible velocity, the muscles can experience iso- Figure 43 Gait and energy expenditure Many
animals, such as ponies, can move with different running
metric stress. By using muscles well below their styles or gaits. Each style of running has an optimal velocity
capacities, the animal reduces the risk of debilitat- at which the cost of locomotion is minimal.
ing muscle damage. (Source: Hoyt and Taylor, 1981)
648
Locomotion
gait, the pony uses the same set of muscles over a Environment determines energetic costs
wide range of velocities. Once the pony reaches a
The costs of locomotion differ greatly for swim-
particular threshold velocity, it changes its gait
mers, fliers, and runners, each moving at the op-
and recruits different combinations of muscles to
timal velocity (Figure 44). The costs are lowest for
power different leg movements. The coordination
swimmers and highest for runners. To travel
of leg movements also differs between gaits. Walk-
1 km, a 1-kg fish would expend about 100 kcal, a
ing ponies move diagonal legs in synchrony. Trot-
1-kg bird about 300 kcal, and a 1-kg mammal
ting ponies move their left legs in synchrony.
more than 1000 kcal. The reasons for these differ-
Galloping ponies move the hind legs in synchrony,
ences relate to the efficiency of movement.
half a cycle out of phase from the front legs. The
Let’s start by considering how animals move on
pattern of leg movement in galloping ponies
land. When an animal walks or runs, energy is re-
makes better use of elastic storage energy. When
quired to fight the effect of gravity. When an animal
the pony plants its hind legs, it also bends its back,
moves one leg forward, its center of gravity drops.
creating and storing elastic tension in the bones
Muscular work is required to slow the descent. The
and tendons. The release of the stored energy
center of gravity rises when the rear leg moves for-
drives the front legs forward. Storing energy in the
ward. More muscular work is required to lift the
bones and muscles of the back allows galloping
center of gravity. The cost of moving the center of
animals to conserve energy. The flexure of the
gravity up and down increases the metabolic rate
back during running is less obvious in a pony than
but does not increase the velocity of forward move-
in other animals. The cheetah, for example,
ment, thus runners have a higher cost of transport.
demonstrates a pronounced bend in the back
In comparison to a walker, a bicycle rider is able to
when it sprints.
move much faster and cover the same distance us-
ing less energy. One reason is
that the bicycle supports the
Crawlers, center of gravity and more en-
Fliers Swimmers
runners
Insects
ergy can be used to move the
Fishes person forward. Similarly, flying
Reptiles is more efficient than walking
Birds because the effects of gravity are
1.0 Mammals minimized by lift. Swimmers are
the most efficient because they
Log minimum cost of transport (kcal/g/km)
Fliers often approach neutral buoy-

0.5 ancy, where body composition
largely negates the effects of
0
gravity. Swimming animals re-
Runners quire less energy than fliers to
Swimmers move at a given velocity, but
–0.5 fliers are able to move much
faster. At high velocities the vis-
cosity and drag of water are in-
–1.0
surmountable obstacles for a
swimmer.
–1.5 The environment affects
the relationship between veloc-
ity and metabolic rate (Figure
–6 –5 –4 –3 –2 –1 0 1 2 3 45). Most terrestrial animals
Log mass (kg) moving with a single gait in-
crease metabolic rate linearly
Figure 44 Cost of locomotion in air, in water, and on land The costs
of locomotion are lowest for swimmers and greatest for runners. Within each
with velocity. The power re-
environment, the mass-specific costs of locomotion decline as animal size increases. quired to generate faster move-
(Source: Tucker, 1975, with modifications) ment of legs is proportional to
649
Locomotion
High drag High drag

Metabolic rate
Metabolic rate
Metabolic rate
Low drag
Low drag
Velocity Velocity Velocity

(a) Swimmer (b) Flier (c) Runner
Figure 45 Work curves for swimmers, fliers, and Bees, and some bird species such as the magpie, have flat
runners The shape of relationship between work and velocity curves that suggest work is nearly equivalent at all velocities.
differs widely between animals, due to both the nature of the Also, the work at each velocity differs widely: although the shape
environment and the locomotor system of the animal. of the curve is similar for pigeons and cockatiels, at most
(a) Swimmers typically show an exponential relationship, as drag velocities pigeons expend more energy to fly. (c) Most running
becomes increasingly important at higher velocities. animals show an increase in work with the velocity of movement.
(b) The nature of the curve in birds differs widely between (Source: Data for (a): Pettersson and Hedenstrom, 2000; data for
species. Many, such as the cockatiel, have a U-shaped curve. (b): Tobalske et al., 2003)
velocity. However, this simple linear relationship ments for swimming are a function of velocity
does not apply to fliers and swimmers. cubed. This relationship (metabolic rate ∝
Flying animals, including insects, bats, and velocity3) accounts for the exponential curve ob-
birds, demonstrate more complex relationships be- served experimentally.
tween metabolic rate and velocity. Many birds show
a U-shaped relationship. Below a critical velocity,
some birds must expend additional energy to move
Body size affects costs of locomotion
wings fast enough to generate the lift required for Another factor that emerges from Figure 44 is the
flight. At the critical velocity, the birds can generate impact of body size. In mass-specific terms, small
minimal power necessary to remain aloft. However, animals use more energy to move than do large
not all fliers show this relationship. A comparison animals. Consider, for example, the relative costs
of three bird species shows three different patterns. incurred by three animals that move 1 meter. A
The magpie has a shallow curve, using similar small insect expends about 1000 J/kg, a mouse 30
power at each velocity. The cockatiel, in contrast, J/kg, and a pony about 3 J/kg. Many confounding
has a pronounced U-shaped curve. The curve for a factors influence the relationship between body
dove is somewhat intermediate, but at most veloci- size and costs of transport.
ties the dove uses significantly more than the mini- The easiest way for a researcher to study the
mal power. The differences between species lie in effects of body size is to examine muscle proper-
properties such as wing-beat frequency, wing ties in the widest range of species possible. The fa-
movement, and wing shape. mous “mouse to elephant curve” reflects the
Swimming animals typically exhibit an expo- metabolic properties of mammals over many or-
nential power-velocity curve, increasing sharply at ders of magnitude. The problem with interpreting
higher velocities. Metabolism must provide the en- this relationship is that mice and elephants differ
ergy to support the mechanical power require- in many ways, so it is difficult to identify the mech-
ments for swimming muscles. The mechanical anistic cause of the observed relationships. It is al-
power required to move an object through water ways easier to understand the basis of differences
is equal to drag times velocity. For most swimming between animals when the species under study
animals, drag is proportional to velocity squared are closely related. Thus, researchers can study
(drag ∝ velocity2) and therefore the power require- different sizes of a single species, or a clade of
650
Locomotion
closely related species. However, these compar- size. The long bones of mammals, for example,
isons inevitably result in a much narrower range are nearly isometric; the relative shape and size
of body sizes. Despite these valid concerns about of the bones is similar among mammals of differ-
the importance of considering phylogenetic relat- ent sizes. However, other aspects of the muscu-
edness, there remains an overriding relationship loskeletal system can differ in important ways.
between body size and cost of movement, one that Elastic storage energy is an important mecha-
is apparent across broad taxa and in terrestrial nism that animals can use to increase the effi-
animals, swimmers, and fliers. No single overrid- ciency of movement. Bones and connective
ing factor is responsible for the greater efficiency tissues are the most important elastic energy
of movement in larger animals. Differences in stores in vertebrates. Within narrow taxa, such
every level of musculoskeletal function and animal as mammals, there is little difference in the me-
locomotion can contribute to the origins of this chanical properties of the biomaterials used to
nearly ubiquitous relationship between body size construct muscle and connective tissue. For ex-
and the costs of locomotion. ample, mouse collagen is not likely to be very dif-
The biomechanical constraints of moving ferent in properties from elephant collagen.
through the environment differentially affect small However, animals may differ in how these bioma-
and large animals. Aquatic animals, in particular, terials are used to store elastic energy. First,
must overcome the effects of drag. Drag increases large and small animals differ in how effectively
with surface area, but power increases with mus- they can store elastic energy. Energy can be
cle mass, which is reflected in body mass. The ra- stored only when a force is sufficient to deform
tio of surface area to mass is greater in small the elastic elements. Larger animals, because of
animals than in large animals. Thus, as body size the effects of gravity, are better able to store elas-
increases, the cost of overcoming drag increases tic energy during movement. Second, animals
but the capacity for power generation increases may differ in the way these materials are com-
more. Thus, large animals use less of their muscle bined into locomotor structures. Larger kanga-
capacity to meet the cost of overcoming drag. The roos, for example, have relatively larger leg
differences in drag provide an important insight muscle tendons than do smaller kangaroos.
into the effects of body mass on locomotor costs in These larger tendons allow them to store even
aquatic animals, but drag has less significance for greater proportions of energy during hopping.
flying and terrestrial vertebrates. The same increase in tendon elastic storage ca-
Animals can produce muscles using building pacity is seen in other mammals, although the ef-
blocks that are grossly similar in structure but with fects of body mass are greater in kangaroos.
important differences that influence musculoskele- One of the reasons it is important to compare
tal function. For example, myosin heavy chain iso- closely related animals is the potential for funda-
forms differ in the relationship between force and mental differences in the organization of the mus-
ATPase activity. Since a fast-twitch muscle differs culoskeletal system. Large mammals use less
from a slow-twitch muscle in the economy of force energy in maintaining posture because their ap-
development, the fiber type recruitment pattern in- pendages are located directly under the body. Ap-
fluences the costs of locomotion. Small animals pendages that extend more laterally have a lower
move their legs at a greater frequency than do mechanical advantage, requiring more muscle
larger animals. Consequently, a small animal has a force to maintain posture. Furthermore, small an-
greater reliance on the less economical fast-twitch imals remain in a crouched posture, which re-
fibers. Furthermore, the fiber type profile of loco- quires muscle activity.
motor muscles differs in large and small mammals. Much of the research in this area of locomo-
For a given muscle, such as the soleus, large ani- tion searches for single unifying themes that can
mals have a greater proportion of slow myosins. explain variation in locomotor properties over
Thus, both fiber type profile and muscle recruit- broad taxa of animals. In reality, there are likely
ment patterns contribute to the greater economy of many different relationships among animals. The
locomotion in larger animals. largest animals may have different allometric rela-
Important differences also occur in the me- tionships than the smallest animals. Certain taxa
chanical properties of muscles in relation to body may be constrained by phylogenetic relationships
651
Locomotion
and evolutionary history. Since the locomotor ap- 2 C O N C EP T CH E CK

paratus is required for other functions, it is rea-
sonable to assume that evolution may have found 7. How do animals use buoyancy to reduce the
different solutions to similar problems. For exam- costs of movement in water?
ple, the benefits of locomotor efficiency may have 8. What are the main constraints governing
movement in water, through the air, and on land?
different evolutionary implications for an herbivo-
rous animal than for an active predator. 9. How do appendages influence fluid dynamics
and affect movement?
Integrating Systems Migration

Animal locomotion requires the integration of the mus- Most but not all migratory animals show each of these
culoskeletal system with all other physiological sys- characteristics. Physiological systems play important
tems. This integration is perhaps best illustrated by roles in the preparation of animals for migration, as well
considering the costs of migration. Many animals move as in the migration itself.
within a limited geographic range in search of food, or Animals that undergo long migrations show a pro-
defense of territory. The energetic costs of such daily nounced reorganization of their physiology to prepare
ranging movements are met by nutrients obtained in the for the journey. Suites of hormones respond to environ-
diet. However, many animals also undertake much mental cues to reorganize physiological systems and
longer trips, leaving their home range to journey many alter normal foraging behavior. Once the migration be-
kilometers. Hugh Dingle has summarized five attributes gins, the animal cannot easily be diverted from its route.
that separate migrations from other types of excursions. In temperate environments, migrations of many
birds and some insects begin in fall, so that species can
1. Migratory movements are persistent and of long
avoid the cold, harsh winter. Although the purpose of
duration. Some birds, such as Arctic terns, travel
the migration may be to avoid cold temperatures, it is
more than 20,000 km between poles during migra-
the change in photoperiod that triggers the premigra-
tory flights. The migratory flights of locusts and
tory reorganization. Seasonal temperatures may vary
monarch butterflies can cross thousands of miles.
each year, but photoperiod obeys a constant pattern.
2. Movement is more linear in direction, without the
The importance of photoperiod was shown in early
frequent turning seen in ranging. Migratory routes
studies with pigeons. Researchers held pigeons under
may be predictable over generations, even without
different photoperiod regimes. Birds kept under a win-
prior experience.
ter photoperiod (8 h light and 16 h dark) flew south
3. Animals are unresponsive to stimuli that would dis-
when released. Birds kept under a summer photope-
tract them during ranging or station keeping. For
riod (16 h light, 8 h dark) flew north when released.
example, many animals will not feed during migra-
Steroid hormones orchestrate the physiological re-
tion, even if food is available.
sponse to photoperiod. Castrated male birds, regard-
4. Particular behaviors precede departure and follow
less of photoperiod, always flew south when released.
arrival. Premigratory birds gorge on food to prepare
Testosterone supplements would result in resumption
for migration. Many usually solitary birds begin to
of the photoperiod-dependent response.
aggregate into groups in preparation for flocking.
The energy demands of migration require exquisite
5. There is a reorganization of energy metabolism in
coordination from multiple physiological systems. Many
support of locomotion. The migration typically in-
animals gorge on food prior to migration, “fattening” for
volves reliance on stored metabolic fuels. At the
the journey. Hummingbirds increase their mass by 50%
end of the migration, the animal is frequently de-
with lipid deposits. Lipids are the preferred fuel because
pleted of energy stores.
of the economy of storage (ATP per gram of fuel). A 3-g
652
Locomotion
hummingbird that deposits 1.5 g in fat droplets would moves 15° longitude each hour. Development of
need to store 15 g of glycogen particles (five times its chronometers and sextants, in combination with de-
body weight!) to achieve the same caloric content. tailed celestial maps, facilitated human exploration and
Changes in body mass also have biomechanical conse- colonization.
quences. Migratory sea birds may gain so much fat that Humans are not the only animals that rely on the
they have a difficult time taking off. Many animals are celestial bodies and geomagnetism for navigation, al-
completely committed to using their nutrient stores though the other species’ “tools” are built in. Animals
during migration, refusing to eat even if they encounter may use both a “compass” to give direction and some
food. Commitment to nonfeeding strategies has several form of “map” to identify the goal. Their mapping is
advantages to a migratory animal. In animals that rely generally thought to be a function of memory, but the
on stored fuels, success of the migration does not de- compass requires some neurosensory mechanism to
pend on successful foraging en route. Foraging in unfa- detect direction. Early research, primarily performed
miliar lands may put the animal at an increased risk of in birds, identified the importance of the sun and stars
predation. In many cases, it also permits animals to al- in navigation. More recent research has shown that
low their digestive systems to degrade, reducing the many animals also detect geomagnetism. In all ani-
costs of routine metabolism. mals studied to date, magnetosensory systems use
Often annual migrations are linked to reproductive tiny crystals of an iron oxide called magnetite. The
development. Frequently, migratory animals reproduce mechanisms by which these crystals are integrated
after they reach their destination. Reproduction, like into neurosensory systems have only recently been
migration, requires a great deal of energy, and success- studied. In birds, it is thought that the signals derived
ful life history strategies must balance the needs of both from magnetoreceptors are interpreted by the visual
functions. Some animals become reproductively mature circuitry.
before migration, but most animals delay reproduction Many humans have an innate ability to use odor to
until they have reached their destination. Consequently, find a local bakery or sewage outlet, but for the most part
animals may undergo reproductive or developmental we do not rely on chemical signatures for navigation. The
preparations in parallel with metabolic changes. Hor- detection of environmental chemicals by taste or smell is
mones coordinate metabolic, reproductive, and devel- made possible through specific receptors and neurosen-
opmental transitions associated with migration. Steroid sory networks. In many cases, these sensory systems are
hormones, such as cortisol and testosterone, are im- used to locate prey, as in a shark’s response to blood.
portant in vertebrates. Migratory insects, such as the Other species use water chemistry to navigate during mi-
monarch butterfly, use juvenile hormone and ecdysone. gration. Salmon imprint on the chemical signature of
Humans have a history of migration and long- their natal streams, allowing them to return to the stream
distance travel. Early hominids used landscape features during spawning many years later. Although this capacity
and the position of the sun and stars to guide them in is impressive, salmon survival also requires that it be im-
their ranging movements. Technological advances in perfect. Misguided fish entering the “wrong” river may
navigation allowed humans to explore their environ- exploit new habitats or enhance the mixing of gene pools.
ment more widely. The compass, developed in China in The energetic costs of migration are extraordinary.
the 4th century B.C., relies on the magnetism of the Many animals use migratory routes or strategies that
North Pole. More than 1000 years ago, early Arab explor- minimize the energetic costs of locomotion. Insects rely
ers developed a kamal to follow the elevation of Polaris, heavily on wind currents to reduce the costs of flight.
the North Star, an indication of latitude. Improvements in Migratory birds ride thermal bubbles to gain altitude
latitudinal navigation arose with the appearance of the without expending energy to flap wings. The oceanic mi-
astrolabe, quadrant, and cross-staff. Sailors used these grations of squid and eels in the Atlantic use the Gulf
tools to travel to the correct latitude, then move east or Stream to reach their destinations. Nonetheless, the
west to port. In the 17th century, explorers looking to costs of locomotion during migration are high and usu-
use the sun to determine longitude realized they needed ally met through mobilization of stored fuels. 2
a way to determine time, because the position of the sun
653
Locomotion
Summary
Locomotor Systems laminar flow to turbulent flow, the object incurs
k Animal locomotion depends upon the coordina- an added cost to move through the fluid.
tion of several physiological systems, including
k The combined effects of fluid properties and ob-
musculoskeletal, circulatory, respiratory, diges-
ject dimensions determine the Reynolds num-
tive, and sensory systems.
bers. Inertial effects dominate animal movement
k Muscles are composed of combinations of fiber at high Reynolds numbers. Viscous effects dom-
types. Fish locomotor muscles are primarily inate at low Reynolds numbers.
two or three fiber types organized into homoge-
k Drag is a force that opposes forward movement.
neous muscles. Tetrapods have more muscles,
Pressure drag results from a buildup of fluid in
each of which possesses multiple fiber types.
front of the moving object, whereas friction
k The pattern of locomotor muscle contraction is drag results from the interaction between the
controlled by motor neurons. Nervous activity surface of the object and the fluid. A stream-
coordinates the contractile pattern and controls lined shape reduces pressure drag to reduce the
muscle recruitment at different velocities. costs of movement.
k Mitochondrial oxidative phosphorylation pro- k Locomotor strategies must also compensate for
vides the fuel for resting muscle activity and the costs of overcoming gravity. In water, the
long-term, low-intensity exercise. Glycolysis, in costs of combating gravity are reduced by buoy-
combination with phosphagen stores such as ancy strategies, such as lipid storage or gas-
ATP and phosphocreatine, fuels activity of high filled sacs such as the swim bladder. On land,
intensity and short duration. the musculoskeletal system is used to overcome
the effects of gravity.
k High-intensity exercise incurs short-term ener-
getic deficits that must be repaid during recov- k Fliers and swimmers can overcome gravity us-
ery. Hormones control muscle metabolic fuel ing specialized appendages that act as aero-
mobilization and utilization. foils or hydrofoils. These structures generate
lift to oppose the downward pull of gravity.
k The cardiovascular system delivers oxygen and
Soaring animals use lift from natural air cur-
nutrients to working muscle via capillary net-
rents to overcome gravity. Appendages also
works. Vasoactive agents regulate blood vessel
generate the fluid movements responsible for
diameter to alter blood flow to muscle.
propulsion.
k Oxygen delivery to muscle mitochondria is
k The metabolic costs of movement depend on ve-
aided by the oxygen-binding protein myoglobin.
locity. For each type of movement, there is an
k Muscles work in conjunction with skeletal sys- optimal velocity for which costs are minimal.
tems. Hard skeletons are composed of cellular
k Many animals use their locomotor systems in
secretions that make up the extracellular ma-
different ways to create distinct styles of move-
trix. Osteoblasts and osteocytes produce the
ment, such as gaits.
matrix of vertebrate skeletons, which then un-
dergoes mineralization, or ossification. k The costs of locomotion differ in each type of
environment because of the combined effects of
Moving in the Environment fluid properties and gravity. The costs of loco-
k In order to move, animals must overcome the motion are lowest in swimmers and highest in
physical forces associated with the environment. runners.
k Fluids, such as air and water, flow in smooth lay- k Locomotor costs are also influenced by body
ers until they encounter objects. When an object size. The largest animals have greater total
encounters a fluid, it alters the flow of the fluid. costs of locomotion, although the mass-specific
When the object causes a fluid to change from costs are lower.
654
Locomotion
Review Questions
1. Why can oxygen consumption be used to mea- 6. How does airflow over an object cause lift?
sure energy expenditures in moving animals? 7. Which would generate more lift, the wing of a
2. Discuss the differences in muscle fiber types bird or the fin of a fish, if they were the same
that suit them for different types of movement. dimensions?
3. Discuss the role of the vertebrate skeleton in 8. How can animals alter their interaction with
locomotion. the environment to reduce the costs of moving
4. How does body size affect the costs of locomo- from place to place?
tion in animals?
5. What is a Reynolds number, and why does it
matter to a moving animal?
Synthesis Questions
1. What anatomical and functional features influ- 4. Predict the physiological properties of the lo-
ence the efficiency of movement of oxygen from comotor system of (a) a cheetah and (b) a tree
the erythrocyte to the muscle mitochondria? sloth.
2. Many animals alter their physiology in re- 5. Discuss the changes in cardiovascular and res-
sponse to frequent bouts of activity. In hu- piratory systems that support (a) high-intensity
mans, this is known as a training effect. How activity and (b) steady-state activity.
would you expect each physiological system to 6. Discuss the recovery from high-intensity activ-
change in response to training? ity. Consider the physiological, physical, and
3. Many marine fish swim into deep, cold water to chemical changes that accompany this type of
pursue prey or avoid predators. How does cold activity and what must happen to prepare the
temperature influence their ability to swim? animal for another bout of activity.
1. What are the mathematical relationships be- • A 2-g hummingbird puts on an additional
tween power, work, and force? Under what 1 g of fat.
physiological conditions will each of these pa- • The hummingbird has a mass-specific
rameters approach zero? metabolic rate of 40 ml of O2 per hour per
2. Small scale models of objects can be con- gram and a total metabolic rate of 120 ml of
structed to explore how the object moves O2 per hour per bird. For simplicity, assume
through fluids. Engineers change the fluid that its total metabolic rate remains con-
movements to ensure that the Reynolds num- stant for the duration of the flight.
ber remains constant despite the smaller di- • The lipid fuel is palmitate (molecular weight
mensions of the object (L). If an object is ⫽ 256 g per mol), although this ignores the
reduced in size by 1/1000, how would you contribution of glycerol from the triglyceride
change the fluid properties to ensure that the backbone.
Reynolds number remains constant?
• Oxidation of 2 NADH consumes 1 O2 and
3. Use the following assumptions to answer the generates 6 ATP, and oxidation of 2 FADH2
subsequent questions about the energy metab- consumes 1 O2 and generates 4 ATP.
olism of a hummingbird on its flight across the
• Though you could translate between milliliters
Gulf of Mexico:
of O2 and moles of O2 using the universal gas
655
Locomotion
law (n ⫽ PV/RT), assume that 1 mole of O2 oc- tate oxidation in terms of moles of
cupies 22.4 liters of volume. palmitate per gram per hour?
(a) What is the metabolic rate of a humming- (c) How long would the 1 g of stored fat be
bird in terms of ATP consumption in able to support flight?
terms of moles of ATP per gram per hour?
(b) If palmitate is the fuel that supports
this activity, what is the rate of palmi-
For Further Reading

See the Additional References section at the end Suarez, R. K. 1996. Upper limits to mass-specific
of the chapter for more readings related to the metabolic rates. Annual Review of Physiology
topics in this chapter. 58: 583–605.
Locomotor Systems Moving in the Environment

These studies discuss locomotion from the These books address how animals interact with
perspective of biomechanics and the design of the environment during locomotion. They are
musculoskeletal systems in vertebrates and very good discussions of the biophysical
invertebrates. constraints on animal locomotion.
Alexander, R. M. 1995. Leg design and jumping Alexander, R. M. 1992. Exploring biomechanics:
technique for humans, other vertebrates and Animals in motion. New York: Scientific
insects. Philosophical Transactions of the American Library.
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Sensenig, A. T., and J. W. Shultz. 2003. Mechanics An excellent review that compares the
of cuticular elastic energy storage in leg joints constraints on animal movement in widely
lacking extensor muscles in arachnids. Journal different animals, identifying common themes
of Experimental Biology 206: 771–784. and explaining why different modes of movement
are necessary.
Many researchers study the determinants of the Dickinson, M. H., C. T. Farley, R. J. Full, M. A. R.
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Credits
572 AKG-Images, Leonardo da Vinci/AKG-Images.
573 Library of Congress, Eadweard Muybridge/Library of
Congress.
573 Jean-Michel Weber, Photo courtesy of Jean-Michel Weber,
University of Ottawa.
579 Dr. Gary Sieck, Dr. Gary Sieck/Mayo Clinic College of
Medicine.
588 Craig Franklin, Nicholas Hudson and Craig Franklin.
598 Robert Campbell, Robert Campbell, University of Victoria.
604 Photo Researchers, Inc., Nick Bergkessel/Photo
Researchers, Inc.
604 Tom Stack & Associates.
610 Kevin Schafer/PhotoLibrary.
658
659
Thermal Physiology
Endothermy, the ability to generate and maintain elevated dominate Earth in later years. Fossils dating back to this
body temperatures, has arisen several times in the evolu- period reveal the existence of several distinct mammalian-
tionary history of animals. It goes hand in hand with the ca- like reptilian lineages. These animals differed from other
pacity to produce heat through metabolism, and therefore reptiles by the morphology of the skull and the organiza-
activity levels. Most modern birds and mammals have high tion of the teeth. Although most of these lineages disap-
metabolic rates and are able to maintain their body tem- peared, one group of reptiles called cynodonts gave rise to
peratures well above ambient temperature, often within true mammals. The earliest mammals retained the reptil-
narrow thermal windows. While both are perceived as ian trait of egg laying, like the modern monotremes,
“higher vertebrates,” birds and mammals arose from sep- echidna and platypus. By the early Cretaceous period (144
arate reptilian ancestors. Thus, endothermy arose inde- million years ago), mammals had diversified into several
pendently at least twice. However, fossil evidence suggests lineages of marsupials and insectivores. When the di-
that other extinct reptiles may also have been endotherms. nosaurs disappeared about 65 million years ago, at the end
The fossil record of the animals in the paleontological pe- of the Cretaceous period, there was an explosion of mam-
riod from 200 to 65 million years ago is particularly clear, malian diversification. New species of mammals began to
showing definitive examples of the transitions from rep- occupy the environmental niches vacated by the dinosaurs.
tiles to mammals and birds. It cannot be said for certain when endothermy arose in the
The first mammals appeared approximately 200 mil- transition from mammalian-like reptiles to true mam-
lion years ago, evolving from small, nocturnal reptiles that mals. However, it is likely that the cynodont reptiles were
were only distantly related to the dinosaurs that would already endothermic. Unlike most other reptiles of the day,
660
Thermal Physiology
Asymmetrical fossilized feather.
symmetrical feathers would be useless in flight, they must

have arisen in these dinosaurs for other benefits, such as
insulation. Although these other lineages of feathered
reptiles became extinct, they were likely also endothermic
Archaeopteryx. animals.
Many researchers believe that endothermy arose in
other, nonfeathered dinosaur lineages as well. The largest
cynodonts possessed a bony, secondary palate in the roof dinosaurs were simply too big to shed metabolic heat, and
of the mouth that would have allowed them to breathe therefore remained warm-bodied. Many smaller dinosaurs
while chewing. This anatomical arrangement is a charac- may also have been endothermic. Multiple lines of evi-
teristic of endotherms because they must maintain unin- dence support the notion that these animals had the high
terrupted respiration to sustain high metabolic rates. metabolic rates necessary for an endothermic animal.
Cynodonts also appear to have possessed hair, which Bone structure and posture suggest rapid rates of locomo-
could have helped insulate their bodies. tion, which in modern animals require high metabolic
Birds, the other group of modern endotherms, also rates that are possible only in warm-bodied animals. Just
arose from reptiles, although much later than mammals as in modern endotherms, many dinosaurs had relatively
and from different reptilian ancestors. Around the time di- large brains associated with superior sensory processing.
nosaurs were declining, several reptilian lineages had al- Since brain tissue has a high energy demand, a large
ready evolved featherlike body coverings. In one group, the brain can have an important influence on the whole body
theropod dinosaurs such as Archaeopteryx, the feathers metabolic rate. Other theories have been raised to sup-
were similar in structure to those of modern birds. Their port arguments that dinosaurs were endotherms. How-
feathers were asymmetrical, a trait that is necessary to be ever, no argument is definitive because of the limitations
useful in feathered flight. In contrast, the other feathered in using the properties of modern animals as guidelines
reptiles of the era, such as Protarchaeopteryx robusta and in predicting the physiological features of these long-
Caudipteryx zoui, had symmetrical feathers. Since these extinct animals. 2
661
Thermal Physiology
Overview reach greater extremes than do water tempera-

tures.
Recall that thermal energy influences chemical in- Many ecosystems exhibit spatial variation in
teractions in ways that affect macromolecular temperature. Underground refuges are buffered
structure and biochemical reactions. Conse- from thermal extremes on the surface. The TA in
quently, temperature has pervasive effects on all alpine regions varies as a result of altitudinal gra-
physiological processes. As a result of these tem- dients arising over only a few kilometers. Large
perature effects, every animal displays a thermal bodies of water, such as lakes and oceans, can vary
strategy: a combination of behavioral, biochemi- in TA with depth. Deep-ocean (bathypelagic) tem-
cal, and physiological responses that ensure body peratures are often close to 4°C, whereas midwa-
temperature (TB) is within an acceptable limit. The ter (mesopelagic) and surface water (epipelagic)
most important environmental influence on the temperatures can be much warmer and more vari-
thermal strategy (though not the only one) is am- able. Large temperate lakes may be nearly uniform
bient temperature (TA). Animals must survive the in temperature, or have sharp demarcations (ther-
highest and lowest TA in their niche (thermal ex- moclines) between top and bottom water, some-
tremes), as well as the change in TA (thermal times differing more than 10°C in less than a meter
change). of depth.
Animals inhabit most thermal niches on the Ecosystems can also change in temperature
planet (Figure 1). The hottest environments ex- temporally. Terrestrial and aquatic ecosystems in
ploited by animals are the regions near thermal the tropics tend to have a relatively constant TA,
vents, such as the hydrothermal vents of the deep but polar and temperate zones experience sea-
sea, volcanoes, and geysers. The coldest places sonal and daily cycles of cold and heat. Air tem-
inhabited by animals are the alpine and polar re- peratures can change more rapidly than water
gions. The animals that survive in the extremes temperatures, sometimes more than 20°C in a sin-
of heat and cold are impressive, but the ability to gle day. Intertidal animals may experience the
tolerate changing temperature is every bit as heat of a summer day mere seconds before the
challenging physiologically. Environmental tem- cold ocean washes over them. Many animals in-
peratures are most variable in terrestrial ecosys- corporate behavior into their thermal strategy, but
tems; air temperatures change more rapidly and animals must also cope with the effects of temper-
ature on biochemistry and physiology.
Hot springs
Alpine (extreme cold)
(high TA )
Hot desert
(daily variation)
Temperate
(seasonal variations)
Intertidal (rapid variation in TA )
Lakes (thermal Epipelagic

stratification, Subterranean (variable TA )
winter freezing) refuges (moderate
and stable TA ) Mesopelagic
(stable TA )
Bathypelagic
(cold, stable TA )
Hydrothermal
vent (>100°C)
Figure 1 Thermal niches in the temperate zone
662
Thermal Physiology
Heat Exchange and

Thermal Strategies
The most important physiological pa-
rameter in an animal’s thermal phys-
iology is body temperature (TB). An
animal’s thermal strategy serves to
control the transfer of energy be-
tween the animal and the environ-
ment. Some animals tolerate wide Radiant
changes in TB and the effects of these (direct
solar)
changes on many physiological Dust
Radiant
processes. Others must use a combi- (reflected solar)
nation of physiological and behav-
ioral means to ensure that TB remains
Radiant Radiant
nearly constant. As in other physio-
(reflected solar)
logical systems, both strategies—tol-
erance and regulation—have costs
and benefits. The physiological mech- Conduction and
anisms that impart a constant TB use convection (air)
energy. When TB is allowed to vary,
important physiological processes
such as development become sensi- Conduction Radiant
tive to environmental changes. Al-
Conduction
though TA has the most obvious
impact on animal thermal biology,
other routes of heat exchange are also
important in many contexts.
Figure 2 Sources and sinks for thermal energy The body temperature
of an animal is influenced by heat exchange with the environment. This snake is
warmed by radiant energy from the sun, as well as thermal energy radiated from its
Controlling Heat Fluxes surroundings. The animal exchanges thermal energy through objects and fluids in
contact with its external surface (conduction). Movement of the air enhances the
An animal’s TB is a reflection of the efficiency of thermal exchange by convection. The animal itself radiates thermal
thermal energy held within the mole- energy to the surrounding air.
cules of the body. Thermal energy can
move from the animal to the environment, or from of the animal and TB will remain constant. If the
the environment to the animal, depending on tem- flow of thermal energy into the animal exceeds the
perature gradients. Metabolism—the sum of all bio- heat loss, TB will increase. Each of these routes of
chemical reactions occurring within the body—is thermal energy exchange depends on the thermal
the main source of thermal energy in the heat bal- properties of the environment as well as the physi-
ance equation of most animals. However, other im- cal properties and physiology of the animal.
portant sources and sinks for thermal energy also
affect an animal’s thermal budget (Figure 2). The • Conduction is the transfer of thermal en-
thermal balance equation takes into consideration ergy from one region of an object or fluid to
all of the routes through which thermal energy, ab- another. Animals can be cooled when ther-
breviated as H, can enter or exit the body: mal energy is conducted away from the
body, or can be warmed as they absorb heat
⌬Htotal ⫽ ⌬Hmetabolism ⫹ ⌬Hconduction ⫹ ⌬Hconvection
from conductive objects.
⫹ ⌬Hradiation ⫹ ⌬Hevaporation
• Convection is the transfer of thermal en-
If the equation above sums to zero (⌬Htotal ⫽ 0), ergy between an object (the animal in this
there will be no net change in the thermal energy case) and an external fluid that is moving.
663
Thermal Physiology
For example, warm air feels cooler when it has more molecules per unit volume, there is a
flows over your skin than when the air is greater likelihood of a molecular collision that re-
still. Most often, convection causes a loss of sults in a transfer of energy.
thermal energy from animals. The Fourier equation describes how thermal
• Radiation is a general term that refers to energy moves in a very simple system: heat trans-
the emission of electromagnetic energy fer in a single dimension (from the heat source to
from an object. An animal can absorb radi- heat sink) in a single uniform material. These same
ant heat emitted from the surroundings, but parameters (λ, ⌬T, and L) apply in thermal biology,
can also emit radiant heat from its own sur- but animals are much more complex systems. Con-
face, a major form of heat loss. The infrared sider the influence of thermal conductance. Heat is
radiation emitted from an object indicates conducted from the internal tissues, through other
its surface temperature. tissues and fluids, and to the external surroundings,
each with a characteristic thermal conductivity
• Evaporation of water molecules from the
(Table 1). The body surface layers may possess in-
surface of an object absorbs thermal energy
sulation that reduces conductive heat transfer. In-
from the object. Thus, evaporative heat ex-
sulation, such as fur and feathers, also increases
change is almost always a heat loss from the
the distance between the hottest point near the skin
animal.
and the coldest point in the bulk phase.
The relative importance and even the direc- Calculations of heat flux are complicated by the
tion of heat transfer from each of these parame- geometry of the environment and the animal. Heat
ters differ among animals and conditions. The does not move from your body through a one-
properties of the animal, including physical com- dimensional cylinder of air extending from your
position and color, have a profound influence on skin, but rather is conducted in multiple dimensions
the relative importance of these exchanges. from the source. Animal geometry also plays a role.
A long, thin animal produces as much heat as a
short, round animal of the same mass, but the differ-
Water has a higher thermal ences in surface area affect heat exchange. Since
conductivity than air conductive heat losses occur across the external sur-
Conduction is difficult to quantify because of the faces, an animal can alter conductive heat exchange
many factors that affect heat exchange. Let’s begin by engaging in activities that alter its effective sur-
our discussion by considering how conduction is face area. For example, a penguin reduces heat loss
involved in the transfer of thermal energy through from the foot by rolling back on its heels, using its tail
a single material, such as a thin metal bar heated feathers for balance. Because its tail feathers are less
at one end. The rate of heat transfer from the conductive than its feet, less heat is lost. Figure 2
warm end to the cool end (heat flux) is described shows a snake simultaneously exchanging heat with
by Fourier’s law and the following equation: multiple surfaces. It loses heat via conduction across
its upper surface while also exchanging heat through
l¢T
Q⫽ its lower surface in contact with the rock.
L
where heat flux (Q) depends upon the temperature Table 1 Thermal conductivity of materials.
gradient (⌬T), the distance over which the gradi- Material Thermal conductivity
ent extends (L), and the thermal conductivity (λ) (W/m per K)
measured in watts per meter per kelvin (W/m per
Air 0.02
K). Thermal conductivity is a specific property of a
material. Those objects we think of as heat sinks Snow 0.10
have high thermal conductivity. For example, an Water 0.59
aluminum pot feels cold to the touch because it has
Rock 1–3
a high thermal conductivity (210 W/m per K) and
readily draws heat from your hand. Similarly, 5°C Ice 2.1
water feels cooler than 5°C air because water has Muscle 0.5
a thermal conductivity that is 25-fold higher than
Fat 0.2
air (0.58 versus 0.024 W/m per K). Because water
664
Thermal Physiology
Convective heat exchange depends

on fluid movements
Imagine yourself immersed in a pool of water that
is 10°C colder than your body. Almost immedi-
ately, your body begins to lose thermal energy as
it warms the water in the boundary layer by al-
most 10°C. Once the boundary layer is warmed,
thermal energy is slowly conducted to the bulk
phase of the water. When the heat exchanges
reach steady state, the body loses thermal energy
at the rate required to rewarm this boundary layer
that slowly cools as it dissipates its thermal energy
outward to the bulk phase. Much less energy is re-
quired to rewarm the boundary layer under these
Figure 3 Heterogeneity of TB in the intertidal
steady-state conditions than was required to heat zone Infrared photography can be used to compare the
the boundary layer in the first place. Now consider body temperature (TB) of animals. In this image, the mussels
how the gradients change when fluid is flowing are warmer than the starfish because they are better at
absorbing radiant energy. The starfish, with its greater
over the body. The body rapidly loses thermal en-
surface area, may also be affected more by evaporative
ergy warming a boundary layer that is immedi- cooling.
ately replaced by another, colder boundary layer. (Photo courtesy of Dr. Brian Helmuth, University of South Carolina)
Heat lost to a moving fluid, either air or water, is
convective heat loss. The rate of convective heat In terrestrial systems, the ground warms dur-
loss depends on the thermal gradient between the ing the day and then becomes an important source
surface and the fluid, the rate of flow of the fluid of thermal energy in the form of conduction and
over the surface, and its conductivity. radiant heat when the sun sets. Animals also lose
thermal energy when they emit radiant heat.
Thus, radiant heat may be a net gain or net loss
Radiant energy warms some animals from animals. The relationship that describes ra-
diation from a warm animal is described by the
In biological systems, radiant heat exchange occurs
Stefan-Boltzmann equation:
through electromagnetic radiation in the long wave-
length, infrared range. Thus, if a red light (long P ⫽ Aeσ(TB4 ⫺TA4)
wavelength) and a blue light (short wavelength) of where P is the radiating power, A is its surface
equal intensities are shown on your skin, the red area, e is the ability of the object to emit radiation,
light will more effectively warm the surface. σ is the Stefan constant, and T the temperature of
In the natural world, the most important the body (TB) or surroundings (TA) in kelvins. Ani-
source of radiant heat is the sun. Photons from the mals can influence their radiant heat loss through
sun excite the molecules in the atmosphere, the changing the nature of the surface (e) and the sur-
soil, and the water, warming them by radiant heat. face area (A).
Thus, when animals are warmed by conduction
from air, water, or soil, the ultimate source of the
heat is radiant energy. But animals can also be
warmed directly by solar radiation, which many
Evaporation induces heat losses
species accentuate by the behavior known as Evaporative cooling arises when fluids draw ther-
basking. White body coloration reflects photons in mal energy from the body surface as the water
the visible range, and dark coloration absorbs the molecules make the transition from liquid to va-
photons within this range of wavelengths. Animals por. The magnitude of the heat loss depends on the
that bask to warm themselves often possess high volume of water and its heat of vaporization. It re-
levels of black or brown pigments to help absorb quires more energy to evaporate water from salty
thermal energy. As a result of diversity in color, an- sweat than from pure water because the solutes
imals in the same area can have markedly differ- increase the heat of vaporization of water. The ef-
ent temperatures (Figure 3). ficiency of evaporative cooling also depends on the
665
Thermal Physiology
partial pressure of water vapor in the air. If the air animal evolution. Bergmann’s rule states that ani-
has a high humidity, then the water is less likely to mals living in cold environments tend to be larger
evaporate. than animals in warmer environments. Allen’s
Sweating is only one of the ways that animals rule states that animals in colder climates tend to
employ evaporative cooling. When a hippopota- have shorter extremities than animals in warmer
mus rolls in the mud of a wet riverbank, the cool climates. Thus, mammals or birds living in polar
mud draws heat from the body (conduction). This regions or high altitudes tend to be larger and
is an effective cooling strategy even if the mud is shorter legged than individuals of the same
warm: thermal energy is absorbed from the body species from more temperate regions. These rules
as the mud dries. Other animals cover their body of ecogeography apply to most of the mammals
surfaces with water, such as an elephant that and birds studied to date, but have little relevance
sprays water onto its back or birds that splash in to animals that allow TB to change.
a pool of water. Wet feathers also have a dimin- An animal regulates heat exchange by altering
ished insulatory capacity, allowing more metabolic the posture of the body to minimize or maximize
heat to be lost. Birds that live in hot environments the exposed surface area. Pythons will roll into a
may soak the belly before returning to the nest, al- ball to conserve metabolic heat during digestion.
lowing the eggs to benefit from evaporative cool- When the python, approximately cylindrical in
ing. Kangaroos, which do not produce sweat, lick shape, rolls into a ball, its externally exposed sur-
well-vascularized skin surfaces, which then cool face area decreases by about 85%, greatly reduc-
as the saliva evaporates. ing heat loss.
Not all evaporative cooling is positive. When Animals can also reduce effective surface area
semiaquatic animals leave the water, they are by huddling with other animals. Naked mole rats
typically left with wet body surfaces, causing (Figure 4) live in burrows at relatively constant
body temperature to decrease due to evaporative temperatures and have a very limited ability to use
cooling. metabolism to control their body temperature. If
housed in groups, they huddle when temperatures
drop below about 22°C. This allows them to main-
Ratio of surface area to volume tain a relatively constant TB near 22°C. However, a
affects heat flux solitary naked mole rat is unable to defend its TB
The ratio of surface area to volume can influence all at low TA. When prevented from huddling, its TB
aspects of the heat exchange equation: conduction, closely reflects TA, decreasing to as low as 12°C.
convection, radiation, and evaporation. Variation From the perspective of the individual animal,
in the ratio is important in several contexts. A given huddling reduces heat by increasing TA, replacing
animal may alter its exposed surface area to cold air with a warm neighbor. From the perspec-
change heat flux. Dogs stretch out when hot to tive of the colony, huddling works as a thermoreg-
maximize conductive heat loss to the ground, but ulatory strategy by reducing ratios of surface area
roll up when cold to minimize conductive heat loss to volume.
to the air. Ratios of surface area to volume also
come into play when comparing animals of differ-
ent body dimensions or body mass.
The significance of body size, or more pre-
cisely, the ratio of surface area to mass, is appar-
ent in many comparisons. An arctic wolf is about
one-tenth the mass of a grizzly bear, but it has
twice the ratio of surface area to volume. Although
they live in similar niches, the arctic wolf incurs
greater thermoregulatory costs because of its size.
Similarly, when an animal grows, its body mass
increases faster than its surface area. In general,
larger animals lose heat more slowly and retain
heat better than do small animals. The effects of
body size and shape also manifest themselves in Figure 4 Naked mole rats
666
Thermal Physiology
Insulation reduces thermal exchange to shed fur in spring. Since much of hair is com-
posed of dead cells, the cost of rebuilding the coat
Internal and external insulation also reduce heat
when temperatures cool is minor in comparison to
losses. Marine mammals have a thick layer of adi-
the metabolic costs the animal would incur trying
pose tissue under the skin in the form of blubber.
to cool itself using physiological mechanisms.
This lipid layer disrupts the flow of thermal energy
Mammals alter the nature of their fur coat season-
from the core to the external surface of the animal.
ally, producing a greater density of hairs. Some
More commonly, animals use external insulation
birds, such as the ptarmigan, produce specialized
to reduce heat loss. Fur and feathers restrict the
feathers with an additional shaft to increase the
movement of molecules between the surface of the
feather density.
animal and the bulk phase of the environment.
Though a main function of hair is thermal insu-
Heat is lost from the animal in proportion to the
lation, it can also serve other purposes. Male lions,
thermal gradient (⌬T) at the surface of the animal.
for example, possess a thick coat of fur around the
Molecules of air or water in the insulation layer
head region. Though it may provide the lion with
are warmed by the animal and then trapped
some defense in male-male encounters, it also cre-
within the insulation. The overall temperature
ates a thermal burden. Box 1, Evolution and Diver-
gradient from the skin to the bulk phase is the
sity: Lions’ Manes Are Hot! describes the
same, but the distance is greater and the animal
evolutionary and physiological trade-offs between
loses less heat to conduction. The fur also impedes
thermal biology and sexual selection.
the flow of fluids over the surface of the skin, so
there is less convective heat loss.
The effectiveness of insulation depends on its
thickness. When faced with cold temperatures,
Thermal Strategies
birds (or mammals) can change the orientation of Invertebrates are the most thermotolerant animals
the feathers (or fur) to alter the volume of air in each thermal niche. The hottest deserts are pop-
trapped within the coat. Similarly, animals that ulated by myriads of insects, but only a few verte-
live in colder environments have thicker coats brates. Invertebrates can also tolerate the coldest
with greater insulating capacity (Figure 5). Some temperatures, often by entering an inactive, dor-
species change the thickness of the external insu- mant state. Once stabilized in this state of “sus-
lation seasonally. Thick coats are a thermoregula- pended animation,” they can survive temperatures
tory burden in the warm season, so it is beneficial far colder than even the coldest natural environ-
ments. In contrast, only a few vertebrates, such as
the wood frog, can survive subzero body tempera-
Arctic fox Wolf tures, frozen in underground refuges.
The lay terms cold-blooded and warm-blooded
fail to reflect the complexity of thermal strategies,
Reindeer which are properly described by two alternate sets
Grizzly bear
of terms: poikilothermy versus homeothermy, or
Rabbit
ectothermy versus endothermy.
Fur insulation
Dog Polar bear

Marten
Poikilotherms and homeotherms differ

in the stability of TB
Squirrel
The terms poikilothermy and homeothermy dis-
Weasel
tinguish animals on the basis of the stability of
Shrew
TB. A poikilotherm is an animal with a variable
African mammals
TB—one that varies in response to environmental
Fur thickness conditions. A homeotherm, in contrast, is an
animal with a relatively constant TB. Most
Figure 5 Insulation There is a direct relationship
between the thickness of fur and its ability to act as homeotherms achieve a constant TB using physi-
insulation. ological processes to regulate the rates of heat
(Source: Modified from Wilmer et al., 2002) production and loss.
667
Thermal Physiology

Lions’ Manes Are Hot!
Lions live in prides, with one mature male slow in the winter. Individual hairs in humans grow for
and a harem of females. The lionesses do the about five years, then remain static for another 12
parental care and all of the hunting, while the male guards weeks. At that point, a new hair from the same follicle
over the pride, defending his position against any male is formed, pushing the old hair out. In principle, lions
challenger. An unmated female will choose a male that she could grow longer hair by having hair grow faster or for
perceives to have superior “quality,” in terms of reproduc- longer periods of time. The growth rate is determined
tive potential. The concept of mate selection is often diffi- by the androgen steroid hormones: testosterone and
cult to interpret in terms of animal physiology. How does a dihydrotestosterone (DHT). The enzyme 5␣-reductase
female lion recognize the reproductive potential of a male converts testosterone to its more active DHT form. The
lion from visible or behavioral traits? Recent studies sug- levels of the pigment melanin, which is produced di-
gest that one feature females assess is the size and color rectly by the hair cells, determine the hair color. The
of the male’s mane, the thick coat of hair that covers his process of pigmentation is also influenced by testos-
neck and throat. Field observations suggest that female li- terone levels. Therefore, high androgen levels can
ons tend to choose mates with a long, dark mane. This trait cause a mane to be long and dark. Since androgens
may be a faithful signal of male quality because of the link also control both sex drive and aggression, mane prop-
between mane properties and thermoregulation. erties may reflect the propensity for aggressive behav-
Most African lions live in hot savanna conditions, iors that aid in mating and defense.
where daytime temperatures can reach greater than An interesting variation in the story of the lion’s mane
45°C. For these animals, the challenge is to keep cool, so comes from the Tsavo lions. The Tsavo region of Africa is
the thick mane of males would seem to be counterpro- much hotter than other lion habitats, such as the
ductive in relation to thermal physiology. Studies using Serengeti. A thick mane would be an even greater hin-
infrared cameras support the presumption that males drance to male Tsavo lions. The Tsavo lions gained notori-
with dark, thick manes have a more difficult time shed- ety for two reasons. First, they were perceived to be more
ding excess heat. Since the mane represents a ther- aggressive than other lions, even gaining a reputation as
moregulatory burden, why might it be subject to sexual man-eaters. The white ghost lions of Tsavo, as they be-
selection? Researchers have investigated several poten- came known, were also remarkable in that they lacked a
tial explanations for this seemingly maladaptive trait. mane. Juvenile males throughout Africa are maneless,
There is little doubt that females use mane appear- and it had long been thought that only the young males
ance in mate choice, but it is less clear why the thicker, were being spotted in the Tsavo. Researchers lured lions
darker manes are most desirable. The simplest theory is from the dense vegetation and discovered that even the
that the thick mane helps protect the vulnerable neck re- dominant males lacked manes. For these animals, the
gion of the male during the violent fights for dominance. mane would be an insurmountable burden, due to both
For the female, a well-protected male is better able to hotter temperatures and dense vegetation. Thus, in the
protect the pride from invaders. From the male’s per- Tsavo lions, evolution has led to a loss of the mane.
spective, the benefits of additional protection exceed the The physiologist might ask how these lions become
additional costs associated with thermoregulation. It is maneless. Although some testosterone is needed for
difficult to establish if long manes provide significant pro- hair growth, excessive testosterone causes hair loss. It
tection in a fight. An alternate explanation for the under- is not yet known if these males have higher testosterone
lying reason for long manes is the handicap hypothesis. levels than their Serengeti relatives. However, there is
Much like the tail of a peacock, a thicker mane may adver- also a change in the social structure of prides that im-
tise to females that the male has a robust physiology ca- plicates testosterone. In the Serengeti lions, a pride
pable of coping with the additional physiological burden. possesses as many as four mature males, but most
Independent of the underlying reason why a mane is Tsavo prides have only a single mature male. Perhaps
a trait under sexual selection, a physiologist might ask high levels of testosterone both cause hair loss and in-
how the properties of the mane of a dominant male are crease the aggressive nature of the Tsavo males, alter-
altered and how this reflects his dominance. The an- ing the social structure of the pride.
swer may lie in an understanding of the cellular basis
of hair growth. Hair length is controlled by the cells of Reference
the hair follicle, and its growth rate changes in relation q West, P. M., and C. Packer. 2002. Sexual selection, temperature,
to environmental conditions: fast in the summer and and the lion’s mane. Science 297: 1339–1343.
668
Thermal Physiology
The distinction between poikilo- Mammals

ENDOTHERMY Mammals HOMEOTHERMY
therm and homeotherm depends on (torpid)
both the properties of the animal and Birds
the nature of the environment. An

Birds
animal could maintain a constant TB (torpid)
by living in an environment with a Large flying insects
constant TA. For example, polar fish Monotremes Fish (polar)
live in waters that are constantly
Invertebrates
cold, and by definition are (aquatic, polar)
homeotherms. However, their closest Large reptiles
Fish (tropical)
relatives live in oceans with tempera-
Naked mole rat
tures that vary seasonally, and are
Invertebrates
therefore poikilotherms. Similarly, a (soil, temperate)
goldfish in an indoor aquarium might
Invertebrates
never experience a change in TB, but (aquatic, tropical)
if it were moved outside to a pond its Amphibians
TB would vary. The goldfish could ar-

Reptiles Fish
guably be called a homeotherm or a POIKILOTHERMY ECTOTHERMY
poikilotherm, depending on the situ- Invertebrates
ation. Since these terms depend
Figure 6 Thermal strategies Most animals can be classified as homeotherm or
more on the nature of the environ- poikilotherm, or alternately, ectotherm or endotherm. This figure illustrates the many
ment than the animal’s physiology, species whose thermal strategies combine elements of multiple strategies. For example,
the terms are not always useful in de- monotremes are less homeothermic and less endothermic than other mammals.
scribing thermal strategies.
Heterotherms exhibit temporal
Ectotherms and endotherms differ or regional endothermy
in the source of body thermal energy Just how constant does TB have to be for an animal
The terms ectotherm and endotherm distinguish to be considered a homeotherm? In actuality, most
animals by the physiological mechanisms that animals experience some variation in temperature,
determine TB. The environment determines the either spatially or temporally. Many endothermic
TB of an ectotherm. If the ectotherm shows a animals place greater priority on maintaining cer-
variable TB, then it might also be called a poi- tain anatomical regions within very narrow thermal
kilotherm. An endotherm is an animal that gen- ranges. Typically, homeotherms maintain the cen-
erates internal heat to maintain a high TB. tral nervous system and internal organs at a more
Endotherms regulate TB within a narrow range, constant temperature, while allowing the periphery
but it need not be constant. to vary. The temperature of these deep, internal re-
Both this and the preceding approach to clas- gions is often called the core temperature. Humans,
sifying thermal strategies work effectively for most for example, maintain a near-constant core temper-
animals. Most birds and mammals can be classi- ature. However, regions of the human body can ex-
fied as homeotherms, because TB is stable, and perience temperatures much lower than the core
also as endotherms, because metabolic heat ele- TB. In the cold, humans change blood flow to allow
vates TB. However, many animals are best de- hands and feet to cool to conserve internal heat.
scribed by a combination of terms (Figure 6). For Males alter the position of the scrotum to keep
example, the polar fish we described earlier in this spermatogenic tissue from overheating. However,
chapter are homeothermic ectotherms; TB is con- human core TB can also change under some cir-
stant but determined by TA. Monotremes, like cumstances. TB can change in females during the
other mammals, are endotherms, but maintain a reproductive cycle. It can rise several degrees as a
lower TB that is more variable. Proper use of these result of a fever. In comparison to other animals,
terms requires an understanding of the physiolog- these are relatively minor regional and temporal dif-
ical capacities of the animal as well as an aware- ferences in TB, and a human is considered an en-
ness of the thermal properties of its environment. dothermic homeotherm.
669
Thermal Physiology
In contrast to humans, many other mammals elevate TB much above TA. However, a regional het-
and some birds can undergo dramatic, prolonged erotherm can retain heat in certain regions of the
changes in TB. When exposed to cold nighttime body. Billfish, such as marlin and swordfish, are ec-
temperatures, TB may decrease by several de- totherms but are also able to warm specific regions
grees (Figure 7). Hibernating mammals, such as of the body. Their heater organs produce enough
ground squirrels and bats, allow TB to drop for heat near the eye and optic nerves to improve visual
the winter months. Although these animals allow clarity when they dive deep into cold waters. Large
their bodies to cool, they are still considered en- pelagic fish possess countercurrent heat exchangers
dotherms because they produce and retain meta- to conserve the heat of digestion within the body
bolic heat to maintain TB above TA. However, core. Tuna and lamnid sharks are able to retain myo-
these endothermic animals are more precisely genic heat within the muscle. Warming of the red
described as temporal heterotherms, to reflect muscle increases metabolic capacity and may im-
the variability in TB over time. Some ectothermic prove contractile performance during swimming.
animals also fit the description of temporal het- Thermal gradients occur within the bodies of many
erotherms. Many large snakes, such as pythons, animals, but these regional heterotherms have spe-
wind their bodies into a ball after they have in- cific physiological mechanisms to produce and re-
gested their prey. This helps the snake retain the tain heat regionally.
metabolic heat produced by digestion. Temporal Although most insects are ectotherms, some
heterothermy is a strategy that has different species are regional heterotherms, others temporal
benefits for endotherms and ectotherms. It al- heterotherms, and some species are both, depend-
lows an endotherm to conserve energy in cold ing on the time of year. The largest of flying insects,
temperatures by reducing the costs of thermoreg- such as bumblebees, large moths, and cicadas, have
ulation. It provides an ectotherm with a period of a very high metabolic rate in the flight muscles. Tho-
accelerated metabolism to speed digestion, nutri- racic temperature in a large flying insect can in-
ent assimilation, and biosynthesis. crease by more than 10°C, even while other regions
Most ectotherms rapidly lose their metabolic of the body remain near TA. Interestingly, these ani-
heat to the environment, and consequently cannot mals are also able to modulate heat production. Prior
to flight they initiate thermogenic pathways to warm
the thorax. When flight commences, they can alter
TA
heat exchange to maintain near-constant thoracic
42 20°C temperatures during flight, even when TA is variable
0°C (Figure 8). Social insects use huddling as a means of
–20°C
controlling the temperature of the colony. Honeybees
survive the cold winters by forming tightly crowded
38 clusters. An individual bee in the colony is uniformly
warm or uniformly cold, depending upon its position
TB (°C)
in the cluster. The clusters act like the body of a re-

gional heterothermic animal. The “core” body heat
of the colony is generated by the bees that are located
34
near the center of the cluster. The outermost bees
(mantle bees) act as insulation.
Animals have a characteristic degree

1600 h 2000 h 2400 h 0400 h 0800 h of thermotolerance
Time of day
Physiological strategies for coping with tempera-
Figure 7 Short-term cooling in birds Many ture differ in ectotherms and endotherms. For ec-
temperate birds allow their body temperatures to decrease
when nighttime temperatures decrease. This strategy of
totherms, a change in TA alters TB and directly
temporal heterothermy saves metabolic energy.
(Source: Modified from Reinertsen and Haftorn, 1986)
670
Thermal Physiology
50 Thermoneutral zone
40 Thermogenesis Active cooling
Body temperature
MR
Metabolic rate
BMR TB
TB (°C)
30
Onset of Onset of
hypothermia hyperthermia
TB
20
LCT UCT
Thorax
Ambient Temperature
Abdomen
Figure 9 Zones of thermal effects of a resting
10 homeotherm Homeothermic endotherms maintain near-
10 20 30 40 constant body temperature over a wide range of ambient
TA (°C) temperatures (purple line). Once ambient temperatures
decrease below the lower critical temperature (LCT), the
Figure 8 Insect heterotherms Many large insects animal must increase its metabolic rate (MR) to generate heat
are able to conserve metabolic heat that arises when their to help maintain a constant TB . By extending the line explaining
flight muscles are activated during flight. This warms the the metabolic rate below LCT to the x-axis, the body
thorax while the rest of the body remains near ambient temperature (TB ) can be obtained as the intercept. Below a
temperature, an example of regional heterothermy. certain point, the animal can no longer maintain a constant
(Source: Based on Harrison et al., 1996) core temperature and hypothermia results. When ambient
temperatures increase past the upper critical temperature
(UCT), the animal increases metabolic rate to shed heat. At
still higher temperatures, the animal can no longer defend its
body temperature and hyperthermia results.
changes the rates of many biological processes.
In contrast, an endotherm responds to a change
in TA by inducing a compensatory regulatory re-
sponse. Despite the differences, both endotherms faced with a hypothermic challenge, animals may
and ectotherms incur physiological costs and reduce TB to maintain homeostasis at metabolic
consequences when environmental conditions rate. In general, these compensatory responses at
change. high TA or low TA allow the animal to maintain a
The effects of temperature can be defined in constant TB, but beyond a point, the animal cannot
terms of its impact on animal function. An animal sustain a constant TB.
typically spends most of its life in a range of temper- The concept of a thermoneutral zone does not
atures that is optimal for physiological processes. apply to animals that alter TB, but ectotherms also
The thermoneutral zone of a resting homeother- have ranges of TA (and TB) where growth and re-
mic endotherm is the range of ambient tempera- production are optimal. Animals actively seek out
tures where metabolic rate is minimal, which is their preferred temperature, a TA that is within its
considered the basal metabolic rate, or BMR (Fig- range for optimal function. At low temperatures,
ure 9). If temperatures rise to a point called the all developmental processes slow because the
upper critical temperature (UCT), the metabolic lower TA reduces the rate of metabolic reactions.
rate rises as the animal induces a physiological re- Higher temperatures damage molecules, cells, and
sponse to prevent overheating. If the temperature tissues, jeopardizing an animal’s health. Re-
falls below a lower critical temperature (LCT), searchers can assess the thermal tolerance of an
the metabolic rate rises to increase heat produc- ectotherm or a poikilotherm by transferring an an-
tion. For many animals, the TB can be predicted imal from its acclimation temperature to a chal-
from the extrapolation of the line that describes the lenging temperature and assessing survival. The
metabolic rate at temperatures below LCT. When incipient lethal temperature is the temperature
671
Thermal Physiology
that has a 50% probability of killing the fish within Acclimation to a high temperature tends to in-
an identified period. The range of tolerance is the crease both the ULLT and ILLT. Likewise, acclima-
difference between the incipient upper lethal tion to a low temperature reduces the upper and
temperature (IULT) and the incipient lower lower lethal temperature points.
lethal temperature (ILLT). For ectotherms and Animals differ in their ability to tolerate
poikilotherms, the ability to tolerate temperature changing ambient temperature. A eurytherm
changes with acclimation history (Figure 10). can tolerate a wide range of TA, whereas a
stenotherm can tolerate a narrow range of TA.
Eurythermal endotherms/homeotherms possess
a wide thermoneutral zone, maintaining a con-
30 stant TB over a wide range of TA; eurythermal
ectotherms/poikilotherms display a large ther-
mal tolerance polygon area, with well-separated
IULT
incipient lethal temperatures.
Lethal temperature (°C)
20 Differences in thermotolerance can be ob-

served in comparisons of populations or species
that have evolved in regions separated by latitude
or altitude. The ability of an animal to tolerate a
10 lower TA than its competitor allows the tolerant
animal to expand into a colder environmental
niche. Many closely related animals have distinct
ILLT
differences in thermal preferences that contribute
0 to their geographical distributions. Latitudinal
0 10 20 30
patterns are common in fish species in both ma-
Acclimation temperature (°C) rine and freshwater. Closely related species of bar-
racuda, for example, live at specific latitudes along
(a) Eurythermal fish
the Pacific coast with a characteristic average TA.
From north to south, one species gradually re-
30
places another once the average water tempera-
ture changes by only 3–8°C. There are also
altitudinal patterns seen with terrestrial animals.
Many bird species exist in high-altitude and low-
Lethal temperature (°C)
20 IULT
altitude populations, each with physiological spe-
cializations and morphological differences. The
thermal environment resulting from the combina-
tion of altitude and latitude also determines the
10
range of many amphibians. Andean tree frogs
(Hyla andina) can be found at low elevation far
ILLT from the equator, but closer to the equator they
can live at higher altitudes.
0
The genetic basis of a difference in thermotol-
0 10 20 30 erance is not always clear. We can often determine
Acclimation temperature (°C) why levels or properties of a single protein differ in
(b) Stenothermal fish two animals in relation to temperature. However,
the underlying basis for complex differences in
Figure 10 Temperature polygon Acclimation
affects the incipient upper lethal temperature (IULT) and thermal physiology is more complex. For example,
incipient lower lethal temperature (ILLT) for ectotherms and two species of Siberian hamsters, Phodopus camp-
poikilotherms. The tolerance of an animal is reflected in the belli and P. sungorus, differ in thermal biology in
area of the polygon created by joining the upper line (IULT,
terms of morphology, insulation, behavior, and
in red) and the lower line (ILLT, in blue). Analysis of a
eurythermal fish (a) yields a larger polygon than that of a physiology. Although these are very closely related
stenothermal fish (b). species, they last shared a common ancestor more
672
Thermal Physiology
than 2 million years ago. A complex trait such as sessed using an Arrhenius plot (see Box 2, Mathe-
fur density depends on multiple genes, many cell matical Underpinnings: Evaluating Thermal Effects
types, and networks of genetic regulators. Further- on Physiological Processes Using Q10 and Arrhenius
more, the two species may have many genetic dif- Plots). Researchers can use this approach to study
ferences, but only some of these may influence how temperature affects the structure and function
their thermal biology. of macromolecules, enzymatic reactions, and com-
plex processes, such as metabolic rate.
2 CO NC E P T C HE C K Animals remodel membranes

to maintain near-constant fluidity
1. What are the sources and sinks in an equation
describing thermal balance? Recall what you’ve learned about the structure of
2. What is the difference between an endotherm cellular membranes and the importance of mem-
and an ectotherm? brane fluidity. Van der Waals forces hold mem-
3. What is the difference between a homeotherm brane lipids together. Although the interactions
and a poikilotherm? between phospholipids are strong, the membrane
4. What is the difference between a regional and a must also remain fluid enough to allow proteins to
temporal heterotherm? rotate and diffuse laterally within the membrane.
Low temperatures cause membrane lipids to so-
lidify, which impairs protein movement. Con-
Coping with a Changing versely, high temperatures liquefy the membrane,
Body Temperature which can compromise its integrity and reduce its
effectiveness as a permeability barrier. Cells regu-
Although many ectotherms and poikilotherms live late the balance between the solid gel state and the
in thermally stable environments—underground liquid sol state.
burrows, tropical rain forests, the deep sea, or a Temperature exerts effects on membranes
homeotherm’s intestine—others must cope with fre- through both protein function and phospholipid flu-
quent and dramatic changes in TB. Because of the ef- idity. The effects on membrane protein function can
fects of temperature on macromolecular function be assayed using kinetic analyses. For example, the
and metabolism, ectotherms and poikilotherms Na⫹/K⫹ ATPase interacts with membrane lipids
must either tolerate or compensate for the complex, during the transport process. The activity of the
often deleterious, effects of changing temperature. transporter can be measured at a series of temper-
atures, then plotted in relation to temperature. A
change in membrane fluidity typically results in a
breakpoint in the Arrhenius plot of membrane pro-
Macromolecular Structure tein function, as shown in Box 2.
and Metabolism Membrane fluidity is measured in biological
Of the four classes of macromolecules, only proteins membranes using a dye (diphenyl hexatriene) that
and lipids are substantially affected by temperature changes in optical properties in relation to its free-
over the normal range encountered by animals. dom to move within the membrane (Figure 11).
Weak bonds (van der Waals forces, hydrogen When membranes from different species are com-
bonds, and hydrophobic interactions) govern the pared, each exhibits a decrease in fluidity (mea-
interactions within and between these macromole- sured as a change in optical properties) when the
cules. Each type of bond has a characteristic re- membrane is cooled. Taking into consideration the
sponse to temperature. Whereas hydrogen bonds differences in thermal niche, this analysis shows
and van der Waals forces are disrupted at high tem- that animals produce membranes that exhibit the
perature, hydrophobic interactions are stabilized at same fluidity at the natural temperature. This
high temperature. Thus, the effects of temperature observation is analogous to the conservation of
on macromolecular structures depend on the rela- Km seen in enzymes from animals in different
tive importance of each type of bond. The effects of niches. The same pattern is seen when an
temperature on a biological process can be as-
673
Evaluating Thermal Effects on Physiological Processes
Using Q10 and Arrhenius Plots
For many physiological processes, a 60 Q10 = 1.6

10°C increase in temperature typically doubles 50
Reaction velocity
or triples the rate of the process. We can describe these 40
effects of temperature on reaction velocity mathemati- 30 Q10 = 2.4
cally by the Q10. The Q10 is essentially the ratio between
reaction rates at two temperatures, adjusted for a 10°C 20
temperature difference. It is calculated as Q10 = 2.0
310>1T2 ⫺T1 24
Q10 ⫽ c d
K2 10
K1 320 325 330 335 340 345 350
Temperature (1/K × 105)
where the rates of a reaction (K) are compared at two
temperatures (1 and 2). Thus, if a rate of 10 units/min
37 29 22 15
(K1) was observed at 15°C (T1), and a rate of 20 units/ min
Temperature (°C)
(K2) at 25°C (T2), then
310>125⫺1524
Q10 ⫽ c d
20
⫽ 21 ⫽ 2 lines show data where one line fits the data at low tem-
10
peratures, but a different line fits the relationship at high
The Q10 for a process is the best way to express the in- temperatures. The point where the two lines cross is
fluence of temperature on reaction rates, but a better ap- called the breakpoint. Since the slope differs between
proach to exploring the mechanism of action is through the two lines, we can infer that different activation ener-
an Arrhenius plot. In the late 1800s, the chemist Svante gies govern the reaction over each temperature range. In
Arrhenius described a mathematical approach to explor- many cases, this is due to a mechanistic transition from
ing the impact of temperature on macromolecular one state to another state. If the process under consid-
processes. We now use his approach to study processes eration is membrane fluidity, for instance, the break-
such as enzymatic reactions, diffusion of molecules, and point might reflect the transition from a liquid to a solid
lipid membrane phase transitions. The sensitivity of a re- phase. If the process is an enzymatic reaction, the break-
action to temperature reflects the activation energy (Ea) of point might occur at a temperature where a critical bond
the process. The Arrhenius equation describes the rela- is broken, converting the enzyme from an efficient cata-
tionship between the activation energy, temperature, and lyst to a less-efficient catalyst or denatured enzyme.
the rate of the process under study: The versatility of the Arrhenius plot allows re-
searchers to describe the thermal behavior of any simple
k ⫽ Ae(⫺Ea /RT )
or complex process. However, the reasons for particular
More often, the Arrhenius equation is shown as relationships are more difficult to ascertain in complex
systems. Thermal effects on membranes are often dif-
ln(k) ⫽ ln(A) ⫺ Ea /(RT )
ficult to assess because of the considerable hetero-
where k is a rate coefficient, R is the gas constant geneity of the membrane. Lipid rafts, for example, are
(8.31447 × 10⫺3 kJ/K per mol), T is temperature (in de- cholesterol-rich regions of the cell membrane that of-
grees Kelvin), A is called the pre-exponential factor, and ten accumulate distinct phospholipids. Temperature will
Ea is the activation energy (kJ/mol). have a different effect on the fluidity of these regions in
Let’s say that a researcher was interested in how comparison to the bulk phase of the membrane. Simi-
temperature influenced the rate of an enzymatic reac- larly, many integral membrane proteins accumulate dif-
tion. She would vary temperature over a range of inter- ferent types of lipids. For example, the mitochondrial
est and measure enzymatic rates. The data she enzyme binds cardiolipin molecules within the inner mi-
collected could be plotted on a graph with axes chosen tochondrial membrane. Changes in the bulk phase of the
from a rearrangement of the Arrhenius equation that membrane do not necessarily reflect changes in the lipid
generates a linear equation (y ⫽ mx ⫹ b): membrane in direct contact with the proteins of interest.
Even more complex processes, such as metabolic rate,
ln(k)⫽ ⫺Ea /R × (1/T ) ⫹ ln(A)
are really the sum of many simple processes, each with
Plotting ln(k) versus 1/T gives a slope of ⫺Ea /R and a y their thermal sensitivity and unique Arrhenius equation.
intercept of ln(A). Suggested Reading
The accompanying figure illustrates two potential q Metz, J. R., E. H. van den Burg, S. E. Bonga, and G. Flik. 2003.
outcomes from an Arrhenius plot. For the green line, the Regulation of branchial Na(⫹)/K(⫹)-ATPase in common carp
data fall along a straight line. The slope of the line re- Cyprinus carpio L. acclimated to different temperatures. Journal
flects the activation energy of the reaction. The purple of Experimental Biology 206: 2273–2280.
674
Thermal Physiology
bonds between fatty acid chains, the mem-

Bird
brane is more fluid. For example, pure stearic
acid (C18:0) becomes liquid only at tempera-
Mammal tures above 69°C, whereas oleic acid (C18:1) is
liquid at 12°C. The position of the double bond
Fluidity)
is also critical. A double bond near the mid-

point of the fatty acid chain (as with oleic acid)
Anisotropy
is more effective than a double bond near the

Tropical fish end of the fatty acid chain.
(
3. Phospholipid classes. The difference in the

shape of the polar head groups alters the
Cold-water fish ability of the phospholipids to interact at
the surface of the membrane. Phosphatidyl-
0 10 20 30 40 choline (PC) is more common in membranes
Temperature (°C) of warm-acclimated cells, whereas phos-
Figure 11 Membrane fluidity Membranes are phatidylethanolamine (PE) is more common in
treated with a dye (diphenyl hexatriene) with optical cold-acclimated cells. The ratio of PC to PE de-
properties that change in relation to membrane fluidity. creases in the cold acclimation and adaptation.
Anisotropy is an optical property that reflects the ability of a
dye to alter the behavior of plane polarized light. Anisotropy 4. Cholesterol content. A pure phospholipid bi-
is inversely related to fluidity; at warmer temperatures, a layer is mostly fluid at high temperature and
decrease in anisotropy reflects an increase in fluidity. mostly solid at low temperature. Cholesterol
Animals that live in different environments produce
added to fluid phospholipid bilayer has little
membranes that possess a similar fluidity at their normal
range of temperatures (indicated by the thickened portion of effect on fluidity. If the same membrane is
the lines). cooled, cholesterol tends to prevent it from so-
(Source: Adapted from Logue et al., 2000)
Low fluidity High fluidity

animal is acclimated to different temperatures. Ec-
tothermic animals reduce the deleterious effects of
temperature by changing the composition of their
Shorter chain
membranes. In this process, called homeoviscous
length
adaptation, cells remodel membranes to preserve
fluidity. Three mechanisms target phospholipids
(Figure 12), and a fourth mechanism alters choles-
terol content.
1. Fatty acid chain length. Phospholipids with Unsaturation

short chain fatty acids cannot form as many in-
teractions with adjacent fatty acids and there-
fore are highly mobile. The effectiveness of
chain shortening depends upon the fatty acid PC PE
position on the phospholipid. Due to the three-
dimensional structure of a phosphoglyceride, Polar head
group
a short chain fatty acid in position 1 makes a
greater contribution to enhancing fluidity than
does the same fatty acid in position 2.
Figure 12 Phospholipid properties and
2. Saturation. Double bonds create a kink in the
membrane fluidity Cells change the fluidity of
fatty acid chain that prevents effective bond membranes by altering the composition of membrane
formation with other fatty acids. With fewer phospholipids.
675
Thermal Physiology
lidifying. Put another way, cholesterol tends to Phospholipids are synthesized de novo within the
make a membrane more fluid when external endoplasmic reticulum, then packaged into vesi-
conditions otherwise encourage a transition to cles that fuse with cellular membranes.
a gel phase.
Cells use two general pathways to modify

Temperature changes enzyme kinetics
membrane composition in response to tempera- Temperature affects protein structure and function
ture: in situ modification and de novo synthesis. in complex ways. Changes in temperature alter the
Both pathways require cells to modify the proper- number of bonds that form within and between
ties of the fatty acids within the fatty acid pool us- molecules. Even minor changes in protein struc-
ing suites of enzymes that elongate, shorten, ture can have important effects on protein func-
saturate, and desaturate fatty acids. Since these tion. In enzymes, for example, these structural
enzymes begin with fatty acids derived from the effects manifest as changes in catalytic properties.
diet, the nature of the diet also affects the profile First, changes in weak bonds can alter the three-
of fatty acids within the membrane. dimensional structure of the enzyme. For instance,
Enzymes alter the structure of individual phos- warm temperatures could break bonds that are
pholipids directly within the membrane (Figure 13). necessary to fold the protein in a way that forms
First, phospholipase A removes an acyl chain from the active site. Second, temperature can alter the
membrane phospholipids to form a lysophospho- ionization state of critical amino acids within the
lipid. Next, lysophospholipid acyltransferase uses a active site. For instance, the amino acid histidine is
more appropriate fatty acid (in the form of fatty acyl important in many active sites, and changes in his-
CoA) to rebuild the phospholipid. tidine protonation state can alter enzyme substrate
More commonly, membranes are remodeled affinity. Any increase or decrease in Km could be
by endocytosis and exocytosis (see Figure 14). The disruptive. Third, temperature can alter the ability
old membrane is removed using endocytosis. of the enzyme to undergo the structural changes
necessary for catalysis. Enzymes must be rigid
enough to maintain the proper conformation, but
flexible enough to undertake conformational
COOH
changes during catalysis. Thus, temperature can af-
fect enzyme kinetics through effects on maximal
velocity (Vmax) or affinities for substrates (Km),
allosteric activators (Ka), and inhibitors (Ki). When
Fatty acid
CoA
animals experience a change in TB, they may either
tolerate the effects on enzyme kinetics or alter meta-
ATP Acyl CoA synthase
bolic regulation to compensate.
Biochemical reactions are accelerated by
COOH CoA higher temperature and reduced at lower tem-
perature. Recall that the rate of a chemical reac-
tion depends on the proportion of molecules
Fatty acid
within the system that possess energy equal to
Fatty acyl CoA
or greater than the activation energy (Ea). As
temperature increases, the average kinetic en-
ergy of the substrates increases and a greater
Phospholipase Lysophospholipid
acyltransferase proportion of molecules has sufficient energy to
be converted to products, causing the enzyme ve-
Phospholipid Lysophospholipid
locity to increase. For most enzymes working
Figure 13 Phospholipid remodeling Cells can over a biologically relevant range of tempera-
remodel the phospholipids directly within membranes by tures, an increase of 10°C results in a two- to
removing a fatty acid. A phospholipid is rebuilt by
lysophospholipid acyltransferase, which attaches another
threefold increase in reaction velocity. Recall
fatty acid produced by the cell. The fatty acid must first be from Box 2 that this implies a Q10 value of 2–3.
activated by the esterification of coenzyme A. Q10 can be calculated for simple reactions
676
Thermal Physiology
such as an enzymatic step, or com- Extracellular

plex processes such as metabolic ER Golgi Endosome Vesicle
fluid
rate.
Consider how temperature af-
fects the Vmax of lactate dehydroge- Endocytosis
nase (LDH) in the muscle of a desert
lizard as it experiences daily transi-
tions in TB. Over the course of a single
Cytoplasm
day, the total number of LDH enzyme
molecules does not change apprecia-
bly, but their catalytic activity changes
Exocytosis
with temperature. LDH maximal ac-
tivity (Vmax) typically doubles when
temperature is increased by 10°C
Vesicle
(that is, its Q10 is 2). Let’s begin at a TB Plasma
membrane
of 40°C, and assume that the muscle
of the lizard has 400 units (U) of LDH Figure 14 Membrane remodeling Cell membranes are constantly
per gram of tissue (One U of enzyme remodeled by endocytosis and exocytosis. When temperature decreases, the cell
can convert 1 µmol of substrate to produces vesicles possessing phospholipids with fatty acids that are shorter and more
product each minute.) With Q10 ⫽ 2, a unsaturated than those in the cell membrane. Over time, the cycles of endocytosis
and exocytosis remove undesirable phospholipids, replacing them with more desirable
decrease in temperature from 40°C to phospholipids.
30°C causes the LDH enzymes to op-
erate at only one-half the velocity, giv-
ing a Vmax of 200 U/g. Similarly, at 20°C the LDH Vmax example, it may increase substrate concentrations
is 100 U/g, and at 10°C only 50 U/g. Over the course or stimulate the enzyme with allosteric regulators.
of a single day, from the midday heat to the cool
evening, a desert lizard may have to cope with an
eightfold change in its LDH Vmax activity as a result
Evolution may lead to changes
of changes in TB.
in enzyme kinetics
It is easy to imagine how an eightfold reduc- When animals are exposed to suboptimal tempera-
tion in LDH capacity might severely impair the ca- tures for generations, there is the possibility of evo-
pacity to produce ATP by glycolysis. How does an lutionary changes in the genes encoding enzymes.
animal cope with such dramatic reductions in the We draw again on research with LDH for examples
rates of enzymatic reactions? The simple answer of evolutionary changes that cause differences in
is that the rates of ATP synthesis decline in paral- enzyme kinetics as well as enzyme synthesis.
lel with the rates of ATP utilization, with each step Mutations may lead to structural changes in
exhibiting a Q10 ranging from 2 to 3. Put another the enzyme that impart a favorable difference in
way, the animal can tolerate lower rates of muscle enzyme kinetics. Lowering temperature increases
ATP production because it slows down and needs the affinity of LDH for its substrate pyruvate. Evolu-
less ATP for muscle activity. However, it is impor- tion has led to a fine-tuning of enzyme properties
tant to recognize that Q10 ⫽ 2 is quite different such that subtle structural differences allow each
from Q10 ⫽ 3. If a 10°C decrease in temperature species to possess a similar Km at its respective
caused ATP supply to decrease threefold when ATP normal TA. This strategy, called conservation
demands decreased only twofold, the tissue would of Km, is commonly seen when we compare the
be depleted of ATP within seconds or minutes. Su- effects of temperature on the enzyme kinetics of
perimposed on the Q10 effects are numerous layers different animals.
of metabolic regulation that ensure that energy Alternately, evolution may lead to mutations in
metabolism remains in homeostasis. If an individ- the promoter for an enzyme, causing a change in
ual enzyme is more sensitive to temperature than the level of gene expression of an otherwise un-
are other enzymes in the pathway, the cell has sev- changed enzyme. Killifish live along the eastern
eral options to increase flux through that step. For coast of North America from Newfoundland to
677
Thermal Physiology
Florida. Within the population as a whole, there Surprisingly little is known about the hor-
are different alleles of the LDH-B gene. One allele mones and signaling pathways that cause an ec-
predominates in northern populations, while an- totherm to remodel its tissues during acclimation
other allele predominates in southern popula- and acclimatization. Cold-sensing and warm-
tions. Intermediate populations have both alleles. sensing neurons are important for detecting tem-
These alleles have differences in enzyme proper- perature, but the links to gene expression are not
ties and differ in the level of gene expression. The well known. In some cases, seasonal changes in
northern allele is expressed at twofold higher lev- physiology that mitigate the effects of temperature
els than the southern allele, due to mutations in are triggered by changes in the photoperiod.
the promoter. The northern fish produce more
LDH enzyme molecules, which compensates for
the debilitating effects of temperature on enzy-
Life at High and Low Body
matic activity that would occur as a result of living
Temperatures
in the colder waters.
Animals that can tolerate extreme temperatures
can invade and colonize niches that are underex-
Ectotherms can remodel tissues ploited by their competitors. Ectothermic animals
in response to long-term changes exposed to thermal challenges must possess
in temperature mechanisms to mitigate the effects of temperature
Many ectothermic animals remodel their cellular on macromolecular structure and metabolism. In
machinery to mitigate the effects of variation in TB. contrast, endothermic animals survive thermal
In the laboratory, where the researcher changes extremes using complex regulatory pathways to
only TA, this remodeling process is called thermal maintain a constant TB. Their existence at ex-
acclimation. In the natural world, seasonal transi- tremes is a testament to their physiological capac-
tions in temperature are accompanied by other ity to resist the effects of TA.
environmental changes and the response of the
animal to complex seasonal changes is called ac-
climatization. In winter, photoperiods get shorter, Some enzymes display cold adaptation
food may be less abundant, and oxygen levels may Earlier in this chapter we discussed how relatively
change. The complexity of these seasonal environ- subtle differences in TA can lead to evolutionary
mental changes makes it difficult to link remodel- changes in enzyme structure and gene expression.
ing with the temperature. On one hand, there is However, the need for enzymatic structural modi-
uncertainty about the trigger for the remodeling fication is much more pronounced at thermal ex-
process; is the change initiated by changes in tem- tremes, particularly at the subzero temperatures
perature, or by some other factor, such as pho- encountered in polar seas. Psychrotrophs are or-
toperiod? On the other hand, it is not always clear ganisms that thrive in the extreme cold, in con-
that the remodeling itself serves to compensate trast to mesotrophs that live at more moderate
specifically for temperature. temperatures. Animal psychrotrophs, including
Temperature-dependent remodeling involves polar invertebrates and fish, remain active at body
combinations of quantitative and qualitative temperatures near the point of freezing. Many
strategies. Low temperature may increase the psychrotrophic organisms possess cold-adapted
number of mitochondria in muscle, or trigger the proteins that function optimally at very low tem-
hypertrophic growth of the heart. This is an exam- peratures. Although these enzymes are more sta-
ple of a quantitative strategy; there is simply more ble in the cold, they are rapidly inactivated at
of the same machinery. Muscles can also alter the slightly higher temperatures.
types of proteins they use to build the contractile The catalytic and structural differences be-
machinery. For instance, animals express differ- tween enzymes of psychrotrophs and mesotrophs
ent myosin isoforms in winter and summer—an
example of a qualitative strategy.
678
Thermal Physiology
can be traced to the weak bonds that stabilize en-

zyme structure. Enzymes undergo pronounced Stress proteins are induced
changes in three-dimensional shape during the at thermal extremes
catalytic cycle, known as protein breathing. During Many proteins are best suited to function over nar-
these transitions in folding, weak bonds break and row ranges of temperature that span the biologi-
form. When temperatures decrease, most of these cal range of the animal. During the normal
weak bonds are strengthened, stabilizing the pro- structural change that occurs when a protein
tein in a form that occupies a smaller volume. In this breathes, the protein is vulnerable to further
conformation, it is much harder for the protein to changes in structure. Occasionally, the protein can
breathe, and consequently enzymes in the cold are unfold or misfold into a nonfunctional conforma-
less efficient. The psychrotroph enzyme has fewer tion. This denatured protein must be repaired or
weak bonds stabilizing its structure; it occupies a cleared from the cell before it disrupts other cellu-
larger volume and has an easier time breathing dur- lar functions. Denaturation is a normal process,
ing catalysis. The reduced stability allows it to func- and cells are able to detect and remove denatured
tion better in the cold, but makes it vulnerable to proteins using pathways of protein quality control.
temperature-dependent unfolding. In comparison These pathways function throughout the lifetime
to mesotroph enzymes, cold-adapted enzymes are of a cell, but become even more important during
more efficient enzymes at low temperatures, but in- times of thermal stress when denatured proteins
ferior enzymes at high temperatures. can accumulate and kill the cell.
Unique loss-of-function mutations also occur Heat shock proteins (Hsp’s) are molecular
in polar animals. Many Antarctic fish have lost the chaperones that use the energy of ATP to catalyze
ability to express functional oxygen-binding pro- protein folding after translation. Chaperones can
teins, such as hemoglobin and myoglobin. These also help refold proteins that have become dena-
fish can survive without these oxygen carriers be- tured as a result of thermal stress. Many cells ex-
cause they have low metabolic rates and the sur- posed to extreme temperatures undergo a heat
rounding polar waters are rich in oxygen. shock response, which leads to a dramatic in-
There are many such examples of thermal crease in the levels of specific proteins that help
adaptations of individual selected genes in polar repair damaged proteins. During a heat shock, the
animals. However, more controversial is the ques- cell undertakes a rapid increase in the synthesis of
tion of whether or not polar animals have a funda- several critical Hsp’s. The cell can halt the tran-
mentally different organization of metabolism as a scription and translation of other genes, sparing
result of evolution in the extreme cold. Early stud- biosynthetic resources for Hsp synthesis. It stimu-
ies suggested that polar animals had metabolic lates the expression of the Hsp genes by activating a
rates that were much higher than the metabolic heat shock factor (HSF), a transcription factor that
rates of temperate animals measured near 0°C. binds to the heat shock elements in the promoters of
These observations were used to support a theory genes for heat shock proteins. Although there is still
that became known as metabolic cold adaptation. some uncertainty about the exact mechanism of acti-
It was proposed that thousands of years in the ex- vation of HSF, the trigger for the process is thought to
treme cold led to evolutionary changes that pro- involve damaged protein (Figure 15). In the absence
vided these polar animals with an ability to elevate of thermal stress, most of the cellular HSF is bound to
their metabolic rate. Even with years of study it re- Hsp70 as inactive monomers. When the cell is
mains unclear whether metabolic cold adaptation stressed, the chaperones are lured away from HSF by
is a real phenomenon. The earliest studies were damaged proteins. The released HSF can then form
based on comparisons of goldfish and arctic cod. trimers, which in turn bind the heat shock element
Now that more species have been analyzed using on the Hsp genes, activating them. Once the damaged
more sophisticated technologies, it seems less likely proteins are repaired, Hsp70 is free to bind HSF
that metabolic cold adaptation occurs as a general monomers and reverse the transcriptional activation.
phenomenon. Nonetheless, many studies have The Hsp response is central to the ability of
identified evolutionary differences and physiologi- ectothermic animals to survive brief periods of
cal peculiarities in some polar animals.
679
Thermal Physiology
Cytoplasm 1 1 Complex of HSF and Hsp's under

Hsp70 unstressed conditions.
9 2
3
2 Heat stress causes complex to
dissociate.
4
HSF monomers 3 Hsp70 binds to denatured proteins.
8 Denatured
HSF protein
trimer 4 HSF monomers associate into trimers.
5 Trimers move into the nucleus and bind

to the promoter of genes with heat
5 shock element (HSE).
6 Hsp70 gene transcription increases.
Hsp70 gene 7 Poly A+ mRNA is exported to the

DNA cytoplasm.
6
7
8 Poly A+ mRNA is translated to form
HSE
more Hsp70.
AAA 9 The increase in Hsp70 levels allows

the complex to form again, stopping
Nucleus Poly A+ mRNA transcriptional activation.
Figure 15 Heat shock response
extreme temperature that often occur within their low their tissues to freeze and even encourage ice
natural environments. For most species, the Hsp to form in the body. Animals that avoid freezing
response is induced at temperatures only a few de- use behavioral and physiological mechanisms to
grees above the typical thermal range. This pow- prevent ice crystal formation and growth. To un-
erful protective process may be central to the derstand why ice is so dangerous, let’s consider
evolution of thermal sensitivities and thermal what happens to water molecules as temperatures
ranges (see Box 3, Methods and Model Systems: decrease.
Heat Shock Proteins in Drosophila). Interestingly, The freezing point of pure water is 0°C. This is
some species have lost their ability to mount a heat the temperature at which ice could form if enough
shock response. Antarctic fish have lived for thou- water molecules cluster together to begin an ice
sands of years at ⫺1.96°C. At some point, the crystal. Below the freezing point, water is on the
species experienced genetic changes that dis- verge of freezing, awaiting an event that triggers ice
rupted the capacity to invoke a heat shock re- formation. When water is below its freezing point,
sponse. Since the Antarctic waters remain very but not yet frozen, it is considered supercooled.
constant in temperature, these mutations have no Pure water, left undisturbed, can be supercooled to
deleterious consequences to the animals. How- almost ⫺40°C before ice forms spontaneously. The
ever, when taken out of their natural environment, trigger for ice formation is a cluster of water mol-
these fish rapidly succumb to temperatures only a ecules that act as a seed for an ice crystal. Alterna-
few degrees above 0°C. tively, a macromolecule in solution can act as a
nucleator, seeding ice crystal formation. Once the
ice formation begins, water molecules bind to each
Ice nucleators control ice crystal growth face of the growing crystal to create a complex
in freeze-tolerant animals three-dimensional structure.
Ectotherms that live at freezing temperatures use Ice crystals forming within a tissue have two
two strategies to survive the cold: freeze-tolerance deleterious effects. First, since ice crystals have
and freeze-avoidance. Freeze-tolerant animals al- points and sharp edges, the growing ice crystal can
680
Thermal Physiology

Heat Shock Proteins in Drosophila
The best-studied Hsp’s are from the tant in thermotolerance, but that other physiological
Hsp70 family. Each subcellular compartment factors may also play roles.
has Hsp70 proteins that help fold proteins into the These studies also showed that flies with a robust heat
proper conformation and target misfolded proteins for shock response also had lower fecundity. In other words,
degradation. Mitochondria have Grp75, the cytoplasm superior thermotolerance comes with an evolutionary
has Hsc70, and the endoplasmic reticulum has Bip. The cost. In a thermostable environment, flies with lower lev-
namesake of the family, Hsp70, is produced by cells els of Hsp70 could outcompete flies with higher Hsp70
mainly under stressful conditions. When temperatures levels because of their greater fecundity. However, at
rise to dangerous levels, cells dramatically induce syn- more thermally challenging conditions, the lower fecun-
thesis of Hsp70. It is produced in the cytoplasm, where dity is offset by the greater thermotolerance. These labo-
it refolds proteins that have been denatured in response ratory studies also reflected the nature of the evolution of
to elevated temperatures. The ability to mount a heat thermotolerance in the natural world. Wild populations of
shock response is central to the thermotolerance of an- Drosophila from around the globe exhibit a wide range in
imals. Genetically modified cells that lack an ability to thermotolerance. In most populations the natural ability
induce Hsp70 are very sensitive to thermal stress. Since to survive thermal stress correlates with the levels of
this gene is essential for thermotolerance, many re- Hsp70 gene expression. For example, flies in Evolution
searchers have studied whether variation in Hsp70 gene Canyon in Israel occur in separate populations that oc-
expression is central to the differences in thermotoler- cupy the north- and south-facing slopes. The flies that live
ance among animals. on the south-facing slopes, which are hotter and drier,
Many studies of thermotolerance and Hsp70 have have a stronger heat shock response. The flies on the
been performed on the fruit fly, Drosophila. If Hsp70 north-facing slope have a weaker heat shock response
helps an animal survive heat stress, then it might be due to a disruption of the promoter of one of the Hsp70
reasonable to hypothesize that an animal could benefit genes. Since these two slopes are only hundreds of me-
from greater expression of Hsp70. Laboratory studies ters apart, individual flies probably move between the two
have provided important insight into the links between populations. Thus, natural selection acts to ensure that
Hsp70 gene expression, thermotolerance, and evolu- the allelic differences between populations are retained.
tion. In one study, lines of flies were manipulated to pos- Similar studies on other Drosophila populations showed
sess extra copies of Hsp70 genes. Larvae from these that flies with lower thermotolerance usually possessed
flies had greater thermotolerance, demonstrating the mutations that disrupted their ability to express one or
importance of Hsp70 to thermotolerance. In other ex- more copies of Hsp70 genes. In most of these cases, the
periments, lines of flies were exposed to high tempera- animals with higher Hsp70 inducibility and thermotoler-
tures for generations to see if natural variations in the ance also showed reductions in fecundity.
Hsp70 genes within a population could be subject to These studies show that, though critical for thermo-
natural selection. Within only a few generations the av- tolerance, Hsp70 can have deleterious effects. Further-
erage thermotolerance of the flies increased. These more, they illustrate why genetic variations in
thermotolerant flies were able to induce Hsp70 to populations are essential for the survival of a species.
higher levels than thermosensitive flies. Surprisingly, References
the difference in Hsp70 gene expression between ther- q Feder, M. E., and G. E. Hofmann. 1999. Heat-shock proteins, mo-
motolerant and thermosensitive flies was never more lecular chaperones, and the stress response: Evolutionary and
than 15%. These data argue that Hsp70 may be impor- ecological physiology. Annual Review of Physiology 61: 243–282.
pierce membranes, killing the cell. Second, ice crys- Still, many ectotherms survive freezing. Intertidal
tal growth removes surrounding water, causing hy- bivalves living in northern tidal flats can freeze
perosmotic stress. If ice forms outside cells, then when exposed to cold air temperatures, then thaw
water is drawn out of cells, causing a hypertonic when the warmer water returns at high tide. Sev-
stress that shrinks the cell, perhaps even killing it. eral terrestrial vertebrates can also survive freezing.
681
Thermal Physiology
A wood frog in the north temperate zone enters the possess antifreeze macromolecules—typically pro-
leaf litter in late fall, in preparation for overwinter- teins or glycoproteins—that reduce the freezing
ing. When temperatures drop below freezing, the point of body fluids by noncolligative actions. They
animal supercools but ice does not form. At still disrupt ice crystal formation by binding to the sur-
lower temperatures, the animal begins to freeze. face of small ice crystals to prevent their growth
First to freeze are the frog’s fingers and toes. The (Figure 16).
body core begins to freeze shortly thereafter. The first antifreeze protein, or AFP, was dis-
Freeze-tolerant animals usually produce ice nu- covered in an Antarctic fish about 30 years ago by
cleators to control the location and kinetics of ice Dr. Art DeVries. Since then, AFPs have been found
crystal growth. Ice is the most damaging when it in many distantly related taxa of fish, as well as in-
forms inside cells, so freeze-tolerant animals secrete sects and plants. Four classes of AFPs are distin-
nucleators out of the cell. This restricts ice formation guished by their structure: types I, II, and III, as
to the extracellular fluids, such as hemolymph, and well as antifreeze glycoproteins, or AFGPs. Inter-
allows the intracellular space to remain liquid. estingly, each of the classes of AFPs has arisen
Many different types of molecules can act as nucle- multiple times in evolution. In fish, AFPs arose less
ators in animals: calcium salts, membrane phos- than 20 million years ago. This coincides with re-
pholipids, and long chain alcohols. However, it is not cent (in geological terms) sea level glaciation,
always clear that these ice nucleators are actually which probably represented a strong selective
necessary or helpful to freeze-tolerance strategies. pressure on the local marine species. The phyloge-
For example, the wood frog has an ice nucleator netic distribution of AFPs suggests an intriguing
that triggers ice formation at about ⫺7°C. The same evolutionary history.
ice nucleator is also found in the tissues of frogs that AFPs provide good examples of parallel evolu-
cannot survive freezing. It may induce the formation tion. For example, AFP II appears in herring,
of ice, but it does not necessarily provide the wood salmon, and sea ravens, fish from three separate
frog with its freeze-tolerance. Some nucleators may orders. This suggests that AFPs arose multiple
simply be present for other functions and have no times in these lineages but well after the modern
adaptive role in freeze-tolerance. species diverged. These AFP II genes may have
Because ice formation draws water from the arisen from similar genes independently in each
cells, freeze-tolerant animals also produce intra- lineage. The structure of AFP II suggests the an-
cellular solutes to counter the movement of water. cestral gene was a Ca2⫹-dependent lectin, a pro-
Large glycogen reserves of the liver are broken tein that binds sugars. In structural models, the
down and converted to compatible solutes consist-
ing of organic polyols, such as trehalose and glyc-
erol. Compatible solutes have two main beneficial
effects. First, by increasing the osmotic pressure
within the cells, they reduce the movement of wa-
ter and cell shrinkage. Second, the solutes help sta-
bilize macromolecular structure. AFP
Antifreeze proteins can prevent Ice crystal Water

intracellular ice formation molecules
Freeze-avoidance is the second strategy animals

use to survive extreme cold. In a car, antifreeze ele-
vates the osmotic concentration of the radiator fluid.
Solutes in general depress the freezing point of a so- Figure 16 Antifreeze proteins Antifreeze proteins
lution, preventing ice formation at subzero temper- bind to the surface of ice crystals to prevent their growth.
atures. Freezing point depression is one of the They bind along the face of the ice crystal, where the protein
forms weak bonds with water molecules immobilized in the
colligative properties of solutes. The solutes in ani- ice crystal. Because ice growth is very orderly, the presence
mal tissues reduce the freezing point of water, but of the bound protein prevents ice crystal growth.
generally not lower than about ⫺2°C. Some animals (Source: Modified from Davies et al. 2002)
682
Thermal Physiology
interaction of a lectin with the hydroxyl groups of Thermogenesis

sugars is similar to the interaction of AFP with the
hydroxyl group of a water molecule. Heat production is an inevitable consequence of
The evolutionary origins of AFGP are also un- being alive. An endotherm warms its body using
usual in terms of protein evolution. The ancestral heat that arises as a by-product of other metabolic
gene was probably a gene for pancreatic trypsino- processes, primarily energy metabolism, diges-
gen. A region between the first intron and second tion, and muscle activity. All animals—endotherms
exon was duplicated not just once but more than and ectotherms—generate heat during these
40 times. The resulting gene possessed multiple, processes, but only the endotherms possess the
tandem sequences that resulted in a repeating physiological adaptations that enable them to re-
Thr-Ala-Ala motif necessary to prevent ice crystal tain enough metabolic heat to elevate TB above TA.
growth. In most cases of gene duplication and di- In addition to the pathways that produce heat
vergence, the resulting gene has properties similar as a by-product, endotherms possess specific ther-
to those of the ancestral gene, with relatively subtle mogenic pathways with the main purpose of heat
differences in function. In the case of AFGP, the reproduction. Thermogenic pathways rely on futile
sultant gene has a totally distinct function. AFGPs cycling, in which chemical potential energy is spent
have no protease activity, and trypsinogen has no to generate heat. Most futile cycles involve cycling
antifreeze activity. of ATP hydrolysis and ATP synthesis. Heat is re-
leased in ATP hydrolysis (ATP → ADP ⫹ phosphate),
but a great deal more heat is produced when the
2 CO NC E P T C HE C K cell uses intermediary metabolism to regenerate
the ATP. Endotherms can enhance heat production
5. Compare and contrast the homeoviscous
adaptation and conservation of Km in relation to either by increasing the rate of ATP turnover or by
temperature effects on macromolecules. reducing the efficiency of ATP production. In both
6. How can an animal alter membrane fluidity? cases, most of the metabolic heat arises directly or
7. Distinguish between freeze-tolerant and freeze- indirectly from mitochondrial oxidative phospho-
avoidance strategies. rylation.
Maintaining a Constant Shivering thermogenesis results from

unsynchronized muscle contractions
Body Temperature
Muscle plays a critical role in the thermal budget of
Endothermy is so inextricably intertwined with a endotherms. Because muscle is the most abundant
high metabolic rate that it is not known which trait tissue in birds and mammals, it produces consider-
arose first. High TB allows metabolic processes able heat, even at rest. Locomotion enhances the
such as growth, development, digestion, and rate of muscle heat production. However, many
biosynthesis to operate at faster rates, and the birds and mammals can also use skeletal muscle to
higher metabolic rate in turn produces more heat. generate heat by shivering thermogenesis. As in
The ability to become warm bodied requires meta- normal contraction, motor neurons from the spine
bolic pathways to produce heat (thermogenesis) release neurotransmitters at the motor end plate,
as well as physiological mechanisms to retain but during shivering the pattern of excitation is dif-
heat. Most endotherms are also homeotherms and ferent. The smallest neurons—those innervating the
committed to maintaining a constant TB. To do so, slow fibers—are recruited first, followed by the
they must control both thermogenesis and heat larger neurons that innervate fast muscle. As a re-
exchange. In cold environments, endotherms sult, individual myofibers contract but the motor
stimulate thermogenesis and reduce heat loss. In units are uncoordinated and the whole muscle un-
hot environments they increase heat loss, but may dergoes no gross movement. Shivering thermogen-
also reduce thermogenesis. To control TB, animals esis is a strategy that works for short periods of cold
must be able to sense both environmental temper- exposure, but it is not useful for prolonged cold
ature and body core temperature. stress. The mechanics of shivering prevent an ani-
mal from using its locomotor muscles to hunt prey
683
Thermal Physiology
or escape predators. Furthermore, if shivering per-

sists, or repeats frequently, the muscles are rapidly Takeoff
30
depleted of nutrients and they become exhausted,
just as they would after high-intensity exercise.
Thorax temperature (°C)

Warm TA
Heat is produced in metabolic futile cycles 20
Shivering thermogenesis is unique to birds and

mammals; however, other animals also use mus-
cle to generate heat. Large flying insects, such as Cold TA
bumblebees and some moths, can generate 10
enough heat to warm the thoracic flight muscles,
which improves flight muscle performance in
terms of energy production, excitation-contraction
coupling, and cross-bridge cycling. The high meta-
0
bolic rate during flight generates abundant heat, 0 10 20 30
enough to warm the flight muscles by several de- Time (min)
grees. Remarkably, these insects are even able to
Figure 17 Thermogenesis in insect flight
warm their flight musculature prior to takeoff. muscle Many large flying insects can undertake a
Three distinct mechanisms allow insects to preflight warm-up, using metabolic futile cycles and muscle
warm the thorax prior to flight. These same ther- activity to elevate thoracic temperatures to a threshold
temperature required for flight.
mogenic pathways also allow social insects to work
(Source: Modified from Heinrich, 1987)
collectively to warm the hive. The first mechanism
is a metabolic futile cycle in carbohydrate metabo-
lism. Within the flight muscle, two opposing en- bution of ions across the membrane. Cells use
zymes are activated simultaneously: the glycolytic chemical energy, usually in the form of ATP, to cre-
enzyme phosphofructokinase and the gluco- ate these gradients. Consequently, any process
neogenic enzyme fructose-1,6-bisphosphatase. that dissipates ion gradients will cause the cell to
The metabolic cycle causes ATP hydrolysis and heat use chemical energy to reestablish the gradient.
production, but without changes in the levels of the Ion gradients collapse for two main reasons.
other substrates and products. A second warming First, many specific membrane proteins use elec-
mechanism relies on muscle contraction. Two sets trochemical energy to drive other processes such
of antagonistic flight muscles power wing move- as metabolite transport and biosynthesis. For ex-
ments during flight. Bumblebees can induce both ample, many cells transport glucose and amino
sets of muscles to contract simultaneously prior to acids into the cell using Na⫹-dependent cotrans-
flight, so that energy is expended without produc- porters, causing the cell to use Na⫹/K⫹ ATPase to
tive movement. The third mechanism for heat gen- pump the Na⫹ back out of the cell. The mitochon-
eration is actual wing movement. The insect moves drial F1F0 ATPase is another transporter that dis-
its wings fast enough to buzz, but controls the fre- sipates ion gradients, in this case the proton
quency and orientation of the wings to avoid gener- motive force. Heat is produced when the mito-
ating lift. Collectively, these thermogenic pathways chondrial electron transport system oxidizes re-
allow the flight muscle to warm up prior to takeoff. ducing equivalents to regenerate the proton
There appears to be a critical thoracic temperature gradient.
that must be achieved before the insect will attempt The second pathway of ion gradient dissipation
to fly (Figure 17). At high TA, less of a preflight is ion leak, in which ion movements are not coupled
warm-up is necessary to reach the threshold. to any other transport process. Since no biological
membrane is completely impermeable, some ions
leak across the bilayer or through gaps between
Membrane leakiness enhances proteins and phospholipids. Ion-pumping mem-
thermogenesis brane proteins produce heat as a by-product, and a
Most cellular membranes maintain an electro- high proportion of the resting heat production, as
chemical gradient arising from differential distri- much as 50% in some tissues, is due to the costs of
684
Thermal Physiology
maintaining ion gradients. Any process that in- BAT is particularly important for thermogenesis in
creases the need for ion pumping will also increase small mammals and newborns of larger animals,
thermogenesis. Typically, an endotherm has a rest- particularly those that live in cold environments.
ing metabolic rate that is as much as 10-fold BAT growth and thermogenesis is under the con-
greater than that of an ectotherm of the same size trol of the sympathetic nervous system. Norepi-
and TB. The higher metabolic rate is due in part to nephrine released from these nerves causes BAT to
membrane leakiness; endotherm plasma mem- grow in cell number (hyperplasia) and cell size (hy-
branes and mitochondrial membranes are inher- pertrophy). Undifferentiated precursor cells are in-
ently leakier than those of ectotherms. Endotherms duced to proliferate and then later differentiate
generate more heat to maintain ion gradients into BAT. Triglyceride is synthesized and mito-
across leakier membranes. chondria proliferate. At this same time, the cells
begin to express thermogenin, which causes the
tissue to increase the rate of mitochondrial respi-
Thermogenin enhances
ration and consequently heat production. BAT heat
mitochondrial proton leak
production is often called nonshivering thermo-
Mammals possess a unique way of generating heat genesis (NST); while the other pathways we have
in specialized deposits of brown adipose tissue discussed also differ from shivering, NST is a term
(BAT), typically located near the back and shoulder usually reserved for BAT-mediated thermogenesis.
region (Figure 18). The brown adipocytes differ In the absence of thermogenin, the processes of
from white adipocytes in important respects. They oxidation of reducing equivalents and phosphoryla-
have much higher levels of mitochondria and ex- tion of ATP are coupled by their shared dependence
press the gene encoding the protein thermogenin. on the proton motive force. When thermogenin is
inserted into the inner mitochondrial membrane, it
accentuates mitochondrial proton leak and dissi-
pates the proton motive force. Since oxidation is no
longer coupled to phosphorylation, thermogenin is
said to cause uncoupling. In the presence of ther-
mogenin, oxidation and proton pumping continue
at high rates but with low rates of ATP synthesis.
The way in which thermogenin induces uncou-
pling is not yet certain. One theory suggests that
Brown
adipose
thermogenin acts as a proton ionophore. It picks up
tissue protons from the cytoplasm and carries them into
(BAT) the mitochondria, dissipating the proton gradient.
An alternative theory suggests that thermogenin dis-
sipates the proton gradient by causing the futile cy-
cling of fatty acids. Thermogenin carries an ionized
fatty acid (R-COO⫺) from the mitochondrial side of
the inner membrane and flips it across the bilayer to
face the cytoplasm. Because of the higher proton
concentration (lower pH), the ionized fatty acid is
rapidly protonated (R-COOH). In this neutral form it
Brown
readily flops back into the inner leaflet of the bilayer,
adipocytes where it ionizes again. The complete “flip-flop” cycle
Arteriole causes a proton to be translocated across the inner
Mitochondria mitochondrial membrane. Still other explanations
Nucleus for UCP (uncoupling protein) function exist, and a
definitive model awaits further experimentation.
The thermogenic capacity of BAT has been
Venule known for decades, and the protein thermogenin
Figure 18 Brown adipose tissue in hamsters was first characterized in the early 1980s. It ap-
Hamsters possess thick pads of BAT behind the shoulders. pears only in mammals and is expressed only in
685
Thermal Physiology
BAT. However, in recent years it has become clear sensing neurons is received and interpreted by a
that thermogenin is only one member of a large thermostat within the central nervous system. The
gene family of uncoupling proteins (UCPs). In ad- central thermostat triggers the appropriate behav-
dition to thermogenin, also called UCP-1, mam- ioral and physiological response.
mals express at least two other UCPs (UCP-2 and
UCP-3). Both can increase mitochondrial proton
leak, but not enough to make a significant contri-
A central thermostat integrates central
bution to heat production. Instead of having a role
and peripheral thermosensory information
in thermogenesis, these UCPs appear to reduce Animals possess different types of neurons to sense
oxidative stress by preventing production of su- and respond to temperature. Temperatures are
peroxide anions by mitochondria. The UCP gene monitored peripherally and centrally by tempera-
family is ancient, with members in ectothermic ture-sensitive neurons, both cold sensing and warm
animals, such as fish, as well as plants, fungi, and sensing. Birds and mammals monitor temperature
protists. It is likely that thermogenin arose in the using similar neurons, although the location of the
mammalian lineage as a duplicated and then mu- central thermostat differs in the two taxa.
tated version of other UCPs. Mammals monitor TA by peripheral cold-
sensitive neurons located in the skin and the vis-
cera. When TA decreases, peripheral neurons send
Regulating Body Temperature signals to the hypothalamus (Figure 19). The pre-
Control of body temperature in endothermic ani- optic area of the anterior hypothalamus has both
mals requires coordination of multiple physiologi- cold-sensing and warm-sensing neurons that
cal systems. Animals must be able to monitor TB in monitor core body temperature. Information from
critical anatomical regions. By monitoring internal the peripheral and the central thermal sensors is
core TB, animals can assess their overall thermal integrated in the posterior hypothalamus, which
balance. Peripheral thermoreceptors allow ani- sends signals to the body to alter the rates of heat
mals to detect TA. The information from thermal
Vasoconstriction of
skin blood vessels BAT
38
37
36
Shivering
38
37
36
38
37
36 Panting
Vasodilation of skin Sweating

blood vessels
Figure 19 Hypothalamus and thermoregulation The hypothalamus is the thermal

control center of mammals. It interprets signals from peripheral and central thermosensitive
neurons and sends neuronal signals to other tissues, altering heat flux.
686
Thermal Physiology
production and dissipation. The hypothalamus is

much more responsive to information from the
central thermoreceptors than from the peripheral Guard hair
thermoreceptors. Changes of less than 1°C can ex-
cite central thermoreceptors, triggering a rapid Accessory hairs
hypothalamic response. Conversely, peripheral
Sebaceous
thermoreceptors may record and respond to a glands
change of several degrees without invoking a hy-
Epidermis
pothalamic response. Surface temperatures can
change by several degrees without harming the
animal, whereas the temperature of the central Erector
nervous system must be more stable. muscle
Bird TB regulation is less understood but is
clearly different from that of mammals. Heating or
cooling the hypothalamus has little effect on the
thermoregulatory response of birds. The central
thermostat in birds appears to be the spinal cord, Nerves
not the hypothalamus. However, the thermostat is
still responsible for integrating information from
central and peripheral thermosensors. When the
central thermostat detects changes in tempera-
ture, it responds by firing neurons that lead to a Subcutaneous fat
compensatory response. Both birds and mammals
alter TB by changing rates of heat production and Figure 20 Hair follicles A hair is produced by cells
heat dissipation. in the hair follicle. Erector muscles attached to the base of
the hair contract in response to neural stimulation, causing
the hair to become upright. Sebaceous glands secrete lipids
Piloerection reduces heat losses into the follicle ducts.
Earlier in this chapter we discussed how body cov-

erings, such as hair and feathers, act as insulation pit of the hair follicle is composed of epidermal
for endotherms. Since the efficiency of the insula- cells. Intimately associated with each hair follicle
tory layer depends on its thickness, animals can is a sebaceous gland, which releases complex se-
regulate heat loss by changing the orientation of cretions of lipid (squalene, wax esters, triglyc-
the hair (in mammals) or feathers (in birds). Birds eride, fatty acids) that form a protective coating on
(and mammals) get fluffier in the cold by forcing the hair and provide moisturization.
their feathers (and hair) to orient perpendicular to Tiny smooth muscles, called erector muscles,
the body surface. The mechanism by which this connect each hair follicle to the undersurface of the
orientation is controlled is best understood with epidermis. When the erector muscle contracts, the
mammalian hair, but the position of bird feathers hair is pulled perpendicular, a process termed pi-
is controlled in a similar way. loerection, so that the fur offers better insulation.
Hair itself is a collection of cells that possess The erector muscle contractility is regulated by
abundant keratin, an intermediate filament of the numerous factors, both bloodborne and neural in
cytoskeleton. The distal end of a hair is primarily origin. The situation is similar in birds, where
dead tissue, but the proximal end is composed of erector muscles also control the orientation of the
living cells embedded within the hair follicle. De- feathers.
pending on the species, a hair follicle can produce
either a single hair shaft or complex combinations
of hairs of various lengths and structures.
Changes in blood flow affect
Whereas human hair follicles produce single
thermal exchange
hairs, dog hair follicles produce a primary guard All animals exchange heat at the external surfaces of
hair and multiple secondary hairs—soft, fine hairs the body, but they are able to alter the effectiveness
that form the undercoat of the fur (Figure 20). The of surface heat exchange by changing the pattern of
687
Thermal Physiology
blood flow. Internal heat is equilibrated throughout ture of the skin, the greater the rate of heat loss. The
the body by the blood. Where blood vessels ap- changes in vascular smooth muscle tone are con-
proach the body surface, they will more readily lose trolled by the posterior hypothalamus.
heat. Similarly, increasing the flow of blood through Changes in blood flow through these capillary
the vessels increases the capacity for heat loss be- beds allow an endotherm to control heat ex-
cause it warms the surface of the skin, the site of heat change. The effects are perhaps most obvious in
loss by conduction, convection, and radiation. Caucasian humans, whose rapid changes in skin
The regulation of the amount of blood flowing color reflect subdermal blood flow. Exercise in-
into the vasculature is known as the vasomotor re- creases the core body temperature and triggers an
sponse (Figure 21). Directly under the skin are cap- increase in blood flow to the skin, causing it to turn
illary beds fed by subcutaneous arteries and red. Similarly, cold temperatures cause peripheral
drained by veins that empty into a network called vasoconstriction, reducing blood flow to the hands
the venous plexus. There is also direct exchange of and feet, causing them to turn white. Prolonged
some blood between the veins and arteries through restriction of blood flow can cause the extremities
connections called arteriovenous anastomoses, or to turn purple, as the blood pooled in the venous
metarterioles. At normal TB, the sympathetic ner- system is slowly deoxygenated.
vous system constricts the arterioles to reduce blood
flow. This tonic constriction is mediated by vascular
smooth muscle in response to ␣ adrenergic signals.
Countercurrent exchangers
When body temperature rises, there is a loss of tonic
in the vasculature help retain heat
constriction and arterioles dilate to allow more In addition to restricting blood flow to the periph-
blood into the skin vasculature. At the same time, ery, some animals are able to extract heat from
the blood vessels of the anastomoses constrict, forc- warmed blood and transfer it to cooler blood. This
ing more blood to move through the vessels near the is accomplished by arranging the vasculature into
skin. The large volume and high compliance of the countercurrent heat exchangers (see Box 4, Math-
venous system allows the blood to readily exchange ematical Underpinnings: Countercurrent Systems).
heat to the skin surface. The greater the tempera- The exact arrangement depends upon the animal
and tissue.
Because fish breathe water, any metabolic heat
Cold (low TA) Warm (high TA)
is rapidly lost across the gills. Some regionally het-
erothermic fish, discussed earlier in this chapter,
are active swimmers that produce abundant heat in
their red muscle. In tuna, veins leaving the red mus-
skin
cle are juxtaposed to the arteries that supply the red
Arteriole Arteriole muscle, allowing the transfer of myogenic heat from
(constricted) (dilated) the veins back to the arteries (Figure 22). This al-
AV shunt AV shunt lows red muscle to reach temperatures more than
(dilated) (constricted) 10°C warmer than other tissues, including white
muscle. Countercurrent heat exchangers are impor-
tant in other regionally heterothermic fish. Billfish
possess a modified eye muscle, called a heater or-
gan, that warms the eye and optical nerves. Coun-
tercurrent heat exchangers help retain heat in the
Artery Vein Artery Vein optical system. Many large fish, such as bluefin
Figure 21 Skin vasculature When blood travels tuna, use countercurrent heat exchangers in the
close to the surface of the animal, heat is lost across the gastrointestinal tract to retain the heat of digestion.
skin. When temperatures are cold (left), blood is diverted Countercurrent heat exchangers are used by
from the skin through arteriovenous (AV) shunts, called endotherms to reduce heat loss at the periphery.
arteriovenous anastomoses, reducing heat loss. When an
Birds standing on cold surfaces, such as ice, can lose
animal is in a hot environment, shunts are constricted and
blood moves through the vessels closer to the skin surface, a great deal of heat through the feet (Figure 23).
enhancing heat loss.
688
Thermal Physiology

Countercurrent Systems
Many physiological processes depend on are required to transfer the entities between proximal
countercurrent systems—a marriage of struc- and distal regions. The loop of Henle of the kidney
tural and functional features that improves the effi- tubule is part of a countercurrent multiplier. The gradi-
ciency of exchange processes. Consider a scenario in ents set up within the medulla result from active trans-
which a tube drains a tank of hot water. As the water port of ions, and the resulting transfer of water. Because
flows through the tube, heat is dissipated to the sur- a countercurrent multiplier requires transporters, it re-
rounding environment, which in this example is the air. quires metabolic energy to create and maintain the gra-
At some point along the length of the tube (if it is long dient. If flow through the tube ceases, or ion pumping is
enough), the water reaches ambient temperature. How- reduced, the gradient can collapse. The efficiency of the
ever, the tube can be rearranged to reduce the magni- countercurrent multiplier also depends on the length of
tude of heat loss. Imagine what would happen to heat the proximal and distal arms of the system that gener-
exchange if you were to align the lower (distal) end of the ate the gradient.
tube alongside the upper (proximal) end, creating a
hairpin structure. Water flowing through one segment
would run in the opposite direction of the water in the
other segment. With this arrangement, some of the
Hot Hot
heat lost from the proximal segment is gained by the
distal segment. Instead of a gradient from one end to
the other, a thermal gradient forms along the length of
Warm
the hairpin loop, coolest at the turn and warmest near
the top. This is the basis of a countercurrent system.
The longer the hairpin loop, the greater the gradients
that can be built. Some researchers distinguish be-
tween two types of countercurrent systems: exchangers
and multipliers.
Countercurrent exchangers transfer entities between
inflow and outflow using only passive processes. The
countercurrent heat exchanger, described above, is an
example of such an exchanger; no specific transporter
or pathway mediates the transfer of the entity (heat),
and the gradient is due to the physical arrangement of
the plumbing. The efficiency of the countercurrent ex-
changer depends on the volume of flow through the
tubes and the overall gradients along the length of the Cold
hairpin. Without counter- With counter-
Countercurrent multipliers are like exchangers in current exchange current exchange
most respects except that specific transport proteins
They can reduce heat loss by restricting blood flow Sweating reduces body temperature
to the periphery, but over long periods this would by evaporative cooling
cause the peripheral tissues to starve. Countercur- Small animals have a favorable ratio of surface area
rent heat exchangers transfer heat from arteries to volume for heat loss, so evaporative cooling is
emerging from the body core to veins returning used primarily by large animals. Many larger ani-
from the cold periphery. Warming of the venous mals use specialized skin fluid secretions (sweat) to
blood lessens the impact of the peripheral cooling. enhance evaporative cooling. Humans are probably
Also, cooling the arterial blood decreases the ther- the smallest animals that effectively use sweating to
mal gradient across the skin and therefore reduces cool their bodies. Sweat is a mixture of water, salts,
heat loss. and some oils. The salt in sweat raises the boiling
689
Thermal Physiology
Spinal cord Venule

Arteriole
Spine
Direction of
Rete blood flow
Dorsal aorta
Postcardial
vein Red muscle Cutaneous Red muscle
veins
Cutaneous
arteries
Figure 22 Countercurrent heat exchangers in tuna smaller lateral vessels run over the surface of the red muscle,
muscle Each heterothermic scombrid species relies on with branches penetrating the muscle. (b) These lateral
different combinations and numbers of retes to retain heat. (a) vessels are arranged in a countercurrent manner, with lateral
Red muscle of bluefin tuna is served by cutaneous arteries and venules transferring myogenic heat to lateral arterioles.
veins that run beneath the skin. From these main vessels, (Source: Part (a) modified from Carey, 1973)
point of water, making evaporative cooling more sympathetic nerves that control the activity of
efficient. Loss of water and salts can affect ion and sweat glands.
osmoregulation, but animals exposed to hot
weather for long periods can change the chemical
composition of their sweat to minimize ionic and
Panting increases heat loss across the
osmotic problems. They produce a larger volume
respiratory surface
of sweat with a lower NaCl content, preserving vi- Another way animals lose heat is through ventila-
tal salts. Sweating is controlled by the anterior hy- tion. The properties that make a respiratory sur-
pothalamus and triggered by activation of the face good at gas exchange—high vascularity, moist
surfaces, and high airflow—also en-
hance heat loss. Whether respiratory
heat loss is beneficial or detrimental
Blood flow depends on the situation. In the cold,
32°C birds and mammals minimize heat
loss from respiration, but at high TA,
animals may alter their breathing
pattern to accentuate heat loss.
Artery Cooling through ventilation is a
strategy that must balance respira-
Vein
tory demands with thermoregula-
tion. Cooling is enhanced when
1°C animals increase ventilation fre-
quency while reducing tidal volume.
Shallow, rapid breathing is a sign
that an animal may be overheated.
Gular fluttering is a cooling behav-
ior seen in birds, characterized by
rapid contraction and relaxation of
Figure 23 Peripheral vasoconstriction in cold endotherms Birds
standing on cold surfaces can alter the flow of blood into the feet, reducing heat loss.
the throat muscles. Mammals pant.
The blood vessels of the leg and foot are arranged in parallel, allowing the formation Each of these behaviors cools the
of a countercurrent heat exchanger. animal multiple ways. First, rapid
690
Thermal Physiology
ventilation increases the heat loss Nasal (40/min)

across the respiratory surface by
convection. Second, and perhaps In
more important, the rapid ventila- Out
tion causes water to evaporate from
Airflow
the surface of the airway, from the
pulmonary surface to the tongue. An-
Mouth
imals that rely on ventilatory cooling
often possess well-vascularized res- In
piratory surfaces that are kept wet Out
through secretions. These ventila-
tory patterns could alter the nature
Time
of the blood gas profile, impinging on
(a) Low temperature
respiratory physiology. The increase
in ventilation frequency is offset in
part by a reduction in tidal volume.
Nasal
Reindeer provide a good exam-
ple of the links between respiration In
and thermoregulation. Although Out
they live in the cold, reindeer are at
Airflow
risk of heat stress because of their

large size and thick layer of fur insu-
Mouth (~200/min)
lation. At normal cold temperatures
(10°C), a reindeer breathes through In
its nose at low frequency. The upper Out
part of the nasal cavity is rich in cap-
illaries, and nasal respiration helps
Time
cool the nearby brain regions. When
a reindeer becomes too warm, it (b) High temperature
shifts its respiratory pattern. Breath- Figure 24 Heat loss during panting Like other mammals, reindeer alter
ing frequency increases, and the an- breathing to increase heat loss. Reindeer breathe through the nose at low
imal begins to pant through the temperatures. The flow of air cools the blood circulating through the vessels that line
the nasal cavity. When temperatures increase, reindeer breathe through the mouth
mouth (Figure 24). Although this
and at a faster rate (200–300 breaths per minute).
change in breathing pattern may re- (Source: Aas-Hansen et al., 2000)
duce direct cooling of the brain, it re-
duces body core temperature more
efficiently. called relaxed endothermy. The time course and
magnitude of reduction in TB differ among animals
and types of dormancy (Figure 25). An arctic
Relaxed endothermy results squirrel, for example, can allow TB to fall close to
in hypometabolic states the freezing point. However, even minor reduc-
In your course, you have encountered various tions in TB can offer important energetic savings
forms of hypometabolism used by endotherms to for a dormant animal.
survive adverse conditions. Hummingbirds, for Under normal (euthermic) conditions, mam-
example, undergo a nightly reduction in metabolic mals and birds maintain TB within a narrow
rates. Hibernating mammals also undergo a meta- range. A euthermic animal induces a compensa-
bolic suppression during the long, cold winter tory response when its central thermostat—the
months when food is scarce. Whether a daily dor- hypothalamus in mammals—senses a decrease in
mancy (torpor) or a more prolonged seasonal dor- TB. During periods of relaxed endothermy, the an-
mancy (hibernation), the hypometabolic phase is imal recalibrates its central thermostat to recog-
accompanied by a decrease in TB, a phenomenon nize and defend a different TB set point. The
691
Thermal Physiology
5 35
endothermic animal may allow TB to fall close to
TA, well below the euthermic set point.
(O2 uptake in ml/g per h)
Body temperature (°C)

4 30 The links between metabolism and TB regula-
TB
Metabolic rate
tion make it difficult to establish which parameter

3 25
Metabolic rate causes hypometabolic cooling. For most animals
2
entering dormancy, TB and metabolic rate decline
20
in parallel, and it is not clear if the colder TB slows
1 15 metabolism, or alternately if the slower metabolic
heat production causes cooling. In some studies,
0 10 animals show a reduction in metabolic rate be-
0 1 2 3 4
Time (months)
fore TB declines, suggesting that hypometabo-
lism initiates the reduction in TB. However, in
(a) Hibernation
larger animals a delay in cooling upon entering
dormancy is due in part to thermal inertia; the
36 large mass and low ratio of surface area to vol-
(O2 uptake in ml/g per h)
2 34 Body temperature (°C) ume delay the impact of reduced thermogenesis,

allowing the animal to remain much warmer
Metabolic rate
32 than TA even with a reduced metabolic rate.
1 30
28 2 C O N C EP T CH E CK
0 20 8. How do endotherms generate heat?
0 6 12 18
9. What regions of the body detect and respond to
Time (hours)
changes in temperature?
(b) Torpor 10. What are the various types of hypometabolism?
Figure 25 Hypometabolic states Many 11. How do animals control heat flux across the
endotherms respond to cold temperatures by entering external body surface?
some form of dormancy. Body temperature generally
declines in parallel with metabolic rate. The dormancy is
called (a) hibernation when the metabolic depression lasts
for weeks to months or (b) torpor when the animal enters a
hypometabolic state in daily cycles.
Integrating Systems Immune System and Thermoregulation

Deviations from optimum TB usually impair physiological processes (2–5). For these processes, an increase of
functions, but in some cases endotherms can induce hy- 2–3°C in regional or systemic temperature would have a
perthermia as part of the defense against pathogens. The relatively minor beneficial effect. However, some aspects
cellular and noncellular defense pathways are collec- of immune function demonstrate Q10 values ranging from
tively called the immune response (Figure 26). When a 100 to 1000 and would be profoundly enhanced by the de-
pathogen mounts a localized attack, such as at the site of gree of hyperthermia seen in inflammation and fever.
a cut, the immune response includes an elevation in tem- Recall that blood carries T lymphocytes as part of the
perature in that region: inflammation. A broad systemic adaptive immune system. When pathogens are present,
pathogen attack induces a more elaborate immune re- some T lymphocytes undergo a maturation process that
sponse, which includes an increase in body core temper- enables them to become cytotoxic T cells. With a Q10 in
ature: a fever. Whether arising from inflammation or a excess of 100, this maturation step is acutely sensitive to
fever, the hyperthermic response serves to improve the temperature. The hyperthermia arising from an immune
ability of the animal to combat the pathogen. Most im- response reflects a remarkable coordination between
munological processes, such as the rate of movement of cellular signaling pathways, cardiovascular changes, and
or ingestion by phagocytotic immune cells, have Q10 val- central control of body temperature.
ues within the range for other cellular and biochemical
692
Thermal Physiology
Pathogen
Infection
Macrophage
Cytokine production
Paracrine Endocrine
Blood vessels Interleukin 1 BBB
Vasodilation Permeability
Arterioles Capillaries Immune cells Capillaries
Temperature Edema Prostaglandin E2
Thermal set point
Blood flow Immune cell migration Hypothalamus
Blood vessels BAT Muscle
Vasoconstriction NST Shivering
Core temperature
Figure 26 Fever
Inflammation is a localized response to the pres- through the capillary beds. Since many of the surface tis-
ence of something that activates the immune system. sues are cooler than body core temperature, the in-
Consider what happens when a virus invades your respi- crease in blood flow may elevate skin by as much as
ratory epithelium. The virus must first pass through the 10°C. The cytokines also alter the permeability of the
physical barriers that separate your respiratory tissues capillary beds, allowing immune cells in the blood to
from the environment. The mucus secreted from exo- squeeze between endothelial cells and enter the inter-
crine cells in the respiratory epithelium reduces the pas- stitial fluids. The main features of inflammation are at-
sive water loss but also acts as a barrier to external tributable to the changes in the vasculature: redness and
viruses, bacteria, and particulates. If the virus passes warmth due to increased blood flow, swelling (edema)
through the mucus, it must be able to enter living epithe- due to fluids moving from the main circulation through
lial cells to propagate. The epithelium of the respiratory more permeable capillaries into the interstitial fluid.
tract is thinner than that of the skin, the stratum If a regional infection spreads, or the infection oc-
corneum, making it more vulnerable to viral attack. If the curs systemically, the animal mounts a more elaborate
virus enters an epithelial cell, it will take over the normal immune response that includes an increase in body
cellular protein synthetic machinery and cause the cell temperature: a fever. The body detects the presence of
to produce the viral proteins needed for viral replication. a pathogen when cells of the immune system bind spe-
After a time, the cell may lyse, releasing additional viral cific pathogen macromolecules, called exogenous pyro-
particles. During this stage, infected and damaged gens. The most common exogenous pyrogens from
cells release a number of factors (cytokines and bacterial infections are lipopolysaccharides, proteogly-
prostaglandins) that alter cellular processes within the cans, and proteins, such as endotoxin. Recall that
region. Though it doesn’t affect the virus directly, mucus macrophages phagocytose pathogenic bacteria. When a
cells enhance secretions to bolster the physical barriers macrophage consumes bacteria, the bacterial macro-
to reduce the likelihood of further infection. Recall that molecules cause the macrophage to secrete cytokines,
cytokines, such as interleukin 1, also signal the local vas- such as interleukin 1. In addition to the local pro-inflam-
culature, altering blood flow regionally. Through va- matory effects, interleukin works as an endogenous
sodilatory effects on arterioles, more blood flows pyrogen. It causes other cells to synthesize
693
Thermal Physiology
another factor—a mediator—that exerts its effects on conservation. Though the neurocircuitry remains un-
the brain. For example, interleukin 1 induces many cell clear, a fever also stimulates shivering thermogenesis.
types in the periphery and in the vasculature of the brain Sympathetic neuronal activity stimulates thermogene-
to synthesize prostaglandin E2. It is not yet clear how sis in brown adipose tissue and vasoconstriction in cu-
this mediator crosses the blood-brain barrier (BBB)—it taneous vasculature.
may be through synthesis and secretion by the endothe- Since this immune response works by increasing
lial cells, or transport across the capillary endothelium— TB, it would seem to be practical only in animals that can
but once across the BBB, prostaglandin E2 binds to retain body heat. Indeed, this aspect of immunity is best
neurons of the hypothalamus, where it alters the neuro- developed in endothermic animals, primarily birds and
circuits that integrate peripheral and central thermal mammals. However, ectothermic vertebrates and many
information. The pyrogenic mediator reduces the firing invertebrates show a behavioral fever in response to
frequency of warm-sensitive neurons and increases pathogens. If a lizard is infected with bacteria or in-
the firing frequency of cold-sensitive neurons. Thus, jected with an exogenous pyrogen, it demonstrates an
the pyrogenic mediator causes the hypothalamus to increase in its preferred TB, moving into a warmer envi-
misinterpret the central and afferent thermal informa- ronment. Thus, the benefit effect of hyperthermia in the
tion, and as a result the brain perceives that the body is immune response is likely a very ancient trait, though
too cool. This triggers a range of compensatory re- the mechanisms by which body temperature is elevated
sponses that increase the rate of heat production and differ among lineages. 2
Summary
Heat Exchange and Thermal Strategies k Poikilotherm TB changes with environmental
k All animals are subject to the physical laws that conditions, whereas homeotherm TB remains
govern heat fluxes, although the effects on en- nearly constant.
dotherms have a greater impact on their physi-
k Ectotherm TB is determined by environmental
ology. Animals that live in water lose heat more
conditions, whereas endotherm TB is determined
readily than those that live in air, because wa-
by metabolic heat production and conservation.
ter has a higher thermal conductivity.
k Heterotherms exhibit combinations of en-
k Although heat production is a function of body
dothermy and ectothermy. Temporal het-
mass, heat exchange depends on body surface
erotherms are typically endothermic for most of
area. Consequently, an animal’s ratio of surface
their lives, but undergo periods of hypothermia,
area to volume has an important impact on
such as in hibernation or torpor. Regional het-
thermoregulation.
erotherms are able to warm regions of the body
k External insulation, such as feathers and hair, cre- above ambient temperature (TA).
ates a dead space that reduces the thermal gradi-
k Endotherms have a thermoneutral zone—a
ent between the animal and the environment.
range of temperatures at which physiological
k Movement of fluids, such as air and water, in- functions are optimal. Outside this temperature
creases the rate of convective heat loss. range, the metabolic costs are greater and ani-
mal function suffers.
k Thermal radiation is an important source of
heat for animals, derived directly from the sun k Thermal effects in ectotherms are influenced by
and also from an animal’s surroundings. Many thermal history
animals can absorb thermal energy from solar
k Eurytherms tolerate a wide TA range, whereas
radiation by basking, often aided by dark col-
stenotherms survive in a narrow TA range.
oration. Many animals employ evaporative
cooling to reduce overheating.
694
Thermal Physiology
Coping with a Changing Body Temperature k Heat is a natural consequence of metabolism,

k Changes in TA have greater consequences for but endotherms have higher metabolic rates
ectotherms than for endotherms, altering many than ectotherms of similar size. Greater mem-
aspects of macromolecular structure and me- brane leakiness is one reason why endotherms
tabolism. Temperature alters membrane fluid- have high metabolic rates.
ity, which animals can mitigate by altering the
k Endotherms use neural systems to detect exter-
fatty acid chain length, saturation, phospholipid
nal and internal temperatures. The mammalian
profile, and cholesterol content.
hypothalamus integrates central and periph-
k Temperature also changes the rates of chemical eral thermal sensory information to cause phys-
reactions, and consequently metabolic rate. It also iological systems to alter heat production and
affects protein structure and enzyme kinetics. retention.
When proteins undergo thermal denaturation,
k Peripheral cold-sensitive neurons trigger
the genes for stress proteins are induced. These
changes in the orientation of hair, or piloerec-
proteins help refold damaged proteins and target
tion, to reduce heat loss.
irreversibly damaged proteins for degradation.
k Nerves and hormones also control the blood
k Ectotherms living in cold environments often
flow to the skin surface to regulate the rate of
remodel their physiological systems to compen-
heat loss.
sate for the effects of temperature. Animals that
have lived for long periods in extreme cold of- k Vasculature may be arranged into countercur-
ten possess cold-adapted proteins. rent exchangers to help retain heat within the
body core.
k Many animals are able to survive freezing tem-
peratures. The greatest risk is the uncontrolled k Overheated large mammals use sweating to en-
formation of ice crystals, which can induce os- hance evaporative cooling, whereas smaller
motic stress and can physically damage cellular mammals shed heat by panting.
membranes.
k Some endotherms can undergo short periods of
k Freeze-tolerant animals use ice nucleators to metabolic suppression, during which body tem-
control ice crystal growth. Freeze-avoiding ani- peratures decrease, although rarely to the point
mals produce antifreeze proteins that prevent where the temperature matches the ambient tem-
intracellular ice formation. perature. During relaxed endothermy, an animal
resets its central thermostat to a new set point.
Maintaining a Constant Body Temperature
k Endothermic animals produce metabolic heat
and retain it to elevate body temperature above
the ambient temperature.
Review Questions
1. Compare and contrast the following terms: 5. Discuss the different sources of energy an ec-
homeothermy and poikilothermy; endothermy totherm can use to raise TB.
and ectothermy; regional heterothermy and 6. What behaviors reduce heat losses due to
temporal heterothermy. (a) conduction; (b) convection?
2. Water at 10°C feels colder than air at 10°C. 7. How do we know that antifreeze proteins
Why? arose several times in evolution?
3. Why are antifreeze proteins found in marine 8. How do countercurrent heat exchangers work?
fish but not freshwater fish?
4. Compare and contrast the mechanisms of
thermogenesis. Which biochemical steps are
responsible for heat production?
695
Thermal Physiology
Synthesis Questions
1. Compare the effects of high and low tempera- 7. What gene regulatory changes must have ac-
ture on molecules, cells, tissues and organisms. companied the evolution of brown adipose
2. How could you convert a stenothermal animal tissue?
to a eurythermal animal? 8. Animal color influences many aspects of phys-
3. Summarize the physiological changes that ac- iology and ecology. Identify some examples of
company thermal acclimation. animals whose color patterns are consistent
with a role in thermoregulation.
4. Why do endothermic animals need both pe-
ripheral and central temperature-sensitive 9. Many mammals grow coats that differ in win-
neurons? ter and summer. What factors affect the costs
and benefits of seasonal shedding?
5. Thermoregulation requires active control of
blood flow through vessels. How do animals 10. Compare and contrast the structures of hair
dilate some blood vessels while constricting and feathers.
others?
6. What would you expect to happen to blood
pressure when a mammal is exposed to cold
temperatures?
1. The metabolic rate of a fish heart is studied at ing ATP level was 5 ␮mol/g tissue. Calculate
various temperatures. The metabolic rate is the change in ATP levels over time that would
20 ␮mol ATP per min per g tissue at 25°C, result if the animal were moved to an environ-
8 ␮mol ATP per min per g tissue at 10°C, ment that caused a 10°C increase in TB.
4 ␮mol ATP per min per g tissue at 5°C, and 3. Recall the Stefan-Boltzmann equation, P ⫽
1 ␮mol ATP per min per g tissue at 2°C. Cal- Aeσ(TB4 ⫺TA4) , where P is the radiating power,
culate the Q10 values over this range of tem- A is its surface area, e is the ability of the ob-
peratures and offer an explanation for the ject to emit radiation, σ is the Stefan constant,
patterns. and T is the temperature of the body (TB) or
2. The levels of ATP are maintained through a surroundings (TA) in kelvins. Consider an ani-
balance between the rates of ATP synthesis mal that uses a strategy of changing posture to
and ATP utilization. For a given tissue (e.g., alter the surface area as a way of controlling
heart) at a given TB (e.g., 15°C), assume that heat loss. It assumes a particular posture
(a) the rates of ATP synthesis and utilization when it is in an environment that is 5°C below
are both 10 ␮mol/min/g, (b) the rate of ATP its body temperature. How does it need to
synthesis exhibits a Q10 ⫽ 2, (c) the rate of ATP change its surface area when it moves to a
utilization has a Q10 ⫽ 2.05, and (d) the start- new environment that is 20°C cooler?
For Further Reading

See the Additional References section at the end This seminal paper uses a quantitative
of the chapter for more readings related to the biophysical approach to describe how energy
topics in this chapter. exchange between animals and the environment
governs the thermal biology of the animal.
Heat Exchange and Thermal Strategies Porter, W. P., and D. M. Gates. 1969.
An interesting book, written for a lay audience, Thermodynamic equilibria of animals with
that discusses the role of energy in biology. environment. Ecological Monographs 39:
Brown, G. 1999. The energy of life. London: 227–244.
HarperCollins.
696
Thermal Physiology
Much of thermal biology focuses on vertebrates, Willmer, P., G. Stone, and I. A. Johnston. 2000.
and the insects are often understudied. Environmental physiology of animals. Oxford:
Heinrich’s book reminds us of the many thermal Blackwell Science.
strategies employed by insects.
Heinrich, B. 1992. The hot-blooded insects.
Cambridge, MA: Harvard University Press.
Maintaining a Constant Body Temperature
This book discusses the impact of changes in This book considers the regulatory mechanisms
temperature on macromolecular structure and animals use to modify metabolic rate. For most
biochemical processes. animals, this involves a reduction in body
Hochachka, P. W., and G. N. Somero. 2002. temperature.
Biochemical adaptation. Oxford: Oxford Hochachka, P. W., and M. Guppy. 1987.
University Press. Metabolic arrest and the control of biological
time. Oxford: Oxford University Press.
These papers discuss the peculiarities of animals
that live in the extreme cold, and consider This paper discusses recent studies on how the
whether the data on metabolic rate of these hypothalamus senses and responds to thermal
animals support the notion of metabolic cold conditions.
adaptation.
DiMicco, J. A., and D. V. Zaretsky. 2007. The
Steffensen, J. F. 2002. Metabolic cold adaptation dorsomedial hypothalamus: A new player in
of polar fish based on measurements of thermoregulation. American Journal of
aerobic oxygen consumption: Fact or artefact? Physiology: Regulatory, Integrative, and
Artefact! Comparative Biochemistry and Comparative Physiology 292: R47–R63
Physiology, Part A: Molecular and Integrative
Physiology 132: 789–795. These papers consider the evolutionary origins of
Various authors. 2002. Coping with the cold: hyperthermia and how hyperthermia in fever
Molecular and structural biology of cold stress and inflammation may accentuate the immune
survivors, D. J. Bowles, P. J. Lillford, D. A. response.
Rees, and I. A. Shanks, eds. Philosophical Kluger, M. J., W. Kozak, C. A. Conn, L. R. Leon,
Transactions of the Royal Society of London, and D. Soszynski. 1998. Role of fever in
Series B: Biological Sciences 357: 829–956. disease. Annals of the New York Academy of
Sciences 856: 224–233.
This textbook considers how the environment
Hanson, D. F. 1997. Fever, temperature, and the
influences physiological processes. The sections
immune response. Annals of the New York
on thermal biology are particularly useful.
Academy of Sciences 813: 453–464.
Aas-Hansen, O., L. P. Folkow, and A. S. Blix. 2000. Panting in Feder, M. E., and G. E. Hofmann. 1999. Heat-shock proteins,
reindeer (Rangifer tarandus). American Journal of molecular chaperones, and the stress response:
Physiology: Regulatory, Integrative, and Comparative Evolutionary and ecological physiology. Annual Review of
Physiology 279: R1190–R1195. Physiology 61: 243–282.
Boutiler, R. G., and J. St-Pierre. 2000. Surviving hypoxia Hand, S. C. 1991. Metabolic dormancy in aquatic
without really dying. Comparative Biochemistry and invertebrates. Advances in Comparative and
Physiology, Part A: Molecular and Integrative Physiology Environmental Physiology 8: 1–50.
126: 481–490. Harrison, J. E., J. H. Fewell, S. P. Roberts, and H. G. Hall.
Carey, F. G. 1973. Fishes with warm bodies. Scientific 1996. Achievement of thermal stability by varying
American 228: 36–44. metabolic heat production in flying honeybees. Science
Davies, P. L., J. Baardsnes, M. J. Kuiper, and V. K. Walker. 274: 88–90.
2002. Structure and function of antifreeze proteins. Heinrich, B. 1987. Thermoregulation in winter moths.
Philosophical Transactions of the Royal Society of London, Scientific American March 1987.
Series B: Biological Sciences 357: 927–935. Helmuth, B., J. G. Kingsolver, and
DiMicco, J. A., and D. V. Zaretsky. 2007. The dorsomedial E. Carrington. 2005. Biophysics, physiological ecology,
hypothalamus: A new player in thermoregulation. and climate change: Does mechanism matter? Annual
American Journal of Physiology: Regulatory, Integrative, Review of Physiology 67: 177–201.
and Comparative Physiology. 292: R47–R63
697
Thermal Physiology
Hochachka, P. W. 1986. Defense strategies against hypoxia Rolfe, D. F. S., and G. C. Brown. 1997. Cellular energy
and hypothermia. Science 231: 234–241. utilization and molecular origin of standard metabolic rate
Hochachka, P. W., P. L. Lutz, T. J. Sick, and M. Rosenthal. in mammals. Physiological Review 77: 731–758.
1993. Surviving hypoxia: Mechanisms of control and Scholander, P. F., V. Walters, R. Hock, and L. Irving. 1950.
adaptation. Boca Raton, FL: CRC Press. Body insulation of some arctic and tropical mammals and
Klingenberg, M., and K. S. Echtay. 2001. Uncoupling proteins: birds. Biological Bulletin 99: 225–236.
The issues from a biochemist point of view. Biochimica et Schulte, P. M., H. C. Glemet, A. A. Fiebig, and D. A. Powers.
Biophysica Acta–Bioenergetics 1504: 128–143. 2000. Adaptive variation in lactate dehydrogenase-␤ gene
Knight, M. R. 2002. Signal transduction leading to low- expression: Role of a stress-responsive regulatory element.
temperature tolerance in Arabidopsis thaliana. Proceedings of the National Academy of Sciences, USA 97:
Philosophical Transactions of the Royal Society of London, 6597–6602.
Series B: Biological Sciences 357: 871–875. Storz, G. 1999. An RNA thermometer. Genes and
Logue, J. A., A. L. de Vries, E. Fodor, Development 13: 633–636.
A. R. Cossins. 2000. Lipid compositional correlates of Sullivan, J. P., S. E. Fahrbach, J. F. Harrison, E. A. Capaldi, J.
temperature-adaptive interspecific differences in H. Fewell, and G. E. Robinson. 2003. Juvenile hormone
membrane physical structure. Journal of Experimental and division of labor in honey bee colonies: Effects of
Biology 203: 2105–2015. allatectomy on flight behavior and metabolism. Journal of
Reinertse, R. E., and S. Haftorn, 1986. Different metabolic Experimental Biology 206: 2287–2296.
strategies of northern birds for nocturnal survival. Journal
of Comparative Physiology, Part B: Biochemical, Systemic,
and Environmental Physiology 156: 655–663.
Credits
624 Bruce Coleman Inc., Scott Nielsen/Bruce Coleman Inc.
625 Dorling Kindersley.
625 Getty Images, O. Louis Mazzatenta/National
Geographics/Getty Images.
629 Photo courtesy of Dr. Brian Helmuth, University of South
Carolina.
630 Photo Researchers, Inc., Gregory G. Dimijian M.D./Photo
Researchers, Inc.
698
699
Reproduction
Evolutionary biologists use the term life history strategy to reproducing, some animals continue to divert energy to-
describe the pattern of growth, behavior, and reproduction ward care of their offspring. Every animal has evolved a
an animal displays over its lifetime. Variations in life his- balance among competing physiological demands in order
tory strategy are interpreted in the context of reproductive to invest maximally in reproduction at some point in its life.
success, the currency of evolution. These elements of a life The life history patterns that emerge are heavily influenced
history strategy are interrelated through physiology. First, by environmental predictability and resource availability.
the animal regulates physiological processes throughout Life history strategies evolve in ways that maximize repro-
its life to ensure that it will be able to reproduce. Second, ductive output given the constraints of the environment.
reproduction itself is a physiological process that impinges Ecologists broadly classify life history strategies as
on other physiological systems. Any specific element of a K-type and r-type. K-type strategists are specialized to
reproductive strategy—such as age of maturity, fecundity, produce relatively few offspring but invest heavily in their
and juvenile survival—has a physiological basis; evolution- development. They often delay reproduction until late in life,
ary trade-offs are often expressed in physiological terms, accumulating resources until they are capable of producing
such as growth rate, size, or metabolic costs. large, healthy offspring. Delaying reproduction ensures
A nonreproductive animal gathers nutrients for that these animals are strong enough to tolerate the costs
growth and maintenance, storing excess nutrients in fuel of nurturing the young, often for extended periods. Parental
depots. Later in life, the animal enters a transition period care may be essential in environments where conditions
where its physiological priorities shift toward building ga- are so harsh that the offspring might not otherwise survive.
metogenic tissues and preparing for reproduction. After Humans are perhaps the most familiar example of this life
700
Reproduction
Salmon eggs.
history pattern, but other animals produce relatively few,

large offspring and provide abundant parental care. For ex-
ample, the kiwi produces one egg that occupies most of its
internal space, constituting almost 20% of its body weight.
This bird’s egg is almost six times larger than the eggs of
other birds of comparable size. To support the growth of the
egg, the female increases food consumption about three-
fold. Later in development, the egg is so large that it com-
presses the stomach, preventing the female from eating.
An r-type strategist reproduces as rapidly as possible,
produces a great many offspring, and typically provides little
or no parental care. Insects exemplify r-type strategies. Sitkas.
Some—such as locusts—can reproduce so quickly that they

give the impression of arising spontaneously and grow to
such numbers that they qualify as a plague, threatening to year, when the offspring are unlikely to survive, it can have
wipe out all vegetation over huge swaths of land. Of course, another chance at more successful reproduction in a sub-
few animals clearly fall into one of these two strategies. Rab- sequent reproductive bout.
bits and hamsters reproduce at a relatively young age and On the surface, these two strategies—semelparity and
produce large litters (both features of an r-type strategy), but iteroparity—would seem to require quite different physiolog-
they also invest heavily in their young (a K-type strategy). ical systems. Surprisingly, there are examples of related an-
We can also describe life history strategies on the ba- imals exhibiting completely different strategies. Consider the
sis of how an animal apportions its reproductive effort over salmonid fish. Atlantic salmon are iteroparous and capable
its lifetime. A semelparous species spends most of its life of repeated spawning for several years. Pacific salmon are
accumulating resources, preparing for a single burst of re- generally semelparous, breeding once and then dying. How-
productive output into which it allocates all of its available ever, when Pacific species become landlocked, the popula-
energy, and then dies shortly thereafter, having withheld tion makes an evolutionary transition to an iteroparous
no energy for its own survival. In contrast, an iteroparous strategy and the fish become repeat spawners. Since closely
animal can undergo multiple reproductive cycles. When it related animals are so similar in genotype, the ability to ex-
reproduces, it retains enough energy to ensure its survival, hibit radically different life history strategies depends on the
presenting the possibility of reproducing again. If an indi- way the physiological phenotype is regulated, largely by com-
vidual happens to reach reproductive maturity in a bad plex hormonal controls on development and reproduction. 2
701
Reproduction
Overview Spermatozoa
The life cycle of an animal begins with a single cell, Ovum

which divides repeatedly through multicellular
stages (zygote, blastula, and gastrula) that differen- Fertilization
tiate to form tissues (morphogenesis). Juvenile
forms then undergo further development to reach
reproductive maturity (Figure 1). The reproductive Zygote
(2-cell stage)
traits of the individual are usually established in
embryonic development, with the acquisition of the Cell division
primary sex characteristics: the gonads. These
multicellular tissues include cells that produce the
gametes as well as somatic tissues that support Blastula
gamete production (gametogenesis). The gonads
develop in combination with other physiological
Gastrulation
and behavioral systems in preparation for mating.
Mating behavior may be linked to environmental
conditions and often follows complex courtship
Gastrula
rituals. Animals then release the gametes—ova or Gametogenesis
spermatozoa—when the chances for successful fer-
tilization are maximized. Spermatozoa, or sperm
Morphogenesis
for short, face many challenges. They must find the
ovum in a complex environment and outcompete
other sperm to be the one that fertilizes the ovum.
After fertilization, the embryo grows under the con- Larva
trol of its unique genome, a mosaic of its parents.
All of the elements of sexual reproduction—sex de-
termination, gametogenesis, mating, fertilization, Metamorphosis
and development—depend on the coordination of
cellular processes in multiple tissues. The responsi-
bility for coordination of these processes falls upon
the endocrine hormones.
Juvenile
Diversity in life histories is remarkable given (nonreproductive)
the relative similarity in hormones, cell signaling,
and gametogenesis. In the next section, we survey
the basic features of reproductive physiology, con- Reproductive
sidering modes of reproduction, hormones, game- development
togenesis, and reproductive anatomy. In the final Adult

section, we focus in greater detail on the reproduc- (reproductive)
tive physiology of mammals, through ovulation,
gestation, parturition and postpartum care, em-
phasizing the role of hormones.
Senescence
and death
Sexual Reproduction Postreproductive
adult
Let’s begin by considering the aspects of reproduc-

tion that are common to most animals. Long before
the animals appeared on the scene, the early eu-
karyotes (for example, the protists) had already
evolved a capacity for sexual reproduction. As Frank Figure 1 Animal life cycle This generalized life cycle
Sinatra once sang, “birds do it, bees do it,” but so do highlights the developmental stages seen in most animals.
702
Reproduction
fungi and plants, although the process may not be as metes (ova). Gametogenesis occurs through meiosis,
song-worthy. The essence of sexual reproduction is although there are important distinctions between
the generation of offspring from two parents, each of spermatozoa production (spermatogenesis) and
which contributes a nearly equal amount of genetic ova production (oogenesis) (Figure 2). Reproductive
material. The biological concept of “maleness” and systems include the gonads, the reproductive tract
“femaleness” is based on the size of the gametes. In through which gametes escape, and the accessory
sexual reproduction, the gametes are of different tissues that provide regulatory molecules, nutrients,
size (anisogametic): the male has gonads (testes) and fluids.
that produce small gametes (spermatozoa), and the Sexual reproduction is one of the reasons why
female has gonads (ovaries) that produce large ga- animals have been so successful in exploiting
Oogenesis Spermatogenesis
Oogonium Spermatogonium
Primary oocyte
Primary
(growth) Meiotic spermatocyte
division I
Primary oocyte
Secondary Secondary
oocyte spermatocytes
First polar
body
Meiotic
division II
Mature
Spermatids
ovum
Second
polar body
(a)
Mature sperm
Differentiation
(b)
Figure 2 Gametogenesis The gametes are asymmetrical cell division, devoting most of the cytoplasm to a
formed by the two-step process of meiosis. Germ cells single daughter cell (secondary oocyte). The other, smaller
(spermatogonium and oogonium) proliferate in the gonads to daughter cell, called the first polar body, is usually degraded.
create a stock of diploid cells that can undergo gametogenesis. The secondary oocyte undergoes another round of
The two alleles for each gene are shown as red and blue asymmetrical cell division, resulting in the ovum and the
chromosomes. Meiosis begins when each chromosome smaller second polar body, which is also degraded.
duplicates; the progression through meiosis differs in males (b) Spermatogenesis continues when the primary spermatocyte
and females. (a) Oogenesis pauses when the primary oocyte undergoes cell division to produce two secondary
grows in size and remains quiescent in the female for long spermatocytes. Meiosis continues and each secondary
periods. When activated, the primary oocyte undergoes an spermatocyte divides to produce two haploid spermatids.
703
Reproduction
diverse ecological niches. The process generates protein to form an active transcription factor. Ani-
genomic variation at three levels. First, an animal mals mediate the effects of steroid hormones by al-
produces gametes with genomes consisting of tering the rates of hormone synthesis, the levels of
combinations of chromosomes originally provided receptors in target tissues, the rates of degradation
by the animal’s own parents. For an animal with of hormones and receptors, and by producing ex-
23 chromosome pairs, more than 8 million geneti- tracellular proteins that bind steroids. Steroid hor-
cally different gametes can be produced by a single mones are all derived from cholesterol, but diverse
individual. Second, during meiosis, chromosomal enzymatic pathways allow animals to produce a
recombinations can create chromosomes that are range of structurally related specific hormones.
hybrids of maternal and paternal chromosomes, In vertebrates, a complex suite of steroid hor-
further adding to the total number of unique ga- mones with subtle structural differences that im-
metes. Third, the diploid offspring produced by part unique activities (Figure 3). Progesterone is
fertilization are unique combinations of the differ- produced from cholesterol in a number of steroido-
ent types of variants arising independently from genic tissues including the adrenal gland and go-
the first two processes in both oogenesis and sper- nads. It can escape into the blood, exerting effects in
matogenesis. For these reasons, each offspring both males and females, or it can be further metab-
produced in sexual reproduction is unlike either its olized to androstenedione. In males, androstene-
siblings or parents. Thus, sexual reproduction cre- dione is further metabolized to various androgens.
ates a population that is a collection of distinct The most common androgen is testosterone, al-
genotypes—a genetic diversity that is the raw ma- though other androgens (11-ketotestosterone,
terial upon which natural selection acts. androstenedione, dihydrotestosterone) predomi-
nate in some species and processes. Although
these are called male hormones, they are also pro-
Reproductive Hormones duced in females and serve as the precursors
Reproductive hormones orchestrate development, for synthesis of estrogens, primarily estrone and
sexual maturation, gametogenesis, and mating. estradiol-17␤.
There are many common themes in how diverse The rates of production of individual steroids
animals use hormones to control reproduction. depend largely on the distribution and activity of
steroid metabolizing enzymes. Central to steroid
• Complex pathways of negative and positive metabolism are the cytochrome P450 enzymes of
feedback control hormone synthesis. the endoplasmic reticulum. Aromatase is a cy-
• Hormone levels are determined by regula- tochrome P450 enzyme that metabolizes androgens
tion of synthesis as well as degradation. to estrogens. For example, it converts testosterone
• Hormone efficacy is influenced by hormone to estradiol-17␤ and androstenedione to estrone.
receptor synthesis in target tissues.
• Males and females of a species use the same Gonadotropins control steroid
suites of hormones, although an individual hormone levels
hormone may have sex-specific functions.
Steroid synthesis in the gonads is controlled by the
• Hormones with major roles in other physi-
levels of nonsteroidal hormones produced by the
ological systems also have vital functions in
anterior pituitary: gonadotropins. Most verte-
reproduction.
brates produce the same types of gonadotropins:
follicle-stimulating hormone (FSH) and luteinizing
Vertebrates rely on progesterone, hormone (LH). Primates produce a third go-
androgens, and estrogens nadotropin, chorionic gonadotropin (CG).
Steroid hormones are critical regulators of animal Gonadotropins are heterodimers of an alpha
reproductive physiology. Recall that steroid hor- subunit (shared by all gonadotropins) and a beta
mones regulate physiology primarily through ef- subunit that imparts the unique properties of each
fects on gene expression. Each steroid hormone hormone. Thus, FSH is composed of a dimer of al-
binds to a nuclear hormone receptor, a protein pha gonadotropin and beta FSH. Each subunit is
that heterodimerizes with another DNA-binding about 100 amino acids long, and heavily modified
by glycosylation. Unlike steroid hormones, each of
704
Reproduction
CH3
C O
12 17
11 13 16
14 15
1 9
2 10 8
O
5 7
Progesterone 3
4 6
O OH OH
O O O
H
Androstenedione Testosterone Dihydroxytestosterone
Cytochrome P450 aromatase
O OH OH
HO HO O
Estrone Estradiol-17β 11-Ketotestosterone
Figure 3 Reproductive hormones Highlighted areas distinguish chemical differences in closely related hormones.
which possesses the same chemical structure re- than 20 different versions of GnRH have been seen
gardless of taxon, the gonadotropins are proteins in vertebrates, and most species produce two or
with taxa-specific sequences. Thus, fish FSH is not more versions of GnRH with subtly different ef-
identical to mammalian FSH, but they are so fects on target tissues. The primary role of GnRH
named because of their structural similarities. The is in reproduction, but it has other roles as well,
exact roles of gonadotropins often differ among such as behavioral control.
vertebrate taxa. They are similar in the most gen- GnRH is produced by hypothalamic neurons
eral respects of controlling gametogenesis and re- and released into the portal system that carries hy-
productive maturity, acting both directly on target pothalamic factors to the anterior pituitary. The
tissues and indirectly through effects on steroid neurons release a burst of GnRH that triggers secre-
hormone synthesis. FSH stimulates spermatogen- tion of LH and FSH. Differences in the way LH and
esis in males and induces the follicles to ripen in FSH are stored affect the profile of these hormones
females. LH induces the interstitial cells of the in the blood. The anterior pituitary stores ample LH
testes to produce testosterone in males, and in- in vesicles that can be released in synchrony to in-
duces the follicle to produce estrogens in females. duce a pulse of LH in the blood. In contrast, the
Release of gonadotropins from the anterior pi- anterior pituitary stores little preformed FSH, pro-
tuitary is under the control of multiple hormones. ducing FSH on demand in response to GnRH.
The main regulator is a hypothalamic hormone, The gonadotropins regulate many aspects of
gonadotropin-releasing hormone (GnRH). reproductive physiology, acting through effects on
GnRH is composed of 10 amino acids (a decapep- their primary target tissue, the gonads. In addition
tide) in all animals studied to date. However, more to effects on the gametogenic tissues and other
705
Reproduction
gonad functions, they induce the release of estro-

gens in the female and androgens in the male.
These hormones then act on other tissues, including
both the primary reproductive tissues (ovary and
testes) as well as those considered to be secondary
sex features (mammary glands, hair follicles, and
male sexual displays). These relationships between
the hypothalamic-pituitary axis and the gonads are
Hypothalamus
depicted in Figure 4.
JH and 20HE control development and

GnRH
reproductive physiology of arthropods Portal
vessels
Recall from Box: Evolution and Diversity: Ecdysone:
An Arthropod Steroid Hormone that invertebrate
steroid hormones differ from those used by verte- Anterior
pituitary
brates. Ecdysteroids, a group of hormones derived
from the steroid ecdysone, control reproduction
and development. Most arthropods rely on 20-hy-
droxyecdysterone (20HE), which is produced from
ecdysone. (In older literature, 20HE is often called
␤-ecdysone, and its precursor ␣-ecdysone.) Al-
though 20HE is the most potent ecdysteroid,
ecdysone and other derivatives also have important
roles in some species. Ecdy-steroids are produced Gonadotropins
by the prothoracic glands or gonads, depending on
the species and life stage.
Levels of 20HE depend on control of both syn-
thesis and degradation. Furthermore, the path- Ovary Testes
ways of synthesis change as the animal matures. A
larva produces ecdysteroids in its prothoracic
glands, but when the animal metamorphoses, these
glands degenerate and the gonads become the Steroids
main site of production. Ecdysteroid synthesis and
release are regulated by numerous peptide hor-
Figure 4 Hypothalamic-pituitary axis The
mones. One of the first such regulators identified
hypothalamus receives signals from the brain and bloodborne
was bombyxin. This hormone, first isolated from hormones, and responds by releasing gonadotropin-releasing
the silk moth Bombyx mori, is a protein that is struc- hormone into the pituitary. This induces the release of
turally related to the vertebrate protein hormones gonadotropins (LH and FSH) into the blood, for transport to the
gonads. The gonads respond by increasing steroid hormone
of the insulin/insulin-like growth factor family.
synthesis. Ovaries release estrogens and progesterone, which
In addition to ecdysteroids, invertebrates use exert effects on primary reproductive tissues, such as the
various terpenoid compounds to control reproduc- uterus, and secondary sex tissues, such as the mammary
tive development, metamorphosis, molting, and glands. In males, the testes release androgens, which exert
effects in the testes, but also affect other tissues, including
metabolism. Insects rely upon juvenile hormone
secondary sex organs and muscles.
(JH), whereas crustaceans use methyl farnesoate.
When an insect egg hatches, a juvenile form (larva)
emerges and begins to eat. As the larva grows, it dergo multiple larval molts prior to adulthood. The
reaches the capacity of its rigid exoskeleton. The last step of development, the emergence of the
first larva, also known as the first instar, undergoes adult, occurs by one of two alternate routes. In
ecdysis (molting): it splits open the exoskeleton, holometabolous insects, the last instar forms a co-
rapidly increases in volume, and then resynthe- coon, a fibrous external coating around the inner ju-
sizes a new, larger exoskeleton. Most insects un- venile form, at this stage called a pupa. While it
706
Reproduction
appears dormant, inside the cocoon the pupa is re- sex-determining chromosome; a male results when
organizing its physiological systems in preparation the zygote is heterogametic (XY) and a female when
for reproductive maturation. An adult form emerges it is homogametic (XX). This pattern, however, is not
from the cocoon, although it may need to undergo universal. In birds and butterflies, for example, the
additional sexual development. In hemimetabolous female is the heterogametic individual (designated
insects, the larval forms, usually called nymphs, un- as ZW) and the male is homogametic (ZZ). In other
dergo repeated molts, with the last nymph emerg- species, the sex is determined by many factors, so
ing as an adult. Holometabolous insects include the genotype is not a good predictor of the sex. Con-
lepidopterans (butterflies), dipterans (flies), and sider, for example, the situation in honeybees. If an
coleopterans (beetles). Odonates (dragonflies), or- egg is fertilized, the diploid offspring is female, but if
thopterans (locusts), and true bugs (hemipterans the egg remains unfertilized, a haploid male results.
and homopterans) are hemimetabolous. The reproductive males produce sperm through a
Juvenile hormone is so named because of its modified form of mitosis. This pattern of sex deter-
role in maintaining juvenile characteristics in the mination, called haplo-diploidy, allows the queen
larvae. It stimulates the synthesis of larval exo- bee to control the numbers of males and females
skeleton, which differs in molecular composition within the colony.
from the adult exoskeleton. High levels of JH also
prevent larvae of holometabolous insects from un-
dergoing pupation. Only when JH levels decline can
Asexual reproduction occurs
the larva enter the pupal stage. During the pupal
by cloning and parthenogenesis
stage, JH levels continue to fall and the pupa devel- The genetic diversity arising through sexual repro-
ops into the adult form. Once JH levels have fallen duction helps animals evolve in changing environ-
to some minimum value, the neurosecretory cells ments, but for those species that live in a relatively
of the brain release another hormone, eclosion constant environment, genomic variation is not nec-
hormone, and the adult emerges from the cocoon essarily an advantage. Evolution has endowed some
(eclosion). Upon eclosion, JH assumes a new reg- sexually reproducing animals with the capacity to
ulatory role, increasing in concentration to trigger reproduce asexually. Corals, for example, reproduce
sexual maturation in both the male and the female. sexually but have evolved the ability for asexual re-
The activity of terpenoids, like 20HE, is con- production, producing buds that are clones of the
trolled by both synthesis and degradation. JH parent. Buds form from somatic tissues of the
biosynthesis in the corpus allatum is regulated by adults, either male or female. This allows a single
factors released from neurons and neuroendocrine individual coral to produce a colony of clones.
cells. Allatotropins are peptide hormones that Most forms of asexual reproduction in animals
stimulate JH production and release, whereas alla- are not through clonal mechanisms, but rather by
tostatins are inhibitory peptide hormones. Insects parthenogenesis (“virgin birth”). In contrast to
also control the levels of JH through degradation, cloning, parthenogenesis occurs through the use of
using enzyme JH esterase to convert JH to less ac- ova and the female reproductive system. In contrast
tive metabolites. Thus, an increase in JH esterase to sexual reproduction, no male is involved.
activity is one way an insect larva reduces JH levels Parthenogenesis is important in many species of in-
to allow it to proceed in development. Many plants vertebrates. For example, when food is abundant a
possess chemical mimics of JH that disrupt the nor- female aphid can use parthenogenesis to rapidly
mal development of insects, protecting the plant produce 50–100 young aphids. Within only a few
from herbivorous insects. Similarly, many insecti- days these offspring, which are tiny versions of their
cides such as methoprene work on the same princi- mother, reproduce parthenogenically, resulting
ple as the natural plant agents that act as JH mimics. in an aphid infestation. Parthenogenesis is less
common in the vertebrates. The whiptail lizard
(Cnemidophorus uniparens) exists as an entirely fe-
Sex Determination male species that reproduces by parthenogenesis.
Sex is strictly defined in relation to gamete size, but Cnemidophorus inornatus, its closest relative and
there is a frequent misconception that sex is always likely the ancestral species, reproduces sexually. Re-
a result of the presence or absence of the Y chromo- markably, many of the mating behaviors that oc-
some. In mammals, the Y chromosome is called the curred in the ancestral species still occur in the
707
Reproduction
parthenogenic species. In the Thelytoky Arrhenotoky

sexual species, a surge of pro-
gesterone causes a male to X X Z W
mount a female. In the asexual Primary oocyte Primary oocyte
species, a progesterone surge
occurs in an ovulating female,
causing her to mount another fe-
male. These “mating” behaviors
Secondary Secondary
are common in parthenogenic oocyte oocyte
species. In some species, the be- First polar First polar
haviors are simply a regulatory body body
remnant of their sexual ances-

try, but some mating rituals take Mature
Second
Mature
Second
polar polar
on new functions. For example, ovum
body
ovum
body
the mating behavior of two
parthenogenic females can in-
duce ovulation.
Parthenogenesis allows a
single diploid female to use its
reproductive tissue to produce Fertilized egg Fertilized egg
offspring that may be diploid

or haploid, depending on the
pathways involved. The most (a) (b)
common pathway of partheno- Figure 5 Automictic parthenogenesis In some species, the females
genesis, called automictic reproduce by parthenogenesis when the second polar body fertilizes the ovum. (a) In
parthenogenesis (automictic = thelytoky, homogametic females produce only female offspring. (b) In arrhenotoky,
heterogametic females produce male offspring through parthenogenesis.
self-mixing), is a variation on
the standard meiotic pathway
for oogenesis, proceeding to the point where the Animals may be simultaneous
secondary oocyte is formed (see Figure 2). When the or serial hermaphrodites
secondary oocyte undertakes the second meiotic Sexual reproduction does not necessarily require
division, the second polar body doesn’t degrade genetically separate sexes. Many species are her-
but instead fertilizes the ovum, resulting in a ho- maphrodites, possessing the capacity to produce
mogametic zygote. Since the offspring from au- both eggs and sperm. Some hermaphrodites, like
tomictic parthenogenesis is homogametic, the sex the earthworm, produce both eggs and sperm at the
of the offspring depends on which of the sexes is same time. The testes are in segments that are sep-
homogametic. Thelytoky is a form of automictic arated from the segments bearing ovaries. When
parthenogenesis in which a homogametic female two earthworms copulate, they arrange their ven-
(XX) produce females; it lacks the Y allele that is tral sides together, but oriented anterior to posterior.
needed to produce a heterogametic male (XY). In Thus, the spermatogenic tissue is directly against the
contrast, in arrhenotoky, heterogametic (WZ) fe- oogenic region. Although this antiparallel arrange-
males produce only males (ZZ). If the ovum and ment optimizes the chance of cross-fertilization for
second polar body originate from the Z allele, both worms, self-fertilization can occur.
offspring are ZZ males. If the ovum and second Other species are serial hermaphrodites, exist-
polar body arise from the W allele, a nonviable ing for part of life as one sex but sometimes exercis-
WW genotype is formed. Populations survive by ing an option to change to the other sex later in life
alternating between sexual and parthenogenic under some circumstances. Protogynous animals
reproduction. These two forms of parthenogene- are first female (producing eggs), then become male
sis are summarized in Figure 5. Note that meio- (producing sperm). Protandrous animals are male
sis is also important in parthenogenesis, and first, then become female. In many cases, the switch
parthenogenic offspring also benefit from chro- from one sex to the other occurs in response to
mosomal recombination. environmental conditions, including social interac-
708
Reproduction
tions. For example, some female coral reef fish

100 20
spontaneously transform into males if the dominant
Estradiol-17β / testosterone
Sex ratio (females: males)
male in the community is removed. The transition
from female to male appears to involve a change in 75 15
the metabolism of the main Sex ratio
sex hormones. The male reproductive system 50 10
is maintained by testosterone and its metabolite
11-ketotestosterone. The female reproductive state Sex hormone
25 ratio 5
is maintained by estradiol-17␤. The control of sex is
linked to the metabolism of testosterone. In females,
testosterone is metabolized to estradiol-17␤ 0 0
140 160 180 200
through a pathway involving the cytochrome P450
Season (day of year)
enzyme aromatase (see Figure 3). When aromatase
inhibitors are given to females, they undergo a sex Figure 6 Temperature-dependent sex
determination In painted turtles, the levels of steroid
change in little more than two months. The new hormones in yolk changes throughout the breeding season,
males possess low levels of estradiol-17␤ and high and correlates with the prevalence of females.
levels of testosterone and 11-ketotestosterone. It re- (Source: Adapted from Bowden et al., 2000)
mains unknown how environmental factors, includ-
ing social interactions, act through physiological come threatened by abnormally high (or low) tem-
regulators to alter steroid hormone metabolism in peratures, resulting in a preponderance of only
the natural setting. one sex in the population. Thus, such species
could be at great risk from global climate change.
Sex is determined in some species The sex ratio resulting from TSD is influenced
by environmental conditions by other factors as well. For example, levels of sex
In most animals, the sex of young is determined by the hormones in the yolk influence the pattern of sex de-
genotype: presence or absence of sex-determining termination during development. These hormone
chromosomes. However, in some species sex is deter- levels vary seasonally, imparting a seasonal aspect
mined by the physical and chemical environment to the sex ratios. For example, in painted turtles, a
around the developing embryo. The most common temperature of 28°C generates near-equal numbers
form of environmental sex determination is tempera- of males and females in the middle of the breeding
ture-dependent sex determination (TSD). It is very season (Figure 6). At the extremes of the breeding
common in reptiles, occurring in all crocodilians and season, the same temperature can yield 75% males
marine turtles, as well as selected species of lizards or 75% females. The difference appears to be linked
and terrestrial turtles. At an intermediate ambient to the relative levels of estradiol-17␤ and testos-
temperature, called the pivotal temperature, equal terone in the egg. When eggs have relatively high
numbers of males and females result. Three main pat- estradiol-17␤ levels, the clutch is more female bi-
terns emerge in studies of TSD. Some turtles produce ased. Species that rely on hormones in the yolk as a
males when temperatures are below the pivotal tem- mechanism to regulate TSD are particularly suscep-
perature and females above. Conversely, some lizards tible to endocrine disruptors, which can alter sex ra-
produce males when temperatures are high and fe- tios independent of temperature.
males at low temperature. A third pattern is seen in
crocodiles and alligators: female offspring dominate at 2 C O NC E P T C H E CK
both high and low temperatures, but male offspring
are more abundant at intermediate temperatures. 1. What are the main hormones in vertebrate
It is not always obvious why one particular sex reproduction and where are they produced?
may be advantageous at a given temperature, and 2. How does the chemical structure of reproductive
hormones affect they way their synthesis is
it is not yet certain that the mother actively biases
regulated?
the sex ratio by choosing where to lay her eggs.
3. What is the difference between clonal
TSD also poses some risks; if temperature were reproduction and parthenogenesis?
the only factor that influenced sex, then conditions
4. What is the difference between XY and ZW sex
could arise in which whole populations would be- determination?
709
Reproduction
Oogenesis parous and release free-living young (naupali) or

oviparous, laying gastrulae encrusted in a shell
In most species, females produce their lifetime (cysts). The reproductive strategy can differ among
supply of gametes early in life and retain them in populations of a single species. The skink Lerista has
a developmental quiescence until needed. The both oviparous and viviparous populations. Among
term ovum typically refers to the unfertilized ga- chondrichthians (sharks and rays), some species of
mete, without distinguishing between primary skates lay fertilized eggs that float in the ocean cur-
oocyte, secondary oocyte, or ovum (see Figure 2). rents, some sharks are ovoviviparous, and others
In some situations, people may use ovum and egg are viviparous. In several shark species, the ovovi-
interchangeably, but in other cases the egg may viparous embryo thrives on the nutrients from the
actually be fertilized and undergoing embryonic egg, but then at some point begins to feed on its
growth. The ovum is a single cell, but it is also as- brothers and sisters within the reproductive tract—
sociated with noncellular material produced by a life history strategy that is difficult to categorize.
the female reproductive tract.
Ova are produced within follicles

The three main modes of reproduction are of somatic tissue
ovipary, vivipary, and ovovivipary The female reproductive tract includes the ovary,
The three main types of reproductive strategies— oviduct, uterus, and gonopore. The ovary is com-
ovipary, vivipary, and ovovivipary—are distin- posed of the ova-producing oogonia as well as sur-
guished by the fate of the ova prior to and after rounding somatic cells that provide structural and
fertilization. Different degrees of parental care are nutritive support for oogenesis. In most species, oo-
roughly commensurate with the three reproductive genesis progresses through the primary oocyte
strategies. Oviparous animals expel the ova from stage (see Figure 2) early in the life of the female, but
the body, and all development occurs externally us- the final steps of the process are delayed until later
ing the resources within the egg. Fertilization may in life. As the oocytes form, the surrounding somatic
be external, as in most fish, or internal, as in birds cells proliferate to form a follicle that encapsulates
and reptiles. The level of parental care ranges from the oocytes. The follicle cells, or granulosa cells,
none to intense. Few insects exhibit parental care, secrete the extracellular matrix components that
whereas most birds guard eggs and feed young. form an acellular layer between the oocyte and fol-
Viviparous animals use internal fertilization, and licle cells, called the zona pellucida. The entire fol-
the young develop within the female body. In early licle is surrounded by a basolateral membrane,
development, the young derive significant re- which in vertebrates is known as the theca.
sources from the mother. Placental mammals are The follicle cells orchestrate oogenesis, includ-
the most obvious examples of vivipary, but it also ing the delayed maturation and ultimate release of
occurs in some species of fish, snakes, and skinks. the ovum. They communicate with the oocytes by
The female reproductive tract produces nutrients paracrine factors and direct cell-to-cell contacts.
for the offspring, which can be a simple slurry of Prior to ovulation, a subset of follicles is stimulated
“uterine milk” secreted from the uterus, or more to mature (folliculogenesis). The oocyte must first
elaborate arrangements that allow the embryo to increase in cytoplasmic volume, although the in-
derive nutrition from the uterine blood vessels. crease in cell size occurs by multiple mechanisms.
Ovoviviparous animals demonstrate features of Vertebrate oocytes grow by accepting biosynthetic
both ovipary and vivipary. They use internal fertil- precursors from the somatic follicle cells. A differ-
ization, followed by extensive internal development ent pattern occurs in many invertebrates. In fruit
of embryos. While in the uterus, the embryos derive flies, for example, oocytes absorb the cytoplasm of
their nutrition from the yolk, rather than the surrounding nurse cells, derived from oogonia
mother. When mature, the eggs hatch within the that fail to differentiate into oocytes (Figure 7).
mother. This strategy is common in fish, including When the follicle ruptures, the ovum escapes
sharks, reptiles, and many invertebrates. the ovary and moves into the coelom. In some
Surprisingly, reproductive mode varies widely species, the ova are retained within the coelom.
within taxa. Some species are able to switch between For example, some insects accumulate eggs until
modes. Brine shrimp, for example, can be ovovivi- the abdomen bursts, killing the female. More com-
710
Reproduction
the oocyte early in oogenesis. Triglyceride from the

extracellular fluid passes from the blood between
the follicle cells to the oocyte, where it is taken up
Nurse cells
and stored within vesicles. The yolk possesses
Follicle cells many proteins, but vitellin is the most abundant. It
is produced in the oocyte from vitellogenin, a
Basal lamina
bulky and complex phospholipoglycoprotein that is
Oocyte produced by the insect fat body, the vertebrate liver,
and, in some animals, the follicle cells. Vitellogenin
(a) Invertebrate follicle (Drosophila)
is taken up from the extracellular fluid by endocy-
tosis. The internalized vesicles then coalesce to
form larger yolk bodies.
Suites of hormones mediate vitellogenesis. Ex-
ternal signals of various forms stimulate the central
Follicle cells nervous system to release vitellogenic factors
(Figure 8). In blood-feeding insects, vitellogenesis
Zona pellucida
begins shortly after the animal consumes a blood
Oocyte
meal, at which point a JH surge causes the fat body
to produce vitellogenin. In vertebrates, vitellogenin
Theca
Invertebrates Vertebrates
(b) Vertebrate follicle External cue
Figure 7 The ovarian follicle Each oocyte is Hypothalamus

Neurosecretory
surrounded by somatic follicle cells. The entire follicle is releases GnRH to
cells release Central signal
encapsulated in a thin layer of extracellular matrix (basal pituitary, which
allatotropins
lamina). (a) Invertebrate oocytes receive cytoplasm from nurse releases FSH
cells through gaps in the plasma membrane. (b) Vertebrate
Corpus allatum/
follicle cells produce a more extensive extracellular matrix at Peripheral target Follicle cells
corpus cardiacum
the apical (zona pellucida) and basolateral (theca) surfaces.
Juvenile hormone Hormonal release Estrogen

monly, the ovum crosses a short stretch of coelom
and enters the opening of the oviduct, called the
fallopian tube in mammals. The ovum passes Fat body Vitellogenesis Liver
through the oviduct into the uterus. Those species
that use internal fertilization retain the ova in the
oviduct or uterus. The uterus may be a simple pas- Transfollicular
transport
sage, or it may be strong muscular tissue that uses
smooth muscle contractions to expel ova, fertilized
eggs, or young through the gonopore: the vagina
Oocyte uptake
in those species with a dedicated reproductive
pore, or a cloaca if the reproductive and excretory
systems have a common pore. Vitellogenin
processing
The yolk provides building blocks Figure 8 Vitellogenesis Animals initiate vitellogenesis in
and metabolic precursors response to external cues, such as an environmental condition
or developmental program. The pathways begin centrally within
Most animals, with the exception of placental mam- the brain, triggering a hormonal cascade that causes
mals, provide each ovum with a source of nutrients biosynthetic tissues to produce and secrete vitellogenin. This
protein passes the follicular cells and is taken up by the oocytes,
in the form of yolk, a complex mixture of proteins
stored, and then converted to vitellin. Invertebrates and
and lipids. Most of the macromolecules in yolk are vertebrates differ in the specific hormones and target tissues,
produced outside the oocyte, then sequestered by but the general features are similar.
711
Reproduction
is produced in response to estro-

gens, primarily estradiol-17␤.
Follicle
(early)
Insect eggs are surrounded
by a chorion
Oogenesis has been well studied in
many insects. In the silk moth, the
ova develop in four ovaries (ovari- Ovariole
oles), each of which contains in ex- Ovary
cess of 100 follicles arranged in

series. The follicle that is closest to
the gonopore undergoes oogenesis
first (Figure 9). After about
2.5 hours, the next follicle enters Follicle
oogenesis, and so on along the en- (late)
tire length of each ovariole. Thus, at Spermatheca
late stages of oogenesis, a single
ovariole possesses each of the de-
Oviduct
velopmental stages separated by
about 2.5 hours of development.
These stages are divided into To oviduct
Accessory
three groups: previtellogenesis, gland Uterus
vitellogenesis, and choriogenesis. Vagina
Ecdysone controls the early devel-
Female insect reproductive tract
opment of ovarioles as well as the
previtellogenic stages. During pre- Figure 9 Oogenesis in the silk moth When the ovarioles of the silk
vitellogenesis, the follicles have not moth undertake oogenesis, the follicles mature in sequence. Each follicle is about
yet begun to produce yolk. The 2.5 h more developed than the follicle next to it. The ova are released and pass
down the oviduct into the uterus where they are fertilized with sperm that was
oocyte then begins to accumulate collected and stored in the spermatheca after a previous mating.
yolk proteins, marking the onset of
the vitellogenic period. The yolk proteins from the fat withstand desiccation yet still able to permit the
body are transferred from the hemolymph to the movement of gases (O2, CO2). As we see in the next
oocyte across the follicle cells. The follicular cells also section, the early terrestrial vertebrates faced the
produce egg-specific proteins that are secreted and same problem but solved it a different way.
taken up by the oocyte. As with the early stages of
development, ecdysone controls the production of
the egg proteins, although not directly through Egg structure differs in aquatic
changes in 20HE levels but rather through induction
and terrestrial vertebrates
of a specific type of ecdysteroid receptor. After vitel- Most fish and amphibians produce eggs that are
logenesis has begun, a reduction in 20HE levels simple in structure. The ovum is physically con-
causes the follicle cells to begin chorion formation nected to yolk. As the ovum passes down the repro-
(choriogenesis). The follicular cells produce and se- ductive tract, it receives a viscous coating from
crete more than 100 types of proteins to construct reproductive tract secretions. The gelatinous eggs
the chorion. The ovum moves into the oviduct, are released from the animal into the water unfer-
where it is fertilized. Sperm cross this impermeable tilized. In amphibians and fish, the young leave the
shell through a tunnel called the micropyle. The fer- egg as aquatic larvae and complete their reproduc-
tilized eggs are then laid. tive maturation. The constraint of this strategy is the
The insects were the first animals to success- need for water at all developmental stages. For the
fully invade land. Central to this invasion was the ancient vertebrates to be truly terrestrial, they
evolution of an egg that could withstand the terres- needed a mechanism to reproduce on land. Like the
trial conditions. The chorion is resilient enough to insects, they produced a hardened external shell
712
Reproduction
around the egg that provided support and pre- ing them into the open environment where a minute
vented dehydration. In contrast to the proteina- proportion of sperm successfully fertilize a few ova.
ceous chorion of insects, the eggshell of reptiles and Other animals engage in mating behaviors that bring
birds is composed of calcium carbonates embedded males and females into close proximity to increase
in an organic matrix. The bird eggshell has a thick the likelihood of successful fertilization. Some clasp
layer of calcium carbonate salts, giving it a brittle onto mates and release sperm in synchrony to max-
but hard texture. Many reptiles produce eggshells imize chances of fertilization. Other species use cop-
analogous to those in birds, but some reptiles, such ulatory organs of various configurations, typically
as crocodilians and turtles, have a leathery and pli- associated with the male. Once the sperm have been
able eggshell. In these animals, the calcium carbon- passed from the male, the individual sperm must
ate crystals are aggregated into separate islands, find and fertilize the egg, often competing with
allowing the eggshell to change in shape and even sperm from other males.
swell in the presence of water. Each egg is endowed
with yolk to serve as an onboard source of fuel. The
eggs also possess a viscous, hydrated protein (albu-
Leydig cells and Sertoli cells
men) to act as a shock absorber.
control spermatogenesis
Since the eggshell in birds and reptiles is imper- The typical testis produces spermatozoa in semi-
meable, even to sperm, the animals also needed to niferous tubules, which are composed of Leydig
coevolve a different mode of fertilization. The ovum cells, Sertoli cells, and spermatozoa at various de-
in reptiles, birds, and monotremes (egg-laying mam- velopmental stages (Figure 10). Leydig cells
mals) must be fertilized before the eggshell is formed.
Thus, fertilization is internal and the eggshell forms
in the oviduct around a fertilized ovum.
Eutherian (placental) and metatherian (marsu-
pial) mammals, of course, have dispensed with the Seminiferous tubule
eggshell and solve the challenges of terrestrial life by
rearing fertilized ova internally. Nonetheless, each
of these terrestrial vertebrate lineages produces em-
bryos that, early in development, produce a com-
plex set of internal membranes and fluid-filled
compartments. Reptiles, birds, and mammals are
collectively amniotes, a name derived from one of Lumen of tubule
the four extraembryonic membranes. We discuss
the origins of these membranes later in this chapter. Spermatozoa
Sertoli cell
Spermatogenesis and Fertilization
Spermatids
In order to reproduce, male reproductive physiology
ensures that sperm are prepared to fertilize the egg Nucleus
(Sertoli cell)
once the male engages in activities that bring the ga-
metes in close proximity. For many species, the Spermatocyte
greatest challenge is finding a mate in order to Spermatogonium

breed. In some species, reproductive maturation co- Basal lamina
incides with an ability to sense and respond to
Leydig cell
mating factors released by one sex to attract the
other (see Box 1, Evolution and Diversity:
Figure 10 Seminiferous tubules Sperm production is
Pheromones). Once mates are found, males must be controlled by Sertoli cells of the seminiferous tubules. The
able to deliver sperm that are ready to move to the Sertoli cells interact through physical connections with
ovum and fertilize it to initiate embryogenesis. There spermatogenic cells at various stages, and interact with each
other to form a blood-testes barrier. Leydig cells are found in
is considerable diversity in the mechanisms by
the interstitial space on the blood side of the blood-testes
which the sperm are delivered to the ovum. Some barrier. These cells produce regulatory factors that act on
species produce copious numbers of gametes, cast- Sertoli cells to control spermatogenesis.
713
Reproduction

Pheromones
Most large animals find mates using vi- ior. Mice are normally quite aggressive and territorial
sual cues that identify specific traits such as mammals. If you put a male mouse alone in a cage for a
sex, receptivity, and evolutionary “quality.” In contrast, day or two, it will establish the entire cage as its territory
smaller animals living in open spaces attract or locate and attack any new males that you introduce. Normal
mates using pheromones—chemicals released from an male mice do not attack intruder females, and they ig-
animal that elicit a specific response from another mem- nore castrated males. However, if urine from an intact
ber of the same species. The specificity of the response male mouse is applied to a castrated mouse, the resi-
is due to the activation of unique pheromone receptors dent male mouse will attack the castrated male in-
that initiate a predictable signaling cascade. Thus, truder, just as it would an intact male. If a TRP2 knockout
pheromones are distinct from other types of chemical male establishes a territory, it ignores introduced cas-
signals, such as those that might, in human terms, trated male mice swabbed with the urine of an intact
equate to pleasant smells. male. It also mates indiscriminately with both females
Sex pheromones are released to attract potential and males. Thus, TRP2 signal transduction is an essen-
mates. Because of this role in reproduction, pheromone tial part of the communication of sexual signals in mice.
mimetics have been developed as alternatives to pesti- Pheromones do not appear to play an important
cides. The pheromones are scattered throughout the role in humans. The vomeronasal organ is greatly re-
crop to confuse males, who are then unable to locate the duced in size in adult humans compared to the size of
trail emanating from a female. Other organisms have this organ in the human fetus and in other adult mam-
also co-opted pheromone signals for their own purposes. mals. Humans also lack an accessory olfactory bulb,
Some predatory spiders emit a chemical that mimics the the part of the brain responsible for interpreting
pheromones used by specific moth species; the male pheromone signals in other animals. In addition, the
moths are lured to the spider and trapped in the web. majority of the genes encoding vomeronasal recep-
Some species of orchids have evolved to produce chemi- tors contain deletions or other changes that would
cals that mimic insect pheromones. This pathway relies likely make them nonfunctional, and humans do not
on specific pheromone receptors, and is distinct from have a copy of the TRP2 ion channel. The TRP2 gene
other pathways used by plants that release chemoattrac- is present in the prosimians and the New World
tants, such as the carrion plant, which attracts flies by monkeys, but is mutated or absent in the Old World
emitting a fetid odor reminiscent of a decaying animal. monkeys and the apes. Interestingly, the loss of
Many (though not all) vertebrates emit pheromones. pheromone-based signaling in the Old World monkeys
Rodents emit a pheromone that, when detected by the roughly coincides with the evolution of color vision. It
female, accelerates the reproductive cycle to induce may be that Old World monkeys, apes, and humans
ovulation. Male mice release the pheromone in their rely more on visual signals than on pheromones for
urine. In tetrapods, most pheromones are detected in a detecting gender. However, many experiments sug-
region of the nostril known as the vomeronasal organ. gest that chemical cues can influence human behav-
Nerves transmit signals from the epithelium of the ior. For example, exposing women to swabs from the
vomeronasal organ to the olfactory lobe. The underarms of other women can alter the timing of
chemosensors in the vomeronasal organ are distinct their menstrual cycles. It is not yet known whether
from the olfactory receptors found elsewhere in the these signals are detected through the small
nostril. Although pheromone receptors and olfactory vomeronasal organ (called Jacobson’s organ in hu-
receptors are both G-protein-linked receptors, the mans) or through the olfactory epithelium.
pheromone receptors are much more sensitive and trig-
References
ger a distinct signaling pathway. Some pheromone re-
q Keverne, E. B. 2002. Pheromones, vomeronasal function, and gen-
ceptors are found outside of the vomeronasal organ. For
der-specific behavior. Cell 108: 735–738.
example, European rabbit dams release pheromones
q Kohl, J. V., M. Atzmueller, B. Fink, and K. Grammer. 2001. Human
from the nipple to attract the pups for a short, intense
pheromones: Integrating neuroendocrinology and ethology.
feeding bout. Destroying the vomeronasal organ of the Neuro-endocrinology Letters 22: 309–321.
pup doesn’t prevent it from rapidly finding the nipple.
q Liman, E. R., and H. Innan. 2003. Relaxed selective pressure on
Activation of the pheromone receptor affects an ion an essential component of pheromone transduction in primate
channel called TRP2. Scientists have used TRP2 knock- evolution. Proceedings of the National Academy of Science USA
out mice to test the role of pheromones in mouse behav- 100: 3328–3332.
714
Reproduction
Table 1 Mammalian reproductive hormones in male sexual development and reproduction.
Hormone Tissue of origin Main actions
Sexual maturation
Androgens Testes Secondary sex characteristics: promote axillary hair growth, voice
deepening, and libido
Spermatogenesis
GnRH Hypothalamus Anterior pituitary: stimulates LH release, FSH synthesis and
release
LH Anterior pituitary Leydig cells: stimulates androgen synthesis and release
FSH Anterior pituitary Sertoli cells: stimulates spermatogenesis
Androgens Testes (Leydig cells) Sertoli cells: stimulate spermatogenesis
Prostaglandins Seminal vesicles Uterus of mate: induce changes within the uterus that affect sperm
motility
are interstitial cells found on the blood side of the

basal lamina. They produce the testosterone that
controls spermatogenesis. Sertoli cells are large
cells that fill the gaps between columns of sper-
matogenic cells. Each Sertoli cell is in contact with
about 50 spermatogenic cells. Sertoli cells serve
many purposes in spermatogenesis, producing
regulatory molecules as well as nutrients that are
used for both metabolic energy and biosynthesis.
They regulate the testosterone-signaling pathway
by producing an androgen-binding protein. They
also mediate the response of the testis to FSH, se-
creting other spermatogenic factors. The main ef-
fects of the sex hormones in mammalian males are
summarized in Table 1.
The progression from spermatogonia to sper-
matids to spermatozoa involves a series of coor-
dinated changes in cellular structure and function,
with many of the precursors provided through
cytoplasmic bridges that interconnect spermato-
zoa to neighboring cells. In the final stages of
spermatogenesis, a spermatid reorganizes its
microtubules to form the axoneme that underlies
the flagellum. The length and structure of the 1 cm
flagellum varies widely in animals. It is essen- Figure 11 Drosophila bifurca The image shows the
tially absent in some species, but can be as long male reproductive tract of a fruit fly (Drosophila bifurca).
long as 6 cm, as with the sperm of the fruit fly The uncoiled tract, at 7 cm, is only slightly longer than is the
Drosophila bifurca (Figure 11). Spermatozoa sperm, each about 6 cm.
(Photo courtesy of Scott Pitnick, Syracuse University)
then eliminate much of their cytoplasm, leaving
small, densely packed cells with abundant mito-
chondria organized around the base of the ax- keep the DNA highly condensed and transcrip-
oneme. They also reorganize the DNA in their tionally silent.
nuclei, replacing the histones with basic sperm- Once these structural changes are complete,
specific proteins called protamines, which the spermatozoa are released from the confines of
715
Reproduction
the Sertoli cells into the lumen of the tubule. From affect the ovarian response to the sperm, and en-
here they progress along the male reproductive zymes that break down chemical antagonists to
tract (Figure 12). At this point, the sperm are not fertilization. The prostate gland also secretes
capable of either swimming or fertilization, and nutrients, mainly citrate, as well as enzymes that
must undergo a series of modifications. As the aid in fertilization. The bulbourethral gland se-
sperm pass into the epididymis, they further ma- cretes mucus that acts as a lubricant.
ture. It is in this region that they gain the capacity In some species, the sperm released from the
to swim. The sperm are stored in the epididymis, male gonopore are not yet capable of fertilizing an
and fluids are removed to concentrate the sperm egg. Mammalian sperm, for example, undergo a
into a small volume. They are propelled by cilia developmental transition known as capacitation
along the tract through the vas deferens, which only after they enter the female reproductive tract.
connects with the urethra, and then exit through Once inside, they are exposed to regulatory factors
the gonopore. produced by the female that change sperm metab-
As the sperm pass through the reproductive olism, ion regulation, and membrane fluidity,
tract, they are bathed in seminal fluid, a rich nu- making the sperm capable of fertilizing the ovum.
trient broth produced by several glands. The
seminal vesicles produce an alkaline fluid with
nutrients and regulatory factors. The high pH
Male copulatory organs increase
neutralizes the acidic ovarian fluid to allow the
the efficiency of sperm transfer
sperm to swim. The sperm use the nutrients, Of the many species that use internal fertilization
mainly fructose, as fuel for flagellar activity. The (arthropods, mammals, reptiles, and some fish),
regulatory factors include prostaglandins, which most possess some form of copulatory organ or in-
tromittant organ. Birds, one notable
exception, transfer sperm directly
Seminiferous
from the male’s cloaca to the fe-
tubules male’s cloaca. In other species, a
Seminiferous
tubules modified or extra appendage is used
as a copulatory organ. A male spider
expels sperm and encases it in silk.
Pre-vesicular
vas deferens The spider then uses a specialized
leglike appendage to transfer the
sperm package to a reservoir on its
underside. During mating, the spider
Seminal vesicle inserts the package of sperm into the
Efferent ductules gonopore of the female. Some fish
Accessory gland
possess modified pelvic fins that in-
terlock to form a channel that guides
Epididymis sperm to the oviduct. Such copula-
tory organs are modified ap-
pendages, and the control of their
Ejaculatory duct Vas deferens
movement is similar in many re-
spects to locomotor control. Many
(a) Insect Seminal vesicle reptiles possess an appendage near
Prostate gland the cloaca, called a hemipene, that
acts as a copulatory organ. A snake
Bulbourethral gland
or lizard will insert a hemipene into
the female, channeling sperm along
(b) Vertebrate a superficial groove. The hemipenes
are often decorated with barbs or
Figure 12 The male reproductive tract Sperm released from the wall of spikes that maximize the duration of
seminiferous tubules are carried along the reproductive tract. As they pass through
the epididymis and vas deferens, the secretions from the accessory glands provide penetration. A true penis is distinct
seminal fluid. from other copulatory organs be-
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Reproduction
cause it is a direct extension of the male reproduc- activates the enzyme nitric oxide synthase (NOS),
tive tract. Some invertebrates possess a penis that resulting in production of the gaseous neurotrans-
they use like a spear, penetrating the female body mitter nitric oxide (NO) (Figure 13). Smooth mus-
wall and releasing sperm into the body cavity that cle contractility is under complex control by
holds the ova. More commonly, the penis inserts signaling pathways that affect the thick and thin fil-
directly into the female reproductive tract. aments. In the vascular smooth muscle of the
The mammalian penis changes its blood distri- penis, NO binds guanylate cyclase, stimulating
bution to create the hydrostatic pressure needed it to increase cGMP production, which activates
for a shape change (erection) that facilitates pene- cGMP-dependent protein kinase (PKG). PKG
tration. Many mammals also have a bone within phosphorylates critical proteins to favor smooth
the penis called an os penis or baculum. This al- muscle relaxation. It phosphorylates Ca2⫹ chan-
lows the male to penetrate the female before the nels, inhibiting them to reduce cytoplasmic Ca2⫹
penis becomes erect. After penetration, the penis levels. PKG phosphorylates thick and thin filament
engorges, locking it into the vagina to maximize the proteins to desensitize the contractile apparatus.
probability of successful sperm transfer. An erecto- PKG may also phosphorylate K⫹ channels to hyper-
genic stimulus, usually visual in nature, triggers polarize the cell. Upon relaxation of the arteriolar
the firing of neurons in the brain that transmit sig-
nals to the vasculature that feeds the penis. This
From brain 1 Nerves from the brain send a signal to

the vascular smooth muscle in the penis.
2 Nitric oxide (NO) produced by the

1 nerves activates a soluble guanylate
NO
cyclase.
NO
2
3 Guanylate cyclase activity increases
the concentration of cGMP.
Guanylate Guanylate
cyclase cyclase
(inactive) (active)
4 Elevated cGMP stimulates protein
3 kinase G (PKG).
GTP cGMP
4
5 PKG phosphorylates myosin light

Protein Protein chain phosphatase, stimulating it.
kinase G kinase G
(inactive) (active)
5 6 7 6 PKG phosphorylates myosin light

chain kinase, inhibiting it.
Activate Inactivate Inhibition of
+
MLCP MLCK Ca2 channels
7 PKG also phosphorylates Ca2+ channels,

+
+ inhibiting them to reduce Ca2 levels.
Dephosphorylation [Ca2 ]
of MLC
8
8 These changes cause vascular smooth
Relaxation muscle to relax, allowing the changes in
blood flow that induce an erection.
Figure 13 Control of erection in a mammalian penis
717
Reproduction
smooth muscle, blood flows into the penis, filling Females use sperm storage to ensure
the surrounding spongy tissue and causing an in- uninterrupted reproduction
crease in blood volume that compresses surround-
The females of some species store sperm for pro-
ing veins. The combination of increased blood
longed periods in specialized compartments
inflow and reduced venous return causes the penis
within the reproductive tract. Sperm storage en-
to engorge.
ables a female to fertilize her ova long after mat-
Drugs marketed to combat erectile dysfunc-
ing, which is adaptive in animals that might
tion in human males target this signaling pathway.
encounter mates infrequently. Some species mate
Sildenafil (Viagra), for example, inhibits the phos-
before the female has reached reproductive matu-
phodiesterase 5 (PDE5) of vascular smooth mus-
rity, and sperm storage allows her to bridge the
cle. Since PDE5 breaks down cGMP, sildenafil
gap between the mating and gonadal maturation.
allows cGMP levels to rise, permitting the changes
Sperm can be stored for long periods. Fruit flies
in the vascular smooth muscle that are needed to
store sperm for little more than a week. However,
respond to an erectogenic stimulus.
mated female honeybees can retain viable sperm
for several years. Some large snakes in captivity
Sperm alter activity in response to have laid fertilized eggs five years after mating.
chemokinetic and chemotaxic molecules The anatomical strategies for sperm storage
are diverse. Reptiles possess sperm storage tubules
Depending on the reproductive strategy, ejacula-
that branch from the uterus, or in some species, the
tion may propel the sperm into freshwater, saltwa-
vagina. Preovulatory surges in estrogens trigger
ter, or the fluid of the female reproductive tract,
contraction of smooth muscle that expels the stored
generally called ovarian fluid. Sperm are induced
sperm from the tubules and into the oviduct, where
to swim (activated) by an external signal, such as
they can fertilize the egg. Insects possess a more
a change in ionic strength or Ca2⫹ concentration.
elaborate sperm storage organ called the sper-
The ionic signal is transduced by receptors in the
matheca. The length of the spermatheca reflects the
sperm cell membrane, inducing changes in intra-
length of the sperm. In Drosophila bifurca, the fe-
cellular second messengers (cAMP or cGMP).
males have very long spermathecae to accommo-
These second messengers activate their respective
date the 5-cm-long sperm.
protein kinases (PKA and PKG), which phosphory-
late regulatory proteins within the axoneme to
stimulate flagellar activity.
Once activated, most sperm swim for only a Individual sperm can compete for
brief period of time. For example, the sperm of the opportunity to fertilize the egg
most freshwater fish swim for only a minute or In monogamous species, a single male mates
two, which allows them to cross distances of only with a single female. However, in many species,
a few millimeters. With such a limited capacity to females undertake multiple matings, creating a
swim actively to the ova, successful fertilization situation where the sperm from multiple males
may rely on chemical signposts that increase the compete to fertilize the ova. DNA fingerprinting
likelihood of contacting an egg. Some chemicals technologies have been used to study the parent-
are chemokinetic, stimulating the sperm to swim age of offspring in many taxa. It is now clear that
faster but not necessarily in any particular direc- polyandry, in which the offspring in a single
tion. Other chemicals are chemotaxic, inducing brood have different fathers, is common in ani-
the sperm to swim toward higher concentrations mals. The multiple matings also create an oppor-
of the agent. In the absence of these chemical tunity for the female to use chemical effectors to
agents, sperm swim at slower velocity, which con- bias sperm utilization. Many of the species that
serves onboard fuels until an egg is detected. The partake in multiple matings may experience
chemical nature of chemotaxic and chemokinetic sperm competition as a result of the order of cop-
agents is diverse, and may include amino acids, ulation. Female fruit flies may mate with multiple
peptides, and sulfonated steroid compounds. males, but the last male to copulate with her is
These chemicals may be released by the female re- likely to fertilize about 80% of the ova. It is not yet
productive tract or by the ovum itself. clear why the last, rather than the first, bolus of
718
Reproduction
sperm is most successful. It is likely that the fe- implantation, whereas other species can use de-
male is able to expel the sperm from the previous layed implantation opportunistically. For exam-
mating, allowing the sperm of the new suitor to ple, a rodent may copulate shortly after giving
fertilize the ova. birth to a litter, then delay implantation of the
embryos for several weeks. In mammals, the
delay can be a few days or weeks or as long as
Some animals delay 11 months, as in the river otter.
embryonic development
Once the sperm enters the egg, the oocyte under-
goes many changes that initiate embryonic devel- Postfertilization development relies
opment. The DNA from the sperm enters the cell on maternal factors
organized into a tight bundle of DNA associated Early embryonic development is a period over
with protamines. The fertilized ovum must re- which the control of cellular processes is trans-
model the condensed DNA from the spermatozoa ferred from two independent parental genomes
into a more conventional organization. Soon after to the integrated genome of the offspring. In the
fertilization, the sperm DNA disperses and then earliest phase, cellular changes are governed by
recondenses as the protamines are replaced by maternal factors that existed preformed in the
histones. Once organized into nucleosomes, the ovum. This includes hormones (androgens and
paternal DNA within the oocyte can become tran- estrogens) that exert regulatory effects on devel-
scriptionally active. At this early stage, the oocyte opmental variables, such as sex determination.
has two separate genomes: the maternal pronu- Gradually, the cellular control transfers to the em-
cleus and the paternal pronucleus. The fertilized bryo, when the contributions from paternal genes
ovum undergoes many rounds of cell division to begin to influence the developmental pattern. In
reach the blastocyst stage. Soon afterward the mammals, this transition from maternal to em-
various germ layers form, which differentiate to bryonic control occurs at about the two-cell stage.
form the complex tissues that ultimately form the In lower vertebrates and invertebrates, the ma-
embryo. In most species, the embryonic develop- ternal control extends until the embryo consists
ment continues until the young escapes the con- of thousands of cells. Even after the paternal
fines of the egg or reproductive tract. A few genes become active, factors present in the oocyte
species interrupt normal development, pausing can continue to play an important role well into
at an early phase of embryogenesis. Such a delay embryological development.
allows animals to ensure that embryogenesis The division of the genomes of the two par-
proceeds at the appropriate time to ensure hatch- ents allows for differential modification patterns
ing or birth occurs under favorable environmen- that influence later development, through the
tal conditions. process known as gene imprinting. Under normal
Brine shrimp are crustaceans that live in salt- conditions, each diploid cell is able to produce
rich water, such as Utah’s Great Salt Lake. As dis- mRNA from either the maternal or paternal allele
cussed earlier in this chapter, brine shrimp can of a gene. Before the maternal and paternal
reproduce through ovovivipary or ovipary. The em- genomes merge into a single nucleus, a small
bryos of brine shrimp develop to the gastrula stage, subset of the genes may be modified in a way that
at which point they can delay further development prevents the maternal or paternal allele from be-
until environmental conditions are adequate. These ing expressed. Furthermore, this imprinted gene
brine shrimp cysts are simple enough to survive remains transcriptionally silent throughout de-
metabolic arrest associated with dehydration. velopment, while the allele of the gene derived
More than 100 species of mammals can con- from the other parent is expressed. Most of the
trol embryogenesis through delayed implanta- genes subject to imprinting encode proteins crit-
tion. The fertilized ovum develops to the early ical for normal growth and neurobehavior, such
blastocyst stage (100–400 cells) in the uterus, as insulin-like growth factor 2 (IGF-2) and its reg-
but implantation in the uterine wall is delayed, ulators. These hormonal pathways control em-
retarding further development. Some mammals, bryonic growth, so the embryo is at the center of
such as seals, have an obligate period of delayed an interesting evolutionary conflict. The embryo
719
Reproduction
possesses genes from both father and mother, but

the costs of producing and raising the embryo are
borne largely by the mother. Thus, it is in the best Amnion
interest of the father to pass on genes that induce

rapid embryonic growth; his offspring thrive but
the mother bears the costs of rapid embryonic Shell
growth. Conversely, it is in the interest of the Chorion
mother to curtail growth to a manageable level.
Within the embryo, the parental genomes have Yolk
conflicting goals, and patterns of gene imprinting

on maternal and paternal alleles of genes for
growth regulatory proteins determine the trajec-
Albumen
tory of embryonic development.
Allantois
Amniotes produce four extraembryonic
membranes early in development
Soon after fertilization, the embryo of amniotes
produces sheets of cells that separate from the Figure 14 The amniote egg Once the ovum of an
amniote is fertilized, it undergoes cell division. Most of these
embryo to form the four extraembryonic mem-
cells form the embryo, but four sheets of cells separate
branes: chorion,1 amnion, allantois, and yolk sac. from the embryonic tissue to form the extraembryonic
These membranes grow in size as the embryo de- membranes—the chorion, amnion, allantois, and yolk sac—
velops (Figure 14). The chorion, the outermost which enclose compartments for storage of nutrients (yolk
sac), fluids (amniotic space), and wastes (allantoic cavity).
membrane that lies beneath the albumen, acts as
a gas exchange surface. The amnion encloses the
embryo. As the embryo develops, the amnion fills
with fluids that act as a hydraulic cushion and
provide a favorable ionic and osmotic environ-
ment for the embryo. The allantois is a membra- 5. Compare the three main modes of reproduction
nous outpouching of the primitive gut. During in animals (vivipary, ovipary, and ovovivipary).
development, it becomes vascularized, delivering 6. Trace the route of the oocyte from ovary to
gases between the embryonic circulation and the gonopore. Trace the route of the sperm from
seminal vesicle to gonopore.
outer surface layers. In birds and reptiles, the al-
lantois is also a storage sac for nitrogenous 7. Which cells are the germ cells of males and
females? Which cells of the gonads are somatic
waste, mainly uric acid. The yolk sac surrounds
tissue in males and females?
the yolk, secreting digestive enzymes that break
the yolk down into macromolecules that can be
transferred to the embryo. The animal grows
within the egg until it reaches a point where it The Reproductive Cycle of Mammals
can break through the shell. Although non-
The reproductive behavior of female mammals is
monotreme mammals lack the hardened shell of
closely linked to the ovulatory cycle, known as the
other terrestrial vertebrates, they are also am-
estrous cycle. Mammals differ in the number and
niotes and the embryo possesses all of the same
timing of estrous cycles. Monoestrous mammals,
membranes. Later in this chapter, we will elabo-
such as canines, undergo a single estrous cycle
rate on the origins and roles of these membranes
each year. Polyestrous mammals undergo estrous
in mammalian reproduction.
cycles throughout the year, although they may
breed only during certain seasons. Humans and
1
other primates are polyestrous animals, although
The term chorion is a general one that refers to an outer layer
of an extraembryonic structure. The chorions of insects and the estrous cycle is more commonly known as the
amniotes are unrelated in origin or composition. menstrual cycle. Some people make a distinction
720
Reproduction
between estrous and menstrual cycles based upon negative feedback cycles. The hormones that drive
female behavior; a species has an estrous cycle if follicular events cause other physiological and be-
the female demonstrates a period of intense inter- havioral changes in the female.
est in mating that coincides with a specific part of The estrous cycle is composed of four phases:
the ovulatory cycle. For example, dogs and cats go estrus, metestrus, diestrus, and proestrus. The
into heat at a specific point of the estrous cycle; first day of estrus is demarked by the onset of in-
they exhibit anatomical and behavioral changes terest in mating, typically identified by the nature
that “inform” potential mates that they are ovulat- of social interactions or the assumption of mating
ing and interested in copulation. Conversely, hu- postures in the presence of males. In the ensuing
man females exhibit interest in copulation at many sections, we discuss the control of ovarian and
phases of the reproductive cycle and show few uterine events from the human perspective,
outward signs of ovulation. Other people distin- where the ovulatory cycle is discussed as two
guish a menstrual cycle from an estrous cycle by phases of two weeks each. The follicular phase
the magnitude of the loss of uterine tissue loss begins on the first day of menses. The luteal
(menses) at the end of a cycle. Although most phase begins after ovulation. Keep in mind that
species exhibit cyclical changes in the uterine wall, the general features are similar among mam-
and many show evidence of vaginal discharge, the mals, but there is considerable variation in the
relative volume is much greater in primates. Thus, details. For example, not all human females show
the differences between estrous and menstrual cy- a standard 28-day ovulatory cycle. A normal cy-
cles are qualitative in nature and any effort to fur- cle is considered somewhere between 25 and 35
ther distinguish between estrous and menstrual days. It can vary within and among women as a
cycles is somewhat arbitrary. result of diet, stress, and exercise. The shortest
ovulatory cycle in mammals, seen in the golden
hamster, is 4 days. In humans, the ovarian and
Hormones control the ovarian uterine changes are tightly linked in each repro-
and uterine cycles ductive cycle. However, in many species, the na-
Hormones control the cyclical maturation of folli- ture of the cycles and linkage between them may
cles, ovulation, and the parallel changes in the depend on copulation, where the mechanical
uterine wall. With the exception of humans, most stimulation of the vagina induces hormonal
mammalian species coordinate ovulation and cop- changes that in turn affect the ovarian and/or
ulation; the same hormones that regulate ovula- uterine changes. For example, some species use
tion induce external and behavioral displays that copulation to trigger the rupture of the follicles
announce they are receptive to copulation. The (ovulation), and other species are programmed to
hypothalamus releases gonadotropin-releasing ovulate cyclically but modify the uterus only in re-
hormone (GnRH) into the portal blood vessels, sponse to copulation.
causing the anterior pituitary to secrete pulses of
gonadotropins (LH and FSH), which in turn cause
the gonads to produce steroids (progesterone and The follicular phase of ovulation
estradiol-17␤). Another hormone that plays a role is driven by FSH
in the regulation of ovulation is inhibin. A peptide We begin our discussion late in the luteal phase,
hormone of the TGF-␤ family of cytokines, inhibin when the levels of estrogen and progesterone de-
is released by the mature follicle cells and exerts cline by mechanisms clarified later in this section
multiple effects. It has endocrine effects at the (Figure 15). Recall that these hormones suppress
hypothalamic-pituitary axis, inhibiting the release the release of GnRH from the hypothalamus, and
of FSH. It also has autocrine and paracrine effects thereby minimize gonadotropin release from the
at the ovary, inhibiting the production of estrogen.2 anterior pituitary. Thus, once the levels of proges-
These hormones interact through both positive and terone and estrogen fall below a critical threshold,
hypothalamic GnRH is secreted into the blood,
2
Estrogen is a general term that does not distinguish between
stimulating the anterior pituitary to secrete go-
the various estrogens. Although estradiol-17␤ is the most im-
portant estrogen in most mammals, the other estrogens such nadotropins; LH increases slowly whereas FSH in-
as estrone contribute to estrogen signaling. creases more rapidly.
721
Reproduction
Unsuccessful cycle Successful cycle
P E M D
Follicular Luteal Follicular Pregnancy
LH
FSH
Estrogen
Progesterone
Follicle Corpus luteum
Ovary
Ovum
Fertilization
To uterus
Endometrium Implantation
Uterus
Time
Figure 15 Ovulation cycle in mammals The estrous cycle is divided into proestrus (P),
estrus (E), metestrus (M), and diestrus (D), or alternatively the follicular and luteal phase.
The exact relationships differ among species, but in general estrus coincides with ovulation, the
demarcation between the follicular and luteal phases. The figure shows two ovulatory cycles, the
first ending without fertilization and the second with fertilization.
(Source: Adapted from McNaught and Callander, 1975)
These two hormones act on different cell types cells) produce and release progesterone; some es-
of the ovary to coordinate the maturation of the fol- capes into the blood and some makes its way to the
licle and the metabolism of sex hormones. The rise theca of maturing follicles. The theca cells use the
in FSH causes the granulosa cells to proliferate. As progesterone to produce androgens, some of
the follicle grows in size, the outermost layer of which makes its way to the inner granulosa cells,
granulosa cells differentiates to form the theca. where it is used to produce estrogen. This differ-
One function of the mature follicle is to produce the ence in steroid synthesis among ovarian cells is
appropriate amount of progesterone and estrogen. due to the expression of the genes for the enzymes
The extrafolliclar cells of the ovary (interstitial of steroid metabolism. Differentiating theca cells
722
Reproduction
express LH receptors, enabling them to respond to the luteal phase. Depending on the species, the
LH by expressing the appropriate genes for andro- transition from estrus to metestrus occurs either
gen synthesis, as well as aromatase. slightly before or slightly after ovulation.
Early in the follicular phase, many follicles After ovulation, the remnants of the follicle
mature in parallel. As the collection of follicles continue to play an important role in hormone
grows, estrogen secretion increases. The elevated synthesis. Driven by the LH surge, the follicle un-
estrogen in the blood exerts negative feedback on dergoes a change in structure, increasing in size
the hypothalamic-pituitary axis, blocking GnRH and complexity as capillaries and fibroblasts pen-
release from the hypothalamus and production of etrate the structure. The remnants of the ruptured
LH and FSH by the anterior pituitary. The decline follicle appear as a dense yellow body in the ovary
in estrogen and the increase in inhibin act to- known as the corpus luteum (which roughly
gether to suppress FSH release. With FSH levels translates as “yellow body”). The corpus luteum
plummeting, most of the follicles are unable to maintains the ability to synthesize and secrete
sustain their own development and undergo large amounts of progesterone and lesser amounts
atresia, a form of apoptosis. However, a subset of of estrogen. These hormones ensure that the uter-
follicles, called dominant follicles, matures to the ine wall changes in preparation for implantation.
point where they can sustain maturation despite In the luteal phase of the cycle, the corpus lu-
falling FSH. It is not yet clear if the dominant fol- teum sustains steroid hormone secretion for a
licles escape the effects of plummeting FSH by in- time, but estrogen and progesterone levels begin to
creasing the number of FSH receptors, or decline. What happens next depends on whether a
modulating the local signaling environment to fertilized ovum implants in the uterus. If the ovum
make FSH more effective. Regardless of the mech- is not fertilized, progesterone levels continue to de-
anisms, the dominant follicles continue to mature, cline and the next ovulatory cycle begins. Before
with the granulosa cells growing in number while considering what happens when the ovum is fertil-
awaiting the signal for ovulation. ized, we will consider the relationship between the
ovulatory cycle and the changes in the uterine wall.
Ovulation and the luteal phase

follow an LH surge The endometrial cycle parallels
The negative feedback interaction between estro-
the ovulatory cycle
gen and the hypothalamic-pituitary axis is essen- The events in the ovulation cycle are coordinated
tial for follicle maturation and selection of the with changes in the uterine cycle, through shared
dominant follicle. However, in the late follicular sensitivity to steroid hormones. The uterus is
phase, the hypothalamic-pituitary axis reorga- composed of a layer of smooth muscle (myo-
nizes its signaling pathways in a way that reverses metrium) covered by a layer of epithelial tissue
the effects of estrogen. Instead of impairing GnRH (endometrium). When the ovulatory cycle is in the
release, estrogen stimulates GnRH release. follicular phase, the endometrial cycle is in the pro-
Of the gonadotropins, the most important hor- liferative phase. The endometrium thickens as ep-
mone for late follicular maturation is LH. The grow- ithelial, immune, and glandular cells replicate
ing follicle continues to produce estrogen, which in (hypertrophy), with blood vessels growing in paral-
turn enhances LH release, an example of positive lel to ensure vascularization. The luteal phase of the
feedback. The dramatic increase in LH, called the ovulatory cycle coincides with the secretory phase
LH surge, causes the granulosa cells to secrete sev- of the endometrial cycle. The endometrial cells se-
eral factors that support oocyte maturation. crete numerous regulatory factors, including cy-
Paracrine signaling factors induce the oocyte to tokines and prostaglandins, that ensure the uterus
complete its meiotic pathway, generating the ovum. is prepared for implantation of the growing embryo.
Enzymes are secreted to digest the extracellular The hormones involved in regulating the ovu-
matrix between the follicle cells. The follicle weak- latory and endometrial cycles of female mammals
ens and ruptures to release the ovum. Just prior to are summarized in Table 2. The birth control pill,
ovulation, the follicle cells increase the production developed in the early 1960s, is a combination of
of progesterone. Ovulation marks the beginning of hormones that impairs ovulation, fertilization,
723
Reproduction
Table 2 Mammalian reproductive hormones in females in the ovulatory cycle.
Sexual maturation
Estrogens Ovary Secondary sex characteristics: promote fat deposition, maturation
of ovaries and mammary glands
Androgens Ovary, adrenal gland Secondary sex characteristics: promote axillary hair growth and
libido
Puberty and menarche
Follicular phase
GnRH Hypothalamus Anterior pituitary: controls LH release, FSH synthesis and release
LH Anterior pituitary Ovarian follicle: triggers ovulation
FSH Anterior pituitary Ovarian follicle: stimulates estrogen synthesis and follicle
maturation
Estrogens Ovarian follicle Ovarian follicle: stimulate proliferation of granulosa cells
Endometrium: stimulate proliferation of endometrial cells,
sensitization to progesterone, angiogenesis
Hypothalamic-pituitary axis: reduce gonadotropin levels by
negative feedback
Luteal phase
Estrogens Corpus luteum Hypothalamus–anterior pituitary: inhibit GnRH release, reducing
release of FSH and LH from anterior pituitary to prevent
folliculogenesis
Progesterone Corpus luteum Uterus: promotes maturation of endometrium and reduces
uterine smooth muscle contractility
Inhibin Corpus luteum Hypothalamus–anterior pituitary: impairs FSH synthesis and
release
and implantation. Although exact compositions to ensure that the fetus matures to the point that it
differ among brand names, most birth control pills can be expelled from the uterus in the process of
are composed of chemical analogues of estrogen parturition.
and progesterone. Since maturation of follicles in
the late luteal phase is possible only after proges-
terone levels decline, the elevated progesterone
A placenta forms after a fertilized ovum
levels prevent ovulation, essentially by convincing
implants in the uterine wall
the ovary that the female is pregnant. In addition A fertilized ovum begins the process of cell division
to its effects on ovulation, the pill also thickens the and continues to divide for several days. It sheds the
cervical mucus layer, impairing sperm movement zona pellucida, and then the remaining cells form
into the uterus, thus reducing the likelihood of fer- the blastocyst. Groups of cells differentiate to form
tilization if ovulation does occur. If ovulation and the embryonic structures. The outermost cells dif-
fertilization occur, the pill also reduces the likeli- ferentiate to form the trophoblast (Figure 16).
hood of successful implantation because it impairs Then the embryo attaches to the uterine wall to be-
endometrial growth. gin the process of implantation. Trophoblast cells
The regular cycle of ovulation changes when proliferate and invade the endometrium, forming
an ovum is fertilized. The embryonic tissues and an association that will develop into the placenta.
placenta gradually become an endocrine gland, The trophoblast cells differentiate to form the
taking over the central control of hormone levels chorion. At the same time, the inner cell mass of
724
Reproduction
the blastocyst continues to divide Invading Amniotic

and differentiate. First, a gap ap- Epithelial cells trophoblast cells cavity
pears between cells to form the am- Inner

niotic cavity. The cells that surround cell mass
the amniotic cavity differentiate to

form the amnion. The remaining
cells of the blastocyst inner cell mass Trophoblast
form the embryo, which grows to

become the fetus. Uterus Blastocyst
Central to the development of
the fetus is the placenta. It is the in- 5 days 6 days
(postfertilization)
terface between mother and fetus,
and composed of cells derived from
both. For the first third of the preg- Endometrium Amniotic
cavity
nancy, the placenta has a vital en- Chorion Fetus
docrine function. The region of the Embryo
placenta that was derived from the
chorion secretes chorionic go-
nadotropin (CG). Like LH, another
gonadotropin, CG targets the cor-
pus luteum in the ovary to ensure
Allantois
that it continues to secrete estrogen Smooth Placenta
and progesterone. These hor- muscle
mones are vital to the remodeling of uterus
of the mother’s physiology neces-

sary to sustain the pregnancy and
3 weeks 5 weeks 8 weeks
prepare her for parturition and
subsequent maternal care. Later in Figure 16 Embryonic development in the uterus of a placental
the pregnancy, the placenta itself mammal Cell division begins once the egg is fertilized, which usually occurs in the
becomes the main source of pro- oviduct. Implantation begins after the blastocyst binds to the uterine wall. Cells in the
gesterone and estrogen, and the outer blastocyst layer, the trophoblast, invade the endometrium of the uterus and begin
to form the placenta. The extraembryonic membranes develop, and the amniotic cavity
corpus luteum degenerates. In increases in volume. The timeline shown in this figure is for a primate.
some mammals, the corpus luteum
remains the main source of steroid
hormones throughout the pregnancy. 3
The duration of gestation varies widely among Precocial
mammals. Altricial species (those giving birth to mammals
Log gestation period (days)
large litters of poorly developed young) have

shorter gestation periods than precocial species
(those having fewer, well-developed offspring). For
animals of similar body size, the gestation period 2
for a precocial species is about three times longer Altricial
mammals
than that for an altricial species. Body size also
plays a role (Figure 17).
Contractions of uterine smooth muscle

induce parturition 1
0 1 2 3 4 5 6 7 8
The uterus has thick walls of smooth muscle (myo- Log body weight (g)
metrium) underlying the endometrium. As the fetus Figure 17 Gestation period and body size in
develops, the elevated levels of progesterone and mammals Larger mammals have longer gestation times.
estrogens remodel the uterine smooth muscle to (Source: Adapted from Martin, 1989)
725
Reproduction
prepare for parturition. The high levels of estro- strengthening the contractions, an example of
gens enhance the contractile strength of the mus- positive feedback regulation.
cle. They also induce the expression of the genes Soon after the young is born, the placenta is
encoding the receptor for oxytocin, which has an expelled. During gestation, the placenta was a ma-
important role in parturition. While the smooth jor source of estrogen and progesterone. At this
muscle grows in strength, progesterone disrupts point, the female experiences a rapid decline in es-
excitation-contraction coupling to prevent the trogen and progesterone production as a result of
smooth muscle from contracting prematurely. the loss of this endocrine gland. Once the fetus is
Parturition begins in response to a series of born, the maternal physiology begins the process
hormonal changes. The levels of progesterone of postpartum recovery from birth, and simultane-
decline, allowing the strong uterine muscles to ously initiates the early steps of maternal care, in-
contract. At the onset of labor, fetal cells produce cluding milk production. The hormones involved
oxytocin, which acts on the placenta to induce in regulating parturition and postpartum events
the release of prostaglandins. At the same time, are summarized in Table 3.
the mounting stress in the mother triggers the
hypothalamic-pituitary axis, causing the release
of oxytocin from her own posterior pituitary. Milk is a secretory product
Prostaglandins and oxytocin act on the uterine of mammary glands
smooth muscle directly to induce contractions Mammals are unique in possessing mammary
that begin to propel the infant along the uterus. glands that enable a female to produce milk for
As labor progresses, the additional stress trig- her offspring. Although a remarkable adaptation,
gers the release of even more oxytocin, further the mammalian mammary gland has many paral-
Table 3 Mammalian reproductive hormones in pregnancy and parturition.
Pregnancy
Chorionic gonadotropin Placenta Stimulates release of estrogen from corpus luteum
Estrogens Placenta Mammary glands: stimulate proliferation of secretory cells but
prevent milk secretion
Cervix: reduce mechanical resistance (ripens)
Uterus: stimulate uterine smooth muscle (blocked by
progesterone)
Uterus: stimulate angiogenesis and mitotic division in
endometrium
Progesterone Placenta Uterus: blocks estrogen’s stimulation of smooth muscle
Ovary: prevents ovulation
Parturition
Oxytocin Posterior pituitary Uterus: promotes smooth muscle contraction
Prostaglandins Placenta Uterus: promote smooth muscle contraction
Prolactin Anterior pituitary Mammary glands: promotes growth and colostrum synthesis
Postpartum events
Oxytocin Posterior pituitary Mammary glands: promotes smooth muscle contraction
Prolactin Anterior pituitary Mammary glands: stimulates growth and milk synthesis
726
Reproduction
lels. As mentioned earlier in this chapter, some ventral skin of the female. There are no teats or
species produce secretions that feed the offspring nipples to localize secretions; the milk oozes
while still in the reproductive tract, such as the through the ducts onto the mother’s fur, where it
uterine milk of ovoviviparous fish. Several non- pools in surface indentations. Marsupials have a
mammalian species produce nutrients for their more complex mammary gland with discrete
free-living offspring. For example, pigeons pro- teats. The young locate the teat and suck it into
duce crop milk, a secretion produced by the upper the mouth, where it engorges to fill the oral cav-
gastrointestinal tract and regurgitated into the ity, locking the pup into position. Eutherian
mouths of the chicks. mammals possess complex mammary glands
Milk is produced by the mammary gland, and that are networks of lobes grouped into alveoli,
in almost all cases only the female produces milk. with ducts that empty through an external teat
In the mid-1990s, researchers in Malaysia discov- (Figure 18). Unlike marsupials, the young of eu-
ered that males of the local fruit bat species could therian mammals can attach and detach at will.
produce and secrete milk. Even human males can Behavioral interactions associated with feeding
undergo changes that induce their quiescent help establish a social bond between mother and
mammary glands to produce milk. Most com- offspring.
monly this is due to pathological changes in en-
docrine tissues, but there have been verified
reports of lactation in pubescent males, and even Mammary gland secretions include two
documented cases of adult men producing enough novel products, casein and lactose
milk to suckle an infant. Mammary gland secretions are the source of wa-
The hormone that controls milk production in ter, salts, and nutrients for the infant, but the na-
mammals is prolactin, a peptide hormone released ture of the milk changes with time. The earliest
from the anterior pituitary gland. Interestingly, the secretions from the mammary gland, called
role of prolactin in mammals is a variation on its colostrum, are rich in immunoprotective agents,
role in other vertebrates, including regulation of se- growth factors, minerals, and vitamins A and D.
cretory function, ion and water balance, and even The colostrum also has a trypsin inhibitor that
behavior (see Box 2, Genetics and Genomics: Pro- protects the vital proteins in the colostrum from
lactin). During pregnancy, estrogen produced by digestion in the infant’s gastrointestinal tract. At
the corpus luteum, and later the placenta, induces this point in development, the infant’s gastroin-
prolactin release. Prolactin prepares the mammary testinal tract is able to transport antibodies intact,
gland for milk production by increasing mammary transferring them to its own circulation.
gland mass and ensuring that the biosynthetic ma- As the colostrum is depleted by the infant, the
chinery is in place. During pregnancy, the high lev- mammary gland produces a milk that is much
els of progesterone and estrogen suppress the richer in lipids and carbohydrates. Lipids provide
actual production of milk. Only after the levels of es- both energy and biosynthetic precursors. The
trogen and progesterone decline during parturition milk of marine mammals can be in excess of 60%
does the mammary gland produce milk. lipid, allowing the pups to accumulate the blub-
Several features of mammary glands are ber needed for insulation. The milk sugars are
shared among all mammals. Like sebaceous dominated by lactose (often called milk sugar),
glands, mammary glands are associated with but there are also more complex oligosaccha-
hair follicles. The mammary glands are com- rides. The sugars serve two main purposes. First,
posed of both exocrine cells, which secrete the they are an energy source that is readily catabo-
milk, and myoepithelial cells, which control the lized by fetal tissues. Second, the sugars are im-
secretions. The milk itself is a mixture of fluids portant biosynthetic precursors, particularly the
and macromolecules released from exocrine cells more complex oligosaccharides with amino sug-
under the control of prolactin. However, the three ars that are important for membrane glycolipids
groups of mammals differ in the complexity of the and glycoproteins. Milk also possesses abundant
secretion and the anatomical structure of the protein, primarily casein (often called milk pro-
gland itself. The monotreme mammary gland tein), which serves as an important source of
consists of convoluted tubes that lie beneath the amino acids for biosynthesis. This protein is
727
Reproduction
mately linked with the evolution of mammals. Lac-

Milk ducts
tose is produced by the enzyme lactose synthase,
which is a complex of two proteins: galactosyl-
Alveoli transferase and ␣-lactalbumin. Galactosyltrans-
ferase, which is found throughout eukaryotes, is
one of the many enzymes that catalyze glycosy-
lation reactions in the Golgi apparatus, adding
Teat galactose to various macromolecules, including
proteins and lipids. However, in the mammary
gland, the galactose acceptor for galactosyltrans-
ferase is glucose, and the disaccharide lactose is
produced. This unique capacity is conferred by the
second subunit of lactose synthase, ␣-lactalbumin.
This subunit is structurally related to another en-
Myoepithelial zyme, lysozyme. Thus, the capacity to produce
cells
lactose may have arisen only after the duplication
of a lysozyme gene early in the mammalian line-
age. The duplicated gene subsequently mutated
Milk-secreting into a form that could dimerize with galactosyl-
epithelial cells transferase to form the unique enzyme lactose
synthase.
The protein casein most closely resembles
the γ-chain of fibrinogen, a serum protein that is
Milk duct involved in clotting of blood. Interestingly, the
most primitive mammary glands produce a se-
cretion that is primarily derived from presynthe-
sized components of the blood, including
Milk-secreting
epithelial cells fibrinogen. More advanced mammals rely prima-
rily on molecules produced directly in the mam-
Milk fat
mary gland. Thus, it is thought that evolution led
globules to a shift from provision of serum proteins, such
as fibrinogen, to production of fibrinogen-like
Capillary
Transcytosis of proteins produced directly within the gland. The
Adipocyte blood proteins mammary gland is an excellent example of the
Nucleus
way evolutionary processes produce something
Secretory vesicle novel by modifying existing genes and anatomi-
(casein, lactose)
cal structures. The production of milk and the na-
ture of the mammary gland reflect an integration
of unique aspects of biochemistry, physiological
Figure 18 Synthesis of mammary gland secretions
The secretory units of the mammary gland are the alveoli. They
regulation, and anatomical structure.
produce casein (milk protein) and lactose (milk sugar) in the ER-
Golgi network, secreting it into the milk duct via exocytosis. Lipid
droplets accumulate within the mammary epithelial cells Prolactin controls parental behavior
through synthesis and uptake from adipocytes. Some proteins
Apart from its effects on milk production, pro-
are taken up from the blood and carried by
transcytosis across the epithelial cell and secreted into the lactin also influences maternal behavior. Preg-
milk duct. nancy and lactation lead to a remodeling of the
hormonal regulatory pathways, including hor-
highly phosphorylated, enabling it to bind Ca2⫹. mone production and hormone receptor expres-
Almost 90% of the Ca2⫹ in the infant diet is locked sion. In mammals, prolactin and steroid hormones
into the structure of casein particles. work in conjunction to alter the biochemistry of the
The two novel products found in the milk— brain and behavior of the female. This remodeling
lactose and casein—have origins that are inti- process begins in pregnancy and continues during
728
Reproduction

Prolactin
Though named for its role in promoting role of prolactin is in the control of water and Na⫹ move-
lactation in mammals, prolactin arose early in ments across the epithelia of the gill, gut, and kidney. Pro-
vertebrate evolution. Somewhere around 850 million lactin also plays a role in osmoregulation of amphibians,
years ago, a gene was duplicated and the pair of genes but its most dominant function appears to be in growth
diverged to give rise to two hormones: prolactin and and development. In the larvae, it promotes growth while
growth hormone. It is not clear whether the ancestral impairing metamorphosis, antagonizing the actions of
gene was involved primarily in growth control (like thyroid hormone. Interestingly, prolactin surges also in-
growth hormone) or osmoregulation (like prolactin). duce amphibians to return to the water to breed, perhaps
The exact timing of these events also remains unclear in foreshadowing the increasing importance of prolactin as
part because modern agnathans produce growth hor- a reproductive hormone. The emergence of reptiles and
mone, but not prolactin. Early in the evolution of bony the movement to land was accompanied by changes in the
fish, after the teleost and non-teleost fish lineages di- regulation of ion and water balance. Prolactin plays a
verged, mutations in the prolactin gene in one of the lin- relatively minor role in osmoregulation in birds and mam-
eages led to a difference in the number of disulfide mals through effects on the kidney, intestine, and salt-
bonds in prolactin structure: two in teleost fish and secreting cells (sweat glands of mammals, nasal salt
three in the animals arising from the non-teleost line- gland of birds). With a diminished role in osmoregulation,
age, such as lungfish and tetrapods. Unfortunately, prolactin gained a greater role in control of reproductive
many of the earliest studies on the role of prolactin in physiology of mammals.
fish were performed using hormone purified from cows Almost 80 years ago, prolactin was identified as a
and sheep, before the fundamental difference in struc- hormone that stimulated milk production in mammals.
ture in teleost and tetrapod prolactin was known. Shortly thereafter, it was also shown to stimulate the
In some taxa, additional gene duplications led to ad- production of crop milk, a secretion produced in the up-
ditional prolactin-like proteins. Shortly after the lineage per digestive tract of some birds. It has since been
of teleost fish arose, another gene duplication event oc- shown to stimulate the growth of the mammary gland
curred, creating a third protein, somatolactin. This pro- epithelial cells, and to induce the expression of genes
tein is similar in structure to both prolactin and growth for milk proteins and metabolic enzymes needed for
hormone, so it is not clear which of the genes was du- synthesis of milk sugars and fats. Prolactin in mammals
plicated. In mammalian lineages, there have been addi- also affects the maintenance and function of the repro-
tional gene duplication events that have led to gene ductive tracts of the female (uterus and ovary) and male
families of prolactin-like proteins. Ruminants and ro- (prostate, seminal vesicles, epididymus, Sertoli cells,
dents independently experienced multiple duplications and Leydig cells). Prolactin also controls parental be-
of the prolactin gene, creating families of prolactin-like havior in numerous species of mammals, birds, and
proteins. Throughout most tetrapods, the structure of even fish, often interacting with regulation by glucocor-
prolactin is highly conserved, though a few lineages ticoids and androgens. Prolactin is an excellent example
have experienced periods of accelerated evolution lead- of a signaling molecule with a function that diversified
ing to structural divergence. In most cases where stud- through evolution of the protein, its receptor, and phys-
ied in sufficient detail, the prolactin-like proteins iological processes that employ this hormone.
appear to have roles that appear similar to that of pro-
lactin. Many of these prolactin relatives are expressed in References
tissues other than the anterior pituitary, though usually q McCormick, S. D., and D. Bradshaw. 2006. Hormonal control of
in tissues involved in reproduction, such as the mam- salt and water balance in vertebrates. General and Comparative
Endocrinology 147: 3–8.
malian placenta and uterus.
The function of prolactin has also changed over the q Bole-Feysot, C., V. Goffin, M. Edery, N. Binart, and P. A. Kelly.
1998. Prolactin (PRL) and its receptor: Actions, signal transduc-
course of evolution; across vertebrates prolactin has
tion pathways and phenotypes observed in PRL receptor knock-
been shown to have roles in (1) water and electrolyte out mice. Endocrinology Reviews 19: 225–268.
balance, (2) reproduction, (3 growth and development,
q Storey, A. E., K. M. Delahunty, D. W. McKay, C. J. Walsh, and S. I.
(4) endocrinology and metabolism, (5) brain and behav- Wilhelm 2006. Social and hormonal bases of individual differ-
ior, and (6) immunoregulation. Its earliest role was in ences in the parental behaviour of birds and mammals. Canadian
the control of ion and water balance. In fish, the main Journal of Experimental Psychology 60: 237–245.
729
Reproduction
lactation. Virgin females that are exposed to unre- help groom the offspring, retrieve wandering pups,
lated newborns may gradually acquire maternal and assist in thermoregulation. Remarkably, the
behaviors and adopt the infant. The acquisition of mates of pregnant females experience hormonal
maternal behavior is related to the increase in changes that alter their paternal behavior. The de-
prolactin synthesis and expression to prolactin re- gree (and skill) of paternal behavior is linked to
ceptors in the medial preoptic area of the hypo- both hormonal changes and experience. Among
thalamus. In mice with their prolactin receptors those species of mammals that exhibit paternal
knocked out, females show less interest in caring care, attending fathers usually have higher levels of
for their own young and less willingness to adopt prolactin in the blood than do nonpaternal males.
other pups. Interestingly, females that have had The superior skills and attention demonstrated by
multiple experiences birthing and rearing infants experienced males may also be due to higher pro-
often show a reduction in prolactin levels relative lactin levels. Interestingly, prolactin has also been
to novices. It is thought that maternal behaviors in implicated in other species that exhibit paternal
these females are sustained through greater sensi- care, including fish and birds. It is not yet known
tivity of the hypothalamus to prolactin. how prolactin affects the central nervous system to
The prevalence of maternal care in animals is influence paternal behavior.
rationalized by evolutionary arguments that only
the mother can be certain of parentage of the off-
spring, so the father’s energy is best spent copulat- 2 C O N C EP T CH E CK
ing. Paternal care occurs in some mammals,
8. What are the main phases of the mammalian
primarily canines, rodents, and a few primates. In-
female ovulatory and endometrial cycles?
terestingly, paternal care also appears to be con-
9. What hormones are produced by the ovarian
trolled by prolactin. In Djungarian hamsters, tissue during the ovulatory cycle?
paternal care may begin at parturition, with fathers
10. Provide examples of negative and positive
acting as midwives by assisting with the birth of the feedback in the regulation of the ovulatory cycle.
pups. During early pup growth, the fathers may
Integrating Systems Reproduction and Stress

Stress and reproduction are inseparable. Reproduc- many effects on nonreproductive physiology. In gen-
tion is a demanding activity that influences other phys- eral, the interactions between reproduction and stress
iological systems and consequently challenges are reciprocal; reproduction causes stress but stress
homeostatic regulation. Reproduction disrupts homeo- impairs reproduction. It has been hypothesized that
stasis and causes stress in two ways. First, it exerts ef- male displays reflect an ability of males to successfully
fects on energy metabolism. Reproducing animals cope with the stresses of reproduction.
incur considerable energetic costs in producing and The many forms of stress are regulated by the
supporting reproductive systems, provisioning re- chemical communication network formed by the hy-
sources for fetal growth, building and maintaining tis- pothalamus, the anterior pituitary, and the adrenal
sues for sexual displays, and enduring physical cortex (or interrenal cells in vertebrates such as fish).
challenges in competing for mates. Second, reproduc- When exposed to an external stress, animals alter
tion causes stress through hormonal antagonism. The hormonal conditions (typically elevated cortico-
glucocorticoids (stress hormones) that trigger mobi- sterone) to mobilize fuels, produce glucose, and sup-
lization of energy metabolism also exert direct effects press energy-dependent processes such as growth
on reproductive physiology. The sex hormones also ex- and reproduction. This defense response allows the
ert their own effects on other systems, which may be animal to survive. Conversely, reproduction itself may
advantageous and expensive, but may also be disrup- create a stressful condition that requires the animal to
tive yet tolerated. Testosterone, in particular, has modify its stress hormone production to gain some of
730
Reproduction
the benefits, like energy production, while curtailing 15

the repressive effects of stress on reproduction. In
many cases, the elevation in the levels of hormones
Corticosterone (ng/ml)
such as corticosterone is a necessary component of Male
10
reproductive physiology. For example, when frogs call,
they are engaging in one of the most energetically ex-
pensive behaviors seen in ectotherms. The energy for
calling is produced when glucocorticoids trigger fuel 5
Female
mobilization, but the calling itself is dependent on
testosterone. More testosterone leads to more calling,
which demands more energy, which requires elevated
glucocorticoids. After a point, glucocorticoids reach 0
0 1–2 3–4 5–6 7–8
such high levels that a stress response ensues, and Time after capture (h)
testosterone production is curtailed.
(a) Effect of sex
Animals can influence the steroid-dependent path-
ways by altering steroid production, by producing
steroid-binding proteins, and by altering the profile of 15
steroid hormone receptors. As a result, the magnitude
of the stress response can depend on the sex and repro-
Corticosterone (ng/ml)
Nonbreeding female
ductive state of the animal. Consider the way sex and re-
10
productive state influence how capture manifests as
stress in sea turtles. When males and females are cap-
tured at sea, males exhibit greater increases in the
stress hormone corticosterone. Similarly, nonbreeding 5
Breeding female
females exhibit a greater degree of capture stress than
breeding females (Figure 19). The hormonal back-
ground associated with sex and breeding status influ-
0
ences how other hormones exert their effects. 0 1–2 3–4 5–6 7–8
Many of the interactions between reproduction and Time after capture (h)
stress physiology can be traced back to the interactions (b) Effect of reproductive status
between testosterone, secondary sex characteristics,
Figure 19 Plasma corticosterone levels in
and the immune system. High levels of testosterone im- green sea turtles Many animals respond to capture by
pair the immune system, compromising immunocom- inducing stress hormones, such as corticosterone. The
petence. The link is shown experimentally by treating magnitude of the response is influenced by other hormones
males with testosterone implants. Studies in many related to (a) sex or (b) reproductive state.
(Source: Adapted from Moore and Jessup, 2003)
species show that increased testosterone augments
secondary sex traits but can also make males more
susceptible to parasites and disease. clined to the point at which the animal became un-
This antagonistic relationship is thought to be one healthy. Since testosterone is linked to male secondary
important factor in sexual selection for male displays. sex traits, many studies have illustrated the relation-
The immunocompetence-handicap hypothesis suggests ship between male displays and immunity. For exam-
that male traits evolve in a way that allows each male ple, male redwing blackbirds sing loud songs at
to build the most impressive display possible without frequent intervals to attract females and defend a ter-
compromising its own health. Thus, in the natural ritory. The hypertrophy of the muscles required to sing
world only those males with impressive immunocom- depends on testosterone levels. Male redwing black-
petence can tolerate the negative effects of building birds with the greatest singing capacity also have
impressive displays. It would not suit a male deer to stronger immune systems, as indicated by parasite
build such a large display that its immune system de- load and bloodborne immune cells.2
731
Reproduction
Summary
Sexual Reproduction k Spermatogenesis occurs in the testes, and cop-
k The hypothalamic-pituitary axis in conjunction ulatory organs increase the efficiency of sperm
with gonadal steroid hormones control verte- transfer.
brate reproduction. The neurons of the hypothal-
k Females of some species can store sperm for
amus secrete gonadotropin-releasing hormone
long periods after mating to ensure uninter-
in the region of the anterior pituitary, which
rupted reproduction.
responds by secreting luteinizing hormone and
follicle-stimulating hormone. k Once the ovum is fertilized, factors derived from
the ovum control early development.
k Invertebrate hormones are less understood
than those of vertebrates, except in arthro- k Amniote embryos produce four cellular ex-
pods where terpenoid hormones and traembryonic membranes: chorion, allantois,
20-hydroxyecdysone control reproduction amnion, and yolk sac. The chorion of placental
and development. mammals interacts with the maternal tissue to
create the placenta.
k The efficacy of these hormones is controlled by
synthesis and degradation of both hormones k The mammalian ovulatory cycle is controlled by
and receptors. the hypothalamic-pituitary axis.
k Some animals reproduce by asexual reproduc- k Once the follicle ruptures, releasing the ovum,
tion, either clonal or parthenogenic, but most the remaining follicular cells differentiate to
animals use sexual reproduction. form the corpus luteum, which continues to
produce estrogens and progesterone.
k Males make small gametes (sperm), and fe-
males make large gametes (ova). k In mammals, the fertilized ovum implants in the
uterine wall and grows.
k Sex may be determined by genotype, as in the
XY system or ZW system, or by environment, as k After the follicle ruptures, the corpus luteum
in temperature-dependent sex determination. produces steroids in response to hypothalamic
and, in primates, chorionic gonadotropins, sus-
k Gametes are produced by meiosis. Ova are
taining the pregnancy. With time, the corpus lu-
produced within follicles of somatic tissue in
teum degrades and the placenta maintains
an ovary. The ovum is augmented with yolk, a
synthesis of progesterone and estrogens.
protein- and lipid-rich source of nutrients for
the growing embryo. k The steroid hormones (estrogen and proges-
terone) and peptide hormones (prolactin and
k Oviparous animals expel either ova (external
oxytocin) prepare the female for parturition and
fertilization) or fertilized eggs (internal fertiliza-
postnatal care.
tion), allowing the embryo to develop externally.
Ovoviviparous animals retain fertilized eggs in- k Milk, a secretory product of mammary glands,
ternally. Viviparous animals bear live young, is unique to mammals, allowing the female to
which develop internally and derive nutrition transfer nutrients to the young. Prolactin con-
from the maternal tissues. trols milk production, as well as both maternal
and paternal behavior.
732
Reproduction
Review Questions
1. Compare the roles of steroid hormones in the 4. Compare the features of ovipary, ovovivipary,
reproduction of vertebrates and invertebrates. and vivipary.
2. Discuss how hormones regulate the ovulatory 5. Discuss the diverse roles of smooth muscle in
cycle of mammals. reproductive physiology.
3. Discuss the various modes of sex determina- 6. Compare the pathways of gametogenesis in
tion in animals. males versus females.
Synthesis Questions
1. Embryos derive nutrition from yolk, except in same cellular machinery is used differently in
placental mammals. Discuss the benefits and males versus females.
risks of the two modes of nutrient delivery. 5. Using only mammalian examples, discuss the
2. Why are animals with temperature-dependent energetic trade-offs for K-type versus r-type
sex determination at risk from endocrine life history strategies.
disruptors? 6. Apart from affecting swimming energetics,
3. Both yolk and milk are products of cellular se- how might sperm tail length be evolutionarily
cretion. Compare their pathways for synthesis advantageous or disadvantageous?
and secretion. 7. Choose examples of male sexual displays and
5. Males and females develop from genomes that discuss the cellular mechanisms that animals
are the same, except for a few genes on the sex would use to produce the features.
determination chromosome. Discuss how the
1. Sperm of most fish are released into the water 100 µm/sec and continues swimming for
and commence swimming to find an egg. The 2 minutes, how far will it swim? What is the
duration of swimming activity can be as short significance of your result in relation to mating
as a couple minutes or may continue for sev- strategies of fish?
eral hours. If a sperm swims at a velocity of
For Further Reading

See the Additional References section at the back Moore, I. T., and T. S. Jessop. 2003. Stress,
of the book for more readings related to the reproduction, and adrenocortical modulation
topics in this chapter. in amphibians and reptiles. Hormones and
Behavior 43: 39–47.
Sex and Hormones
These papers discuss how anthropogenic factors, Most animals have a sexual reproduction
including global warming, influence the health of mode much like that of humans, but insects
animals through effects on reproductive biology. differ in both the way sex is established and
Guillette, L. J., Jr., and M. P. Gunderson. 2001. the role of sexual reproduction in life history
Alterations in development of reproductive strategy
and endocrine systems of wildlife populations Normark, B. B. 2003. The evolution of alternative
exposed to endocrine-disrupting genetic systems in insects. Annual Review of
contaminants. Reproduction 122: 857–864. Entomology 48: 397–423.
733
Reproduction
Insect reproduction is well studied because of its Riffell, J. A., P. J. Krug, and R. K. Zimmer. 2004.
impact on human activities, particularly disease The ecological and evolutionary consequences
and agriculture. of sperm chemoattraction. Proceedings of the
Simonet, G., P. Poels, I. Claeys, T. Van Loy, V. National Academy of Sciences, USA 101:
Franssens, A. De Loof, and J. Vanden Broeck. 4501–4506.
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Credits
662 Exactostock/SuperStock
663 National Geographic Image Collection, Paul
Nicklen/National Geographic Image Collection.
663 jspix jspix/Imagebroker/
PhotoLibrary.
677 Photo courtesy of Scott Pitnick, Syracuse University.
735
736
Appendix
The International System of Units
(Système Internationale d’Unités)
Measurements are useful only if they are expressed units and some selected conversion factors are
with a unit. If a person said that his dog weighs 30, shown in the accompanying table.
it would be impossible to determine whether he The Système Internationale is based on seven
was talking about a Chihuahua or a Great Dane; fundamental units of measure (the meter for
but if he described the dog as weighing 30 kilo- length, the kilogram for mass, the mole for an
grams, it would be clear that the dog was about the amount of a substance, the second for time, the
size of an adult German shepherd. Thus, a good ampere for electrical current, the kelvin for tem-
system of units allows us to interpret measure- perature, and the candela for luminosity). All of
ments, and to share them with other people. the other units can be derived from these base
Système Internationale (SI) units are the pre- units. For example, the unit for velocity (distance
ferred units of measure for most scientific disci- traveled per unit time) is meters per second.
plines. The SI system has the advantage of being Derived SI units can be expressed using either
decimal, internally self-consistent, and precisely numerator/denominator notation (e.g., m/s) or ex-
defined. Most physiological journals require that ponential notation (ms1). The correct SI form is
physical quantities be expressed in SI units. How- exponential notation, because it allows complex
ever, you will often see other units used in the units to be expressed clearly. However, in this text
older physiological literature or in clinical situa- we have generally used numerator/denominator
tions, so it is important to be able to convert notation, because most students find it easier to un-
among the various systems of units. The main SI derstand, and we are generally working with rela-
tively simple units such as velocity.
SI and Derived Units

Quantity SI unit Abbreviation Selected conversion factors
Base units
Length meter m 1 m 3.28 ft
Mass kilogram kg 1 kg 2.20 lb
Amount of matter mole mol
Time second s
Temperature kelvin K A difference of 1 K is equal to a difference
of 1°C (Celsius); 0 K 273°C
Electric current ampere A 1 A 6.24 × 1018 charges per second
Luminosity candela cd
Derived units
Area square meters m3 1 m2 10.8 ft2
Volume cubic meter m2 1 m3 1000 liters (l)
1 cm3 1 milliliter (ml)
3.785 l 1 U.S. gallon
3
Density kilograms per cubic meter kgm 3
(or kg/m ) 1 kgm3 1 g/l
Velocity meters per second ms1 (or m/s) 1 ms1 3.28 ft/s
1
Frequency events per second; hertz Hz s
Acceleration meters per second squared ms2 (or m/s2) 1 ms2 3.28 ft/s2
(continued)
From Appendix A of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
737
Appendix: The International System of Units
SI and Derived Units (continued)

Quantity SI unit Abbreviation Selected conversion factors
Force newton (N) N mkgs2 1 N 0.102 kg of force

1 N 0.225 lb of force
2 1 2
Pressure pascal (Pa) Pa Nm m kgs 1 Pa .0075 millimeters of mercury
(mm Hg)
1 kilopascal (kPa) 7.5 mm Hg
1 atmosphere (atm) 101.3 kPa 760
mm Hg
Energy (work) joule (J) J Nm m2kgs2 1 J 0.239 calories (cal)
3
Power watts (W) W J/s m kgs
2
1 W 0.239 cal/s
Electrical potential watts per ampere; volts (V) V WA1 m2kgs3A1
Electrical resistance volts per ampere; ohm () V/A m2kgs3A2
Electrical charge coulomb (C) C sA
Capacitance farad (F) F CV1 m2kg1s4A2
Prefixes for Units Prefixes for SI Units

Prefixes can be added before an SI unit to indicate Prefix Abbreviation Factor English name
decimal multiples and submultiples of that unit. 24
yotta Y 10 U.S. septillion;
These prefixes are used to avoid very large or very U.K. quadrillion
small numeric values. You are probably already fa- zetta Z 1021 sextillion
miliar with units such as the kilometer, which rep- 18
exa E 10 U.S. quintillion;
resents 1000 meters. U.K. trillion
These prefixes can be used with any SI unit,
peta P 1015 U.S. quadrillion
with the exception of the kilogram; the kilogram is 12
tera T 10 U.S. trillion;
the only SI unit that comes with its own prefix. In- U.K. billion
stead, the prefixes are used with the unit “grams”
giga G 109 U.S. billion
(g). Thus, 106 kg 1 mg (one milligram), not 1 µkg
mega M 106 million
(one microkilogram).
3
Here is a list of the 20 accepted SI prefixes, kilo k 10 thousand
only some of which (indicated in bold) are com- hecto h 10 2
hundred
monly encountered in the biological literature. deca da 10 1
ten
deci d 101 tenth
2
centi c 10 hundredth
3
milli m 10 thousandth
6
micro µ 10 millionth
nano n 109 U.S. billionth
12
pico p 10 U.S. trillionth;
U.K. billionth
femto f 1015 U.S. quadrillionth
18
atto a 10 U.S. quintillionth;
U.K. trillionth
zepto z 1021 U.S. sextillionth
24
yocto y 10 U.S. septillionth;
U.K. quadrillionth
738
Appendix
Logarithms
Logarithms are important in physiology in three bases. For example, natural logarithms are pow-
main contexts: (1) the pH scale is logarithmic, ers of the mathematical constant e. The base of a
(2) the membrane potential of a cell depends on the logarithm is indicated by the subscript following
natural logarithm of the ratio of the intracellular the abbreviation “log.” For example, a base 10 log
and extracellular ion concentrations, and (3) phys- would be written log10, and a base 4 logarithm
iological data are often presented on graphs with would be written log4. However, by convention
logarithmic or semilogarithmic scales. Thus, it is base 10 (or common) logarithms are generally
important that you have a clear grasp of logarithms written simply as the abbreviation “log” (without a
in order to understand physiology. subscript), whereas base e (or natural) logarithms
A logarithm is essentially the same thing as a are generally abbreviated as “ln.”
power or exponent. For example, we know from Recall that the pH of a solution is equal to the
basic mathematics that 102 ⫽ 100. The common negative log of the hydrogen ion concentration of
logarithm of 100 is simply the power of 10 that that solution (pH ⫽ ⫺log[H⫹]). To calculate the pH
gives you 100; that is, 2. Similarly, the common of a solution, you need to know two simple rules
logarithm of 1000 is 3, and the common logarithm about logarithms and exponents:
of 10,000 is 4. The logarithms of numbers be-
⫺log(x) ⫽ log(1/x)
tween these values can easily be determined using
a “log table” or on most calculators. One important 1/(10x) ⫽ 10⫺x
point to note about logarithms is that the loga-
A solution whose hydrogen ion concentration is
rithm of a number less than one but greater than
10⫺8 M has a pH equal to ⫺log(10⫺8). Using the first
zero is a negative number. For example, the num-
rule above, you can rewrite this expression as
ber 0.1 can be written as 10⫺1. Thus, the loga-
log(1/10⫺8), and using the second rule, you can
rithm of 0.1 is ⫺1.
rewrite this equation as log 108. Thus, the pH of
Note that the common logarithm always refers
this solution is 8.
to a power of 10; 10 is the base of the common log-
arithm. We can also have logarithms of other
From Appendix B of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
739
Appendix
Linear, Exponential, Power, and Allometric Functions
Physiological variables can often be analyzed Power functions are superficially similar to ex-
graphically. A graphical presentation allows us to ponential functions, and have the form
determine the relationship between two variables
y ⫽ bxa
(for example, body size and metabolic rate, or age
and blood pressure). These relationships can then where x is the independent variable, y is the de-
be expressed as mathematical functions. The most pendent variable, and a and b are constants. It is
common types of mathematical functions that ap- easy to confuse power functions with exponential
ply to physiological data are (1) linear functions, functions, but note that in a power function, the in-
(2) exponential functions, and (3) power functions. dependent variable is raised to a constant power,
The standard form of a linear function is whereas in an exponential function a constant base
is raised to a variable exponent.
y ⫽ ax ⫹ b
As with exponential functions, we can lin-
where x is the independent variable, y is the de- earize a power function using logarithms. By tak-
pendent variable, a is the slope of the line, and b is ing the log of both sides of the power function we
the intercept of the line on the y-axis. obtain
The standard form of an exponential func-
log y ⫽ log b ⫹ a log x
tion is
Using a log-log scale we can plot log y against log x
y ⫽ b⭈ax
and obtain a straight line with a slope of a and an
where x is the independent variable, y is the de- intercept of log b.
pendent variable, and a and b are constants. We Power functions are commonly used in physi-
can take the logarithm of both sides of this equa- ology to study allometric, or scaling, relationships.
tion to yield In fact, this use is so widespread that physiologists
typically refer to power functions as allometric
log y ⫽ log b ⫹ x log a
functions. Galileo was one of the first scientists to
Note that this equation now has the same form as notice scaling relationships. He observed that
a linear function where the slope of the line is log large animals have limb bones that are dispropor-
a, and the intercept is log b. Using a semilog scale, tionately thicker than those in small animals.
we can plot log y against x, giving a straight line. In Many other physiological parameters also vary
this way we can transform an exponential function nonproportionally with body size, and these rela-
into a linear function, which is often easier to ana- tionships can usually be described using power
lyze than a graph of an exponential function. functions.
From Appendix C of Principles of Animal Physiology, Second Edition. Christopher D. Moyes, Patricia M. Schulte.
740
Appendix: Linear, Exponential, Power, and Allometric Functions
Useful Formulae Physical and Chemical Constants

Ohm’s law V ⫽ IR Constant Value
V ⫽ voltage drop across the system
I ⫽ current Avogadro’s number NA ⫽ 6.022 × 1023
R ⫽ electrical resistance (molecules in a mole)
Power (electrical) P ⫽ IV Faraday constant F ⫽ 96,487 C/mol

P ⫽ Power
Gas constant R ⫽ 8.314 J⭈K⫺1⭈mol
I ⫽ current
⫽ 0.082 L⭈atm⭈K⫺1⭈mol
V ⫽ voltage drop across the system
Planck’s constant h ⫽ 6.626 × 10⫺34 J⭈s⫺1
Pressure P ⫽ f/a
⫽ 1.58 × 10⫺34 cal⭈s⫺1
P ⫽ pressure
f ⫽ force Speed of light in a vacuum c ⫽ 2.997 × 108 m⭈s⫺1
a ⫽ area
Specific heat of water 4187 J⭈mol⫺1⭈°C⫺1
Law of bulk flow Q ⫽ ⌬P/R
Q ⫽ flow Heat capacity of air 1.21 kJ⭈m⫺3⭈°C⫺1
⌬P ⫽ pressure drop across the system (20°C, 101.3 kPa)
R ⫽ resistance to flow
Heat capacity of water 4.18 MJ⭈m⫺3⭈°C⫺1
Power P ⫽ w/t (20°C, 101.3 kPa)
P ⫽ power
w ⫽ work
t ⫽ time
Ideal gas law PV ⫽ nRT
P ⫽ pressure
V ⫽ volume
n ⫽ number of molecules
R ⫽ gas constant
T ⫽ temperature (in kelvins)
Boyle’s Law P1V1 ⫽ P2V2
P ⫽ pressure
V ⫽ volume
Dalton’s law of PT ⫽ P1 ⫹ P2 ⫹ P3 . . .
partial pressures PT ⫽ total pressure
P1, P2, P3, etc. ⫽ pressure of each constituent gas
in a gas mixture
Newton’s second F ⫽ ma
law (of motion) F ⫽ force
m ⫽ mass
a ⫽ acceleration
Potential energy E ⫽ mgh
E ⫽ energy
m ⫽ mass
g ⫽ acceleration due to gravity
h ⫽ height above surface
Kinetic energy E ⫽ 1/2mv2
E ⫽ energy
m ⫽ mass
v ⫽ velocity
Weight and Mass W ⫽ mg
W ⫽ weight
m ⫽ mass
g ⫽ acceleration due to gravity
Hooke’s law F ⫽ kT
of elasticity F ⫽ force
k ⫽ spring constant
T ⫽ tension
Fick’s law dQ/dt ⫽ DA dC/dx
of diffusion dQ/dt ⫽ rate of diffusion
D ⫽ diffusion coefficient
A ⫽ area of the membrane
dC/dx ⫽ concentration (or energy)
gradient
741
742
Index
Page references followed by "f" indicate illustrated Adipose tissue, 1, 4, 16, 22, 24, 79, 88, 125, 153, 162, definition, 449
figures or photographs; followed by "t" indicates a 355, 570, 587, 590, 596, 599-600, 620, 646, developmental, 573, 594, 643-644, 702
table. 667, 685, 694, 696 surface, 223, 356, 449, 494, 560, 573, 610-611,
Adrenal cortex, 1, 152, 158-160, 325-326, 371, 541, 644
543, 549, 551, 730 systemic, 398-399, 401
A Adrenal gland, 1, 158-160, 162, 358, 371, 534, 542, Androgen-binding protein, 715
A site, 2, 16, 503, 516 704, 724 Androgens, 2, 6, 152, 160, 162, 325-326, 668, 704,
Abdomen, 296, 383, 400, 422, 460-461, 468, 614, Adrenal glands, 158-160, 358 706, 715, 719, 722, 724, 729
671, 710 Adrenal medulla, 1, 5, 158, 160, 212, 355, 358-360, Androstenedione, 704-705
arteries, 383 370-371, 405, 414 Anemia, 2, 482, 562
muscles of, 614 Adrenaline, 5, 8, 213 Angiogenesis, 2, 388-389, 432, 543, 622, 724, 726
veins, 383, 422 Adrenergic, 1-2, 132, 159, 210, 213-215, 217, 219, Angiotensin I, 2, 543, 549-550
veins of, 422 355-359, 405-406, 410-411, 415, 418, 431, Angiotensin II, 2, 414-415, 419, 540, 543-544,
Abdominal cavity, 465 590, 593, 688 549-551
Abdominal muscles, 460, 464-465, 470 Adrenergic receptors, 1, 159, 213-214, 217, 219, 357, Angiotensin-converting enzyme, 2, 549, 553
Abdominal wall, 558 405-406, 410, 415, 418 Angiotensinogen, 2, 162, 543, 549, 599-600
Absolute refractory period, 1, 20, 179, 181, 186-187 Adrenocorticotropic hormone (ACTH), 152, 158-159, Angle, 6, 18, 226, 240, 300, 316, 450, 638, 645
Absorption, 3, 8, 162, 314, 504, 511, 534, 547, 551, 325, 371 Anisotropic, 1, 241
555, 560, 562, 564, 566, 577, 581, 587, 591, Adventitia, 386 Antagonist, 2, 8, 131-133, 543
603 Aerobic exercise, 429, 647 Antagonists, 2, 131-132, 212, 716
Acceleration, 283, 295, 300, 302-303, 378, 423, 481, Aerobic metabolism, 148, 429, 484, 492, 494, 615, Anterior chamber, 314, 463
617, 737, 741 621 Anterior pituitary, 2, 10, 17, 19, 150-152, 158-159, 161,
Accessory structures, 276, 292-293, 296 Afferent arteriole, 529-530, 539-541, 551-552 164, 325-326, 704-706, 715, 721, 723-724,
eye, 276, 292 Afferent arterioles, 13, 539, 541 726-727, 729-730, 732
Acclimatization, 1, 38-39, 41, 489, 678 Afferent pathways, 373 Antibodies, 190, 428, 568, 613, 727
Accommodation, 1, 316, 328 Aging, 375 structure of, 727
Acetic acid, 56, 58 Agonist, 1, 132 Antidiuretic hormone (ADH), 123
Acetylcholine, 1, 5, 15-17, 129, 158, 165, 188-190, Agonists, 131-132, 212 functions, 123
206, 209-213, 217, 253-254, 268, 306, 357, Airway resistance, 471 Anus, 2, 454-455, 468, 578-583, 588, 592
360, 370, 372-373, 406, 414, 429, 433-434, Albumin, 1, 125, 426, 553 Aorta, 2, 9, 383, 385, 388, 390, 394, 399-401,
586, 592-594 Albuterol, 357 403-404, 409-410, 416-417, 419, 425, 433,
Acetylcholine (ACh), 188-189, 211, 357, 594 Aldosterone, 1, 81, 125-126, 158, 162, 541-544, 435, 488, 595, 690
Acetylcholinesterase (AChE), 189 549-552 abdominal, 383
Acid-base balance, 490, 535, 555 blood pressure and, 549-550 blood pressure in, 400, 417, 433
renal, 535, 555 Alertness, 345, 357 branches of, 2
respiratory, 490, 555 Alimentary canal, 3, 341 Aortic bodies, 541
Acidic solution, 57, 577 Alkaline tide, 496 Aortic valve, 409
Acidosis, 1, 12, 14, 20, 272, 481, 485-486, 490, 535 Alkalosis, 1, 14, 20, 486, 489-492, 496 Apex, 408
metabolic, 1, 12, 14, 20, 486, 490, 535 effects of, 492 heart, 408
physiological, 1, 12, 272, 486 metabolic, 1, 14, 20, 486, 489-490, 496 Apical membrane, 2, 502, 513-514, 516, 518-519,
Acinar cells, 153 Allantois, 720, 725, 732 530, 534-535, 541-542, 546, 568
Acrosome, 1, 234 Alleles, 1, 12, 107, 323, 678, 703, 720 Apnea, 2, 7, 449, 490, 494
Actin, 1, 6, 9, 13-15, 18, 21-24, 98-99, 224, 226, Altitude, 1, 87, 427, 440-441, 443, 448, 482, 489-493, Apoenzyme, 2
231-242, 244-247, 251, 258, 260-261, 496, 498, 638, 653, 672 Apoptosis, 2, 723
264-265, 269, 271, 296, 411, 581 Alveolar cells, 467, 471 Appendages, 238, 384, 454, 572-574, 608, 623, 625,
Action potential, 1, 3, 8-9, 12, 20, 22-23, 169, 172, Alveolar dead space, 471 631, 636-637, 639-641, 643, 651-652, 654,
177-189, 191, 193, 195-206, 210, 215-216, Alveolar pores, 467, 471 716
218-221, 251-254, 256-259, 267-268, 274, Alveolar ventilation, 472, 485 body, 238, 384, 454, 573-574, 608, 623, 631,
277, 279, 282-283, 285, 291, 319, 327, 329, Alveoli, 2, 4, 18, 467-472, 484, 493, 495, 727-728 636-637, 640-641, 643, 651, 654
355, 367-368, 404-408, 410, 412, 429, 549, Alveolus, 2, 471-473 skin, 454, 573, 636, 639
614, 628 Amino acids, 2-3, 17-19, 40, 52, 57-58, 63, 67-69, 81, Appendicular musculature, 614, 643
cardiac muscle, 22, 198, 210, 252, 254, 256, 106, 122-123, 125, 128, 163, 209-210, 217, arm, 614
258-259, 407-408, 412 229, 288, 290, 323, 342, 371, 442, 478-479, development, 643
conduction velocity of, 191 483, 508-509, 520-522, 531-532, 546, 561, leg, 614, 643
propagated, 218 563, 565-568, 570, 579, 591, 595-597, 600, Appendix, 579, 737-738, 739, 740-741
propagation of, 206, 218, 251 616, 618, 676, 684, 704-705, 718, 727 Aqueous humor, 5, 314-315
Activation energy, 1-2, 23, 48-49, 59, 61, 110, 674, Ammonia, 2, 16, 44, 502, 520-522, 524-526, 535, Arachidonic acid, 130, 145-146
676 544-545, 551, 554-555, 565, 597 Arachnoid mater, 342
Active site, 1-2, 5, 16, 59, 61-65, 110, 676 Amnion, 2, 720, 725, 732 Arches, 457-458
Active sites, 62-63, 676 Amniotic cavity, 725 Arcuate nucleus, 587, 590, 734
Active transport, 1, 15, 19, 21, 90-93, 146, 500, 503, Ampulla, 299-301, 303, 305 Arginine, 2, 67, 75, 123-124, 130, 508, 522-524, 555,
518, 529, 531, 536, 566-567, 587, 689 Amygdala, 2, 346-349, 370-371 563
Adaptability, 42 Amylase, 2, 559, 566, 586, 591 Arm, 235-237, 339, 496, 614, 626, 630
Adaptation, 1, 11, 19, 21, 34, 39-41, 43, 90, 112-113, pancreatic, 566, 586 Arrhythmias, 526
229, 283, 323, 329, 498, 506, 553, 565, 658, salivary, 559, 566 Arterial anastomosis, 400
675, 678-679, 683, 697-698, 726 Anabolism, 2, 87-88, 153 Arterial blood pressure, 7, 22, 417, 423-424, 436, 539,
Adaptive immune system, 692 Anaerobic glycolysis, 481, 486, 615, 617 549
Adductor muscles, 268 Anatomical dead space, 2, 18, 471 Arteries, 2, 29, 377, 383, 385-389, 391-392, 396-398,
Adenohypophysis, 2, 150 Anatomical regions, 669, 686 401-404, 408, 415-420, 425, 432-433, 437,
Adenosine, 1-2, 6, 117, 120, 131, 133-134, 144, 148, Anatomy, 29, 46, 160, 223, 304, 349, 356, 375, 391, 488, 529, 537, 540, 600, 621, 688-690
210, 253, 414-415, 522, 593 398-399, 401, 436, 449, 494, 554, 560, 573, abdominal, 383
Adenosine triphosphate (ATP), 1, 131 594, 604, 607-608, 610-611, 628, 643-644, arterioles, 385-389, 401, 415-417, 419-420,
Adenylate cyclase, 1, 4, 6, 117, 144, 146-147, 154, 646, 702 432-433, 529, 621, 688, 690
156, 159-160, 214, 285-286, 289-291, 327, clinical, 391, 604 blood pressure in, 415, 417, 433
367-368, 405, 411, 519, 542, 586, 593-594 comparative, 160, 375, 399, 436, 554, 607, 610, blood volume in, 420
Adipocytes (fat cells), 155, 165 646 brain, 2, 29, 383, 387, 419, 425, 488, 600
Adiponectin, 599 cross-sectional, 628 cerebral, 425
743
chest, 418 87, 94, 111, 119, 148-149, 216, 230, 236, pH of, 12, 485-487, 490, 526, 535, 584, 591
coronary, 29, 377, 389, 396-397, 415, 432, 600 243, 245, 248-249, 251, 254, 256, 264, 274, physical characteristics of, 17
elastic, 386-387, 396, 398, 402, 416-417, 425, 432 300-301, 305, 310, 314, 317-318, 341, 345, plasma, 1-2, 4, 7-8, 10, 13-15, 18, 20-23, 102, 119,
functions, 29, 401 360, 362-363, 370, 378-379, 381-383, 388, 129, 140, 156, 162, 165, 212, 258-259,
intercostal, 488 396, 417-418, 421-424, 429, 431, 449, 342, 380, 392, 414, 421-423, 427-428,
intestinal, 600 453-456, 458, 460, 463-464, 466, 470, 481, 474-476, 479, 484-486, 488, 502, 504,
muscular, 383, 386-387, 396, 398, 402, 425, 432, 493, 529, 533-534, 536, 539, 546, 581-582, 509, 514, 517-519, 523, 525, 530-531,
621 592-593, 609, 614-615, 621-622, 627, 538-539, 541-544, 548-550, 553, 594,
pericardial, 383, 397, 403 629-630, 634, 637, 641, 644, 649, 660, 664, 600, 620, 711
pulmonary, 29, 388-389, 398, 401, 403-404, 419, 666, 684-685, 688, 731, 733 regulation of, 4, 6, 22, 73, 119, 121, 129, 148,
425, 432-433, 488 innervation of, 360 151-157, 162, 165, 238, 258, 262, 325,
renal, 529, 537, 540 Ball-and-socket joints, 626 346, 352, 359, 378, 394, 410-413, 415,
spiral, 387, 398 Baroreceptor reflex, 419-420, 424, 431, 433-434, 419-420, 433, 436-437, 485-486, 488,
structure of, 2, 29, 386-388, 397, 432-433, 621 436-437 495, 502, 526, 535, 537, 540, 549-551,
systemic, 385-386, 388-389, 398, 401, 404, 419, Baroreceptors, 2, 4, 292, 327, 419-420, 430, 540-541, 590, 594-595, 601, 622, 688, 704, 721,
425, 433, 537 543, 549-551 730
systemic circuit, 386, 388-389, 398, 401, 404, 425 blood pressure and, 549-550 viscosity, 18, 24, 391-392, 419, 426, 475, 490, 493
thoracic, 418 Basal ganglia, 22, 346 volume, 2-4, 8, 11-12, 18, 22, 35, 45, 140, 154,
thorax, 425 Basal lamina, 3, 22, 101-102, 266, 711, 713, 715 223, 242, 291, 360, 391-394, 396,
Arterioles, 7, 13, 24, 355, 385-389, 394, 401, 413-417, Basal metabolic rate, 1, 3, 20-21, 86, 602, 647, 671 402-403, 409-412, 418-422, 424, 427,
419-420, 430-434, 472-473, 491, 494, Basal nuclei, 3, 344, 347 430, 432-436, 438, 448-449, 452, 456,
528-529, 539, 541, 543, 549, 621-622, 688, functions, 3, 344, 347 462, 465-466, 472-473, 475-476, 480,
690, 693 Base, 1-4, 6, 10, 16, 18, 21, 55, 57-58, 103, 150, 231, 487, 489, 493, 496-497, 502-503, 509,
blood pressure in, 415, 417, 433, 528, 549 286, 292, 295-296, 300, 313, 347, 384, 395, 518-519, 526, 529, 533, 536-540,
blood volume in, 420 398, 400, 449, 454, 468, 490, 516-517, 526, 542-543, 549-553, 621, 629, 633,
glomerular, 13, 528, 539, 541, 543, 549 535, 554-555, 563, 565, 584-585, 601, 611, 688-692, 694, 706, 710, 718, 721
Arteriovenous anastomoses, 688 624, 687, 715, 737, 739, 740 Blood cells, 8, 11, 13, 21, 93, 238, 380, 387, 392, 419,
Aspartate, 67, 74-75, 209-210, 475, 521-523 heart, 2-4, 6, 10, 21, 292, 384, 395, 398, 400 421-422, 425-429, 434, 474-476, 482, 484,
Aspirin, 130 lung, 449, 454, 468 489-491, 493-495, 528-530, 621
Association areas, 352, 372 of heart, 4 Blood clotting, 426, 428, 434, 562, 599
auditory, 352 stapes, 21 Blood flow, 12, 14, 21, 23, 29, 131, 148, 158, 258,
limbic, 352, 372 Basement membrane, 3, 101, 386, 389, 512-513, 528, 335, 353, 357, 371, 383-385, 388-389, 393,
somatosensory, 352 530, 610, 623-624 399, 403, 412-413, 415-416, 421-425,
visual, 352 glomerular, 528, 530 427-428, 430-434, 437, 450-453, 455-456,
Association cortex, 352, 365 Basilar membrane, 3, 304-306 458, 465-466, 473, 490-491, 493-494, 497,
Asthma, 357, 449, 473 Basolateral membrane, 2, 502, 513-514, 518-519, 503, 518, 527, 529-530, 539-540, 543, 583,
Astrocytes, 2, 194-195 529-530, 532-534, 542, 546, 710 586, 592, 622, 654, 669, 687-690, 693,
Atmospheric pressure, 4, 423, 467-469, 471, 480 Basophil, 3, 428-429 695-696, 717
Atresia, 2, 19, 723 Basophils, 426-427 pressure gradient, 416, 423, 450, 466, 539
Atria, 3, 19, 121, 379, 382, 398-400, 402-403, 408, Beriberi, 559, 562 resistance, 393, 399, 403, 413, 415-416, 422, 424,
411, 434, 541 Bernard, Claude, 29, 559 431-434, 539-540
Atrial natriuretic peptide (ANP), 2, 149, 543 Bile, 3, 9, 81, 568, 585-586, 590-591, 601 Blood plasma, 21, 427
Atrial systole, 402, 410, 433 Bile duct, 3, 585 Blood pressure, 2, 4, 7, 13-14, 22, 121, 140, 149, 162,
Atrioventricular (AV) node, 408 Bile pigments, 3 213, 278, 291, 327, 345-347, 352-353,
Atrioventricular (AV) valves, 399 Bile salts, 3, 568, 585 359-360, 371, 379, 391, 394, 400, 402,
Attachment, 233, 259, 294, 305, 513, 572-573, 609 Biochemistry, 5, 20, 30, 38, 41-43, 44, 46-114, 412-421, 423-425, 428, 431-434, 436, 491,
epithelial tissue, 513 166-167, 170, 221, 229, 272, 331, 435, 526, 528-529, 537, 539-543, 549-553,
intercellular, 513 437-438, 499, 507, 554, 559, 603, 629, 646, 599-600, 696, 740
Auditory cortex, 306, 351-352 658, 662, 697, 728, 734-735 alterations in, 600
Autocrines, 122 Biogenic amines, 4, 128-129, 164, 209-210, 213 arterial, 2, 7, 14, 22, 400, 416-421, 423-425, 431,
Autonomic ganglia, 1, 3, 18, 356, 358 Biotin, 562 433, 436, 491, 539-541, 549, 551
Autonomic ganglion, 355 Bipolar cells, 317-320, 329 baroreceptors and, 2, 4
Autonomic nervous system, 3, 8, 17, 22, 211-212, 347, Bipolar neurons, 192-193, 284-285, 294, 327 capillary, 2, 4, 413, 421, 425, 432-433, 491,
352-356, 358-362, 370, 373-374 Birth, 151, 248, 335, 345, 471, 707, 719, 723-726, 730 528-529, 537, 539-541, 550
anatomy of, 356 oxytocin and, 151 measuring, 2, 4, 537
blood pressure and, 353 Bitter taste, 288 systemic, 22, 400, 414, 419, 425, 433, 537, 539,
control of, 3, 359, 374 Bladder, 10, 18, 22-23, 29, 263, 301, 303, 341, 543, 549
divisions of, 353 354-355, 479-481, 496, 527, 536-537, venous, 412, 417-419, 421, 423-425, 433, 528, 549
interactions of, 8 544-545, 547, 552, 633-634, 654, 657 Blood supply, 262, 584, 608
physiology of, 374 Blastocyst, 3, 23, 719, 724-725 esophagus, 584
Autoregulation, 411, 413-415, 433 Blastula, 579-580, 702 skeletal muscle, 262, 608
capillary, 413, 433 Blind spot, 313, 317 stomach, 584
Autorhythmic cells, 405-406 Blindness, 155, 389, 562 Blood vessels, 2-5, 8, 11, 20, 23-24, 35, 102, 131-132,
Axis, 16, 152, 159, 392, 485, 534, 537, 609, 671, 706, night, 562 148-149, 151, 159, 212-213, 215, 223,
721, 723-724, 726, 732, 740 Blood, 1-8, 10-24, 29, 35, 39, 45, 53, 73, 75, 78, 80, 238-240, 258-259, 262, 292, 314, 338, 345,
Axoaxonic synapse, 3, 208 85, 93, 102, 119, 121, 126, 129, 131-132, 358, 376-377, 379-389, 391-395, 397, 400,
Axoaxonic synapses, 209 135, 140, 148-159, 162, 164-165, 212-213, 403, 413, 416-419, 422, 424-425, 427-428,
Axodendritic synapse, 3, 208 215, 223, 238-240, 242, 258-259, 262, 278, 431-433, 438, 467, 473, 476-477, 509, 518,
Axodendritic synapses, 209 283, 291-292, 314, 325, 327, 335, 338, 342, 529, 536, 539-540, 543, 575, 578, 584, 599,
Axon, 3, 9-10, 15, 18-19, 33, 97, 171-172, 174, 344-347, 352-353, 357-360, 362-363, 371, 608, 622, 625, 633, 686, 688, 690, 693, 696,
176-181, 183-209, 213, 215-221, 230, 232, 376-403, 408-438, 441, 448-453, 455-456, 710, 721, 723
253, 271, 277-278, 280, 283, 285, 294, 327, 458, 462, 465-467, 472-497, 502-504, anatomy of, 391
338, 340, 360, 367-368, 610 508-509, 512-519, 523, 525-531, 533, overview, 385, 608
Axon hillock, 3, 171-172, 176-181, 183-185, 193, 217, 535-545, 548-553, 562-563, 567-570, 573, pulmonary circuit, 388-389, 403, 422
219-221, 277 575, 578, 583-587, 590-592, 594-595, 597, systemic circuit, 386, 388-389, 422, 425
Axon terminals, 171-172, 208, 217, 277-278, 280, 285, 599-601, 608, 617, 619-622, 625, 629, 633, Blood volume, 140, 419-421, 427, 433, 476, 489, 519,
360, 367 653-654, 669, 686-696, 704-706, 710-711, 526, 538, 540, 542-543, 549-551, 718
Axons, 4, 6, 10, 15, 20-21, 24, 33, 172, 180, 184, 713, 715, 717-718, 721-723, 728, 730, 740 blood pressure and, 433, 526, 549-550
193-196, 198-199, 201, 203-206, 217-218, components of, 5, 35, 102, 135, 278, 363, 378, Blue cones, 322
220-221, 228, 232, 317-318, 338, 342, 351, 528, 592, 728 Body, 2-24, 29, 33-37, 39, 41, 52-53, 58, 63-64, 78-80,
356, 360, 365-366, 587, 610 composition, 11-12, 212, 380, 425, 427, 485, 488, 86, 117, 120-123, 125, 127, 130, 132-134,
Axosomatic synapse, 3, 208 502-503, 509, 527, 544, 569, 575, 690 148, 151, 153, 155, 157, 159-160, 168,
Axosomatic synapses, 209 functions, 1, 3-4, 10, 18, 29, 39, 102, 129, 131, 171-172, 174, 176-181, 184, 186, 191-193,
150-151, 153, 155, 157, 159, 164, 215, 204, 209, 217, 219, 221, 223, 229-230, 238,
B 262, 335, 344-345, 347, 352-353, 360, 245, 249-250, 254, 259, 266, 278-279,
B cells, 426, 428 395, 399, 401, 409, 426-428, 434, 467, 284-285, 287-288, 290, 292-297, 299-301,
B lymphocytes (B cells), 428 476, 541, 562, 599, 653, 692, 694, 704, 306, 309, 313-315, 317, 320, 325, 327,
memory, 428 706, 740 335-348, 351, 353, 355, 357, 359-363, 365,
Back, 4, 13, 20, 22-23, 27-28, 37, 46, 48, 59, 77, 84, in thermoregulation, 696, 730 368, 372-373, 376-385, 387-391, 395-396,
744
398-399, 401-403, 408-409, 415, 418-419, complexity, 191, 212, 215, 290, 320, 338, 350, 362, Capillary beds, 18, 151, 383, 385, 401, 413, 422,
422-425, 433, 435, 442-444, 447-449, 375, 613 432-433, 528, 569, 621-622, 688, 693
452-455, 459-462, 464, 468-469, 475, 477, development, 3, 6, 13, 127, 151, 194, 305, 315, nephron, 528
479, 482, 487-488, 490, 493, 500-503, 325, 342-343, 374, 526, 555, 576, 587, Capsule, 4, 19, 293, 527-530, 537, 539-540, 548, 552
505-509, 511, 513, 516, 520-521, 523, 600, 706-707, 729, 734 organ, 19
526-527, 535, 540, 545-547, 549-551, 555, development of, 305, 315, 343, 374, 526, 576, 600, Carbaminohemoglobin, 4, 478, 482-484
560-562, 564-565, 569, 573-576, 578, 582, 707 Carbon, 1, 4-5, 9-12, 14-15, 17-18, 20-21, 44, 46, 49,
591, 595-600, 602, 604, 607-614, 618, 623, functions, 3-4, 18, 29, 131, 150-151, 153, 157, 67, 70, 76, 79-80, 85-87, 125, 128, 130, 157,
629, 631-633, 635-638, 640-641, 643, 191-192, 215, 311, 315, 334-336, 376, 378, 413, 441-443, 445-446, 452-453,
645-646, 649-651, 653-655, 660-667, 343-345, 347-348, 350-353, 360, 461, 473-474, 477-478, 482-485, 489,
669-671, 673, 678, 680, 682-683, 686-689, 372-374, 409, 434, 576, 694, 706, 734 493-496, 520, 564, 582, 590, 595, 607
691-698, 701, 703, 708, 710-712, 717, 723, protection and support, 127 isotopes of, 86
725, 740 veins, 24, 29, 383, 387, 419, 425 Carbon dioxide, 4, 9-12, 14, 20, 46, 86, 376, 378, 413,
epididymis, 8, 23 ventricles, 3, 8, 343, 347, 400 441-443, 445-446, 452-453, 461, 473-474,
gallbladder, 3, 9, 353, 591 ventricles of, 8 478, 482-485, 489, 493-495, 582, 590, 607
muscle, 2-9, 12-24, 36, 58, 79, 120, 123, 127, Brain stem, 583 alveolar, 485
132-133, 148, 151, 153, 171-172, 180, Brain vesicles, 343 solubility of, 11, 445, 452, 474, 485
192, 223, 238, 245, 249-250, 254, 259, primary, 343 transport of, 9, 473
266, 293-294, 314, 341, 345-346, 355, secondary, 343 Carbonic acid, 11, 56, 58, 482, 485
357, 360-361, 365, 373, 379, 384, 387, Breast, 125, 151-152, 161, 165, 325-326 Carbonic anhydrase, 4, 482-489, 495, 515, 535, 590
389, 396, 399, 408-409, 415, 418-419, Breast cancer, 165 Carboxypeptidase, 567-568, 585, 591
422-423, 425, 433, 453, 460, 464, 475, Bronchi, 2, 4, 22, 464, 466-467, 471, 488 Cardiac action potentials, 406-407
477, 493, 508, 526-527, 549-550, 555, functions, 4, 467 phase 0, 407
591, 595-597, 599-600, 602, 607-614, primary, 2, 4, 466-467 phase 1, 407
618, 623, 629, 631, 633, 643, 645-646, secondary, 2, 466-467 phase 2, 407
650-651, 654-655, 664, 670, 678, 683, tertiary, 22, 467 phase 3, 407
687-688, 693, 711, 717, 723, 725 Bronchioles, 4, 132, 212-213, 354-355, 357, 371, 467, phase 4, 407
of bone, 574 471 Cardiac arrhythmias, 526
of stomach, 20 Bronchoconstriction, 471, 473, 488 Cardiac cycle, 7-8, 12, 14, 22, 394, 396, 401-403,
of uterus, 725 Bronchodilation, 471 409-410, 412, 416-417, 425, 435
pancreas, 10-12, 17, 153, 155, 353, 355, 591, Brown fat, 4 conducting system, 409
598-599 Brush border, 4, 581, 585, 597 Cardiac muscle, 4, 22, 120, 198, 210, 238, 243, 245,
penis, 125, 717 Buccal cavity, 4, 456-457, 462-464, 467, 486 247-250, 252, 254-256, 258-259, 396,
rib, 464, 469, 611 Buffers, 17, 58, 110, 188, 483, 510 407-408, 412, 414, 421
stomach, 7-8, 10, 15, 19-21, 37, 338, 360, 462, chemical, 17, 58, 188 cells, 4, 22, 120, 238, 243, 245, 250, 252, 258-259,
582, 591, 598, 701 respiratory, 17, 483 396, 407-408, 412, 414, 421
tongue, 288, 341, 505, 560, 573, 691 Bundle branches, 408 functions, 4, 243
uterus, 6, 8, 10, 15, 151, 325, 355, 388, 710-712, Burns, 324, 735 tissue, 4, 22, 120, 238, 249, 259, 396, 414
723, 725 Bursae, 455 Cardiac output, 4, 245, 409, 418-421, 430-431,
Body mass index (BMI), 598 433-435, 438, 472, 476, 487, 537, 549-550
Body movements, 343, 379, 383, 459 C blood pressure and, 433, 549-550
Body stalk, 223 Calcified, 295 Cardiomyocytes, 12, 15, 243, 245, 252-253, 259, 396,
Body temperature, 3-4, 7, 9, 11, 18, 20, 36-37, 58, 64, Calcitonin, 162, 593 403, 406-407, 410-412, 433
130, 343, 346-347, 359, 444, 479, 506, 597, Calcium, 4, 6, 16-17, 21, 81, 117, 120, 244, 246, 258, Cardiovascular center, 14, 420
618, 662-663, 665-666, 671, 673, 683, 686, 272, 295, 370, 555, 562-563, 575, 625, 682, Cardiovascular system, 4, 380, 417, 425, 429-431,
688-689, 692-697 713 435-437, 527, 537, 543, 549, 608, 654
metabolic rate and, 130, 597 dietary, 81, 563 blood vessels, 4, 380, 417, 425, 431, 543, 608
muscles in, 37 excitation-contraction coupling and, 272 development, 436
normal, 4, 11, 37, 64, 479, 597, 673, 683, 688, 693 metabolism, 6, 81, 117, 555, 575 heart, 4, 380, 417, 425, 430-431, 435-436, 537,
skin in, 18 regulation of, 4, 6, 246, 258, 555 543, 549
Body water, 507 skeletal muscle, 16, 21, 244, 258, 272 overview, 608
Body weight, 35, 344, 347, 640, 653, 701, 725 smooth muscle, 4, 17, 21, 258 Carotid artery, 4, 419, 488
Bohr effect, 3, 478-479, 481-482, 496, 498 Calcium phosphate, 575, 625 Carotid bodies, 17, 420
Bolus, 3, 17-18, 261, 567, 588-589, 591, 597, 601, Calmodulin, 4, 144-145, 147, 235, 260-261, 269-270, Carrier proteins, 20, 123, 125-126, 128, 133, 163, 166,
718 370, 546 381, 426
Bone, 3, 6, 9, 14, 16, 22, 34-35, 101, 133, 162, 387, Calories, 4, 561, 600, 602, 646, 738 Cartilage, 3-5, 8-9, 71, 101, 466-467, 623, 625, 632
428, 574, 578, 614, 623, 625-627, 632, 647, Canal, 3, 16, 299-300, 303-304, 341, 517, 545 trachea, 4, 466-467
661, 717 spinal cord, 341 types, 3, 5, 9, 467, 623
diameter, 387 Cancer, 125, 141, 165, 388-389, 423, 571 Catabolism, 3-4, 67, 77, 87-88, 110, 153, 502
humerus, 614, 627 breast, 125, 165 Catalase, 83
incus, 14 development, 125, 141, 388-389 Catalysts, 59, 61, 110, 139
length, 3, 14, 22, 625-626 lung, 423 Catecholamines, 1, 3-4, 128, 144, 158-159, 213, 253,
malleus, 14 uterine, 165 371, 619
nasal, 16 Capacitation, 4, 716 Caudal, 4, 343, 388, 486, 611, 629, 640-642, 657
periosteum, 625 Capillaries, 10, 14, 18, 24, 29, 238, 342, 377, 385-391, Cecum, 4, 545, 564, 578-580, 583, 588
radius, 35 403, 416, 420-423, 425, 432-433, 435, 448, Cell, 1-24, 29-30, 33, 35, 37, 44-114, 116-167,
regulation, 6, 22, 133, 162 450, 458, 465-467, 481, 490, 493, 497, 502, 168-184, 186-199, 201-202, 204-221, 222,
remodeling, 625 518, 527-530, 536-537, 539, 549, 552, 587, 224-226, 228-234, 236, 238, 240, 242-245,
stapes, 14 621-622, 691, 693, 723 247-248, 250-253, 255-260, 262-263,
temporal, 22 blood, 10, 14, 18, 24, 29, 238, 342, 377, 385-391, 265-267, 269-271, 274-279, 281-282,
Bone marrow, 387, 428 403, 416, 420-423, 425, 432-433, 435, 284-303, 305-314, 317-321, 324-325,
functions, 428 448, 450, 458, 465-467, 481, 490, 493, 328-332, 337-338, 340, 342, 350, 355-362,
Borders, 318 497, 502, 518, 527-530, 536-537, 539, 367-370, 378, 387, 403-408, 410-411,
Bradycardia, 4, 7, 410, 494 549, 552, 587, 621-622, 691, 693, 723 413-414, 426-429, 436-438, 442, 444, 448,
Bradykinin, 414 blood pressure in, 423, 433, 528, 549 460, 467, 473, 476, 481, 484-485, 489-491,
Brain, 2-9, 11, 13-14, 16, 18, 20-22, 24, 29, 37, 47, 78, blood volume in, 420 496, 499, 500, 502-503, 509-511, 513-516,
81, 127, 130-131, 133-134, 144, 149-151, continuous, 387, 421, 466 518-519, 523-524, 526, 528-534, 540,
153, 157-158, 191-192, 194, 203, 207, fenestrated, 387, 528 542-546, 551, 553-555, 560, 563-564,
211-212, 215, 274, 276-279, 284-285, 290, functions, 10, 18, 29, 467 566-569, 572-573, 577, 579, 583-585, 587,
300, 305-306, 311, 315, 318, 320-322, lymphatic, 422-423, 433 590, 594-595, 608, 613, 616, 620-622, 624,
325-326, 329-330, 334-336, 338-340, mechanisms, 18, 388, 390-391, 425, 433, 458, 629, 673-674, 676-677, 679, 681-685,
342-348, 350-353, 358-360, 362-365, 490, 502, 518, 549, 552, 723 693-694, 702-703, 710, 713-715, 717-720,
368-375, 383, 387, 400, 409, 413, 419, peritubular, 518, 528-530 722, 724-725, 728, 734-735, 739
424-425, 429-431, 434, 486-488, 494, 497, structure, 10, 14, 18, 29, 238, 377, 385-388, anatomy, 29, 46, 160, 356, 436, 554, 560, 573,
526, 543-544, 549, 555, 571, 576, 583, 432-433, 458, 465, 467, 527-528, 552, 594, 608, 702
586-587, 590, 595-596, 600-601, 613, 647, 621-622, 723 cytoplasm, 6, 17, 20, 53, 55, 58, 73-75, 77, 81, 87,
658, 661, 691, 694, 706-707, 711, 714, 717, structure of, 29, 386-388, 432-433, 458, 465, 467, 90, 92, 95, 99-100, 105-106, 119, 125,
728-729, 734 621 131, 136-143, 145-147, 159, 176, 182,
arteries, 2, 29, 383, 387, 419, 425, 488, 600 true, 422 188, 199, 205, 211, 214, 222, 234, 247,
745
255-256, 259, 270, 405-406, 411, 502, Chemical synapses, 194, 206-209, 217-218 Commissures, 4, 338
509, 514, 519, 523-524, 530, 543, 567, Chemistry, 17, 34, 41, 44, 46-114, 170, 229, 483, 508, Common hepatic duct, 585
569, 579, 594, 677, 681, 685, 703, 710, 524, 653 Comparative anatomy, 160
715 bonds and, 50, 69, 76 Compartments, 7, 13, 45, 59, 88, 96-97, 99-100, 109,
definition, 1, 16, 205, 528 chemical reactions and, 60 199, 216, 254, 261, 304, 314, 398, 421, 450,
diversity, 9, 30, 33, 45, 67, 96, 102, 108, 111-113, composition of, 89, 109 502, 504, 509, 524, 578-579, 581-582,
117, 125, 127, 142-144, 146, 159, energy and, 44, 48, 51, 64, 67, 70, 75, 87, 109 600-601, 713, 718, 720
191-193, 195-197, 206-208, 213, 215, Chemoreceptors, 2, 4, 17, 276, 278, 283-284, 286, Complex carbohydrates, 71
218, 221, 222, 224-225, 229-230, 234, 327, 430, 487-489, 496, 583, 591-592, 600 Compliance, 5, 392, 418, 470-471, 495, 688
238, 240, 244-245, 247, 262, 265, in digestion, 17, 591 lung, 5, 470-471, 495
270-271, 299, 305, 307, 310, 314, 328, Chief cells, 584, 590-591 Concentration, 3, 5-9, 12-17, 19, 21, 23, 48, 52-56,
378, 436, 460, 489-490, 513, 564, 584, gastric, 584, 590-591 59-63, 67, 74, 84, 87, 91-97, 110-112, 116,
587, 613, 616, 702, 713-714 stomach, 584, 590-591 124, 126, 128, 133-136, 142, 144, 146, 148,
life cycle, 702 Chloride, 5, 13, 15, 96, 484-485, 515, 519, 555 152-154, 157, 165, 170, 173-176, 181,
light microscopy, 427 regulation of, 485, 555 187-190, 208, 219, 221, 227-228, 232, 244,
mitosis, 16, 21, 232 Chloride shift, 5, 484-485 246, 250, 269, 297-298, 307, 311, 380, 421,
overview, 46, 113, 118, 170, 221, 224, 276, 378, Cholecystokinin, 154, 162, 586, 591, 593 423, 425, 442-445, 475-476, 481, 484-485,
426, 442, 502, 560, 608, 702 Cholecystokinin (CCK), 154, 586, 591, 593 489, 497, 503, 508-509, 517, 519, 521, 525,
Cell body, 3-4, 6, 9, 15, 18, 21, 23, 171-172, 174, Cholesterol, 5, 13, 21, 80-81, 88-90, 111, 125-126, 529, 531, 536, 538-539, 553, 566, 589,
176-181, 184, 186, 191-193, 209, 217, 219, 159, 163, 371, 568-569, 599-600, 674-676, 622-623, 682, 685, 707, 717-718, 739, 741
221, 230, 285, 294, 309, 317, 340, 355, 368 695, 704, 734 Concentration gradient, 8, 15, 53-54, 91, 93-97, 297,
neuron, 3, 6, 9, 15, 18, 21, 23, 171-172, 174, in membranes, 89, 675 443-444, 529, 539, 566
176-181, 184, 186, 191-193, 209, 217, synthesis of, 80, 159, 704 diffusion and, 529
219, 221, 230, 285, 294, 340, 355, 368 transport of, 13, 21, 111 Conductance, 22, 254-255, 433, 514, 519, 664
Cell division, 6, 87, 228, 243, 427, 702-703, 719-720, Cholinergic, 5, 211-212, 268, 356, 359, 586, 590, 594 Conducting fibers, 19
724-725 Chondroblasts, 101 Conduction velocity, 191, 198, 203, 205-206
control of, 702, 719, 724 Chondrocytes, 4-5, 625 Conductivity, 664-665, 694
Cell junctions, 17 Chondroitin sulfate, 71, 101, 625 Conductor, 200
Cell theory, 29 Chordae tendineae, 401, 403 Cones, 5, 309-310, 317-318, 322, 325, 329
Cellular extensions, 193, 233 Chorion, 5, 18, 712-713, 720, 724-725, 732 Congestive heart failure, 551
Cellular secretions, 623, 625, 654 Choroid, 314-315 Connective tissue, 3, 9, 13-14, 45, 102, 238, 259,
Cellulose, 4, 71, 76, 561, 564, 566, 582-583 Chromaffin cells, 5, 158-160, 358, 360 292-294, 314, 338, 342, 396-397, 399-400,
Cement, 101 Chromatin, 105 434, 465, 475, 559, 562, 585, 608, 610-611,
Center, 1, 4, 7, 9, 14, 19, 24, 47-48, 148-151, 154, Chromosome, 5, 104, 108, 323, 703-704, 707, 733 625, 627-628, 651
157-158, 192-193, 213, 225, 239-241, 249, Chromosomes, 103-104, 107-109, 232, 703-704, 709 blood, 3, 13-14, 45, 102, 238, 259, 292, 314, 338,
276-277, 279-281, 316-317, 319-320, 329, Chronic, 371, 470, 485 342, 396-397, 399-400, 434, 465, 475,
336-339, 343, 346, 359-360, 372, 392, Chylomicrons, 568-570, 600 562, 585, 608, 625
405-406, 409, 419-420, 430, 447, 474, 526, Chymotrypsin, 563, 567-568, 585, 591 cartilage, 3, 9, 625
541, 543-544, 549, 641, 645, 649, 670, 686, Chymotrypsinogen, 585 dense, 259
719 Cilia, 3, 5, 7, 21, 194, 216, 224, 230-232, 269, 274, elastic, 396, 627-628, 651
Central nervous system, 2-4, 7, 9-10, 14-18, 21, 24, 284-285, 295-296, 305, 309, 329, 381, 447, fluid, 3, 9, 13, 314, 342, 396-397, 434, 475, 610,
171, 180, 192, 194, 203-204, 208, 210, 213, 453, 455, 495, 544-545, 716 625, 628
293, 325, 336, 340-343, 352-353, 355-356, epithelial, 3, 232, 296, 305 functions, 3, 102, 399, 434, 562
358, 360, 372, 374-375, 387, 419-420, 486, olfactory, 284-285 in smooth muscle, 13
488, 544, 587, 591, 608, 611, 647, 669, Ciliary body, 5, 314-315 structure, 3, 9, 14, 238, 259, 292-294, 314, 338,
686-687, 711, 730 Ciliary muscle, 5 397, 434, 465, 562, 625, 628, 651
brain, 2-4, 7, 9, 14, 16, 18, 21, 24, 192, 194, 203, Ciliary muscles, 314, 316 Connexons, 119
325, 336, 340, 342-343, 352-353, 358, Cingulate gyrus, 349 Consciousness, 334, 374, 486, 493
360, 372, 374-375, 387, 419, 486, 488, Circadian rhythm, 5, 36, 325 Continuous capillaries, 387, 421
544, 587, 647, 711 Circular folds, 581 Contractile proteins, 245, 264, 593, 608, 613
nuclei, 3, 325 Circulation, 5-6, 10, 21, 29, 79, 151, 154, 157, 345, Contractility, 4, 253, 260, 410-411, 421, 430, 541, 622,
spinal cord, 4, 7, 21, 192, 336, 340-343, 353, 356, 358, 371, 376-377, 380, 383, 389-390, 394, 687, 717, 724
358, 360, 372, 374, 687 396, 399-401, 412, 418-419, 432-437, 452, Contraction, 2, 9-10, 12-13, 15-18, 20, 22-24, 120,
tracts, 10 476-477, 488, 493-494, 499, 540, 548, 563, 123, 146, 151, 158, 190, 203-204, 213, 235,
Central nervous system (CNS), 194, 587 569-570, 600, 622, 629, 693, 720, 727 238-244, 246-272, 325, 355, 357, 360, 363,
development, 194, 587 arteries of, 377 371, 379, 381, 384, 386, 394, 396, 401-404,
Central pattern generators, 30, 364, 486-487, 495 physiology of, 435-437, 569, 629 407-412, 416, 418, 420, 425, 429-430,
Central thermoreceptors, 322, 687 pulmonary, 29, 389-390, 399-401, 419, 432-433, 432-434, 455, 461, 463-465, 469-470, 473,
Centromere, 104 435, 488 476, 528-529, 537, 541, 549-550, 591-592,
Cephalization, 4, 338-339, 344, 372 systemic, 389-390, 399-401, 419, 433, 435, 569 594, 607-612, 614-615, 623-624, 626-631,
Cerebellum, 5, 11, 192, 340, 343-346, 352, 364-366 veins of, 418 644-645, 654, 657, 683-684, 690, 718, 726
development of, 343 Cirrhosis, 553 muscle, 2, 9, 12-13, 15-18, 20, 22-24, 120, 123,
functions, 192, 343-345, 352 Cisternae, 22, 255-256, 259 146, 151, 158, 190, 203, 213, 235,
Cerebral cortex, 5-6, 22, 343, 347, 351, 364-365 Citric acid, 5 238-244, 246-272, 355, 357, 360, 379,
functional regions of, 351 Cleavage, 19, 124, 146, 585 384, 386, 396, 404, 407-409, 411-412,
Cerebral edema, 425 Clitoris, 414 418, 420, 425, 429-430, 432-434,
Cerebral hemispheres, 5, 347, 351, 372 Cloaca, 5, 454-455, 548, 711, 716 463-464, 473, 528-529, 537, 541,
Cerebrospinal fluid (CSF), 5, 342 Clone, 5 549-550, 591-592, 594, 607-612,
circulation, 5 Clotting factors, 21 614-615, 623-624, 626-631, 645, 654,
formation, 5 Coagulation, 428 657, 683-684, 690, 718, 726
Cerebrum, 4-5, 340, 346-347, 350, 352, 488 Coagulation cascade, 428 Contraction phase, 409
association areas, 352 Coccygeal nerves, 341 Conus arteriosus, 4, 6, 398, 402, 432
basal nuclei, 347 Cochlea, 3, 5, 16-17, 20, 299-300, 304-305, 328 Convergence, 2, 6, 196, 318, 361, 375, 629
limbic system, 488 Cochlear duct, 5, 300, 304, 328 Convex lens, 316
lobes, 346, 352 Coelom, 5, 544-545, 548, 578-580, 600, 710-711 Copper, 11, 18, 59, 475, 563
Cervical mucus, 724 Coenzyme A, 5, 59, 67, 129, 189, 676 Core temperature, 669, 671, 683, 691-693
Cervical nerves, 340 Collagen, 5, 40, 45, 101-102, 386, 592, 625, 651 Cornea, 6, 313-316, 322
Cervix, 151, 726 Collagen fibers, 386, 625 Coronary arteries, 377, 396-397, 415, 432, 600
Chemical bonds, 6, 34, 47, 49, 82, 112 Collaterals, 172 Coronary artery disease, 389
Chemical energy, 5, 46-47, 59-60, 64, 81, 85, 109, axon, 172 Coronary circulation, 29, 629
560-561, 601, 618, 684 Collecting duct, 5, 518, 527-528, 531-536, 540-541, Corpus callosum, 6, 347-348, 352
Chemical equilibrium, 7 552, 554-555 Corpus luteum, 6, 722-727, 732
Chemical neurotransmitters, 206 Collecting ducts, 518, 534-536, 543, 552 Cortex, 1, 5-6, 22-24, 152, 158-160, 162, 306,
Chemical properties, 51-52, 119 Collecting tubules, 7 320-321, 325-326, 343-344, 347-353,
Chemical reactions, 4, 8, 14, 29, 44, 46-49, 59-60, 62, Colliculi, 346 358-359, 364-366, 370-372, 375, 527-529,
86, 695 inferior, 346 533, 535-536, 541, 543, 549, 551, 730
Chemical signaling, 7, 117, 130, 132, 143, 164, 211, superior, 346 bone, 6, 22, 162
734 Colon, 5, 579, 587 hair, 306, 358
Chemical synapse, 5, 8, 188, 206-207 Columns, 350, 715 ovarian, 6, 730
746
renal, 5, 23, 527-529, 535-536, 543, 549, 551 388-389, 395, 426, 436, 438, 471, 499, 582-585, 589-591, 600, 603, 625, 720
thymus, 162 525-526, 547, 554-555, 565, 575-577, Digestive system, 154, 261, 353, 511, 513, 526, 573,
Cortical nephrons, 527-529 579-581, 587, 600, 604, 611, 625, 633, 639, 575, 581, 588-591, 608
Corticosteroids, 161-162, 325 643-644, 651, 653, 657, 663, 683, 698, development, 261, 526, 575, 581
Corticosterone, 81, 125-126, 159, 595, 730-731 700-702, 704, 706-707, 709-710, 712-713, functions, 353
Corticotropin-releasing hormone (CRH), 159, 371 715, 719-720, 723, 725, 727, 729, 732-735 gallbladder, 353, 591
Cortisol, 81, 125-126, 152, 155-156, 158-159, 162, bone, 3, 6, 34, 162, 625 liver, 591
164, 326, 371, 516, 541, 595, 619, 653 brain, 3, 6, 13, 127, 151, 194, 305, 315, 325, overview, 608
Cortisone, 125, 595 342-343, 374, 526, 555, 576, 587, 600, pancreas, 154, 353, 591
Covalent bonds, 6, 49-51, 54, 69, 109 706-707, 729, 734 pharynx, 581
Cranial, 6, 340-342, 354 cardiovascular system, 436 stomach, 588, 590-591
Cranial nerves, 6, 340-341 connective tissues, 651 teeth, 575
Cranium, 342 definition, 34, 249 tongue, 573
Creatine, 2, 6, 17, 67, 84, 538 digestive system, 261, 526, 575, 581 Dihydrotestosterone, 668, 704
Creatinine, 538 ears, 328 Dihydroxyacetone phosphate, 72-73, 79
Cross-bridges, 20, 242, 250-251, 260-261, 269-270 embryonic, 3, 6, 10, 33, 233, 243, 245, 248-249, Dimers, 22, 69, 140, 226-230, 235, 237, 248, 262, 478
Cupula, 299-301, 303 262, 342-343, 388, 438, 471, 525-526, Dipeptidase, 563
Current, 29, 97, 143, 166, 168, 175-177, 184-185, 555, 576, 579-581, 702, 710, 719-720, Dipeptide, 68, 563
193, 195, 197-207, 212, 217, 220, 274-275, 725, 734 Disaccharides, 70, 73, 564, 566
284, 306, 331-332, 375, 389, 392, 405-407, endocrine system, 117, 160, 166 Disease, 29, 33, 39, 123, 130, 153, 155, 190, 194,
409, 433, 437, 554, 604, 734, 737, 741 epithelia, 13, 233, 525, 555, 729 271-272, 315, 329, 346, 388-389, 422, 470,
Cuticle, 6, 21, 266, 287, 291, 293-294, 296, 313, 460, eyes, 3, 315, 325, 328 489, 496, 551, 554, 559, 562, 571, 599, 697,
468, 512, 609, 623-624, 639 fetal, 162, 244, 248, 727 731, 734
hair, 21, 293-294, 296 heart, 3, 6, 10, 159, 162, 243, 248-249, 270, 377, Dissociation, 1, 3, 7, 11, 17, 54-57, 134, 553
Cyclic AMP, 1, 4, 6, 146, 214 388-389, 395, 436, 438, 600 Diuretics, 526, 537
Cyclic GMP, 5-6, 139, 144, 311 muscles, 13, 38, 159, 228, 232-233, 243-245, Divergence, 7, 109, 245, 361-362, 683, 729
Cysteine, 67, 69, 229 248-249, 261-262, 265, 270, 305, 395, Diversity, 9, 26-28, 30, 32-33, 39-40, 42, 45, 67, 96,
Cystic duct, 585 471, 526, 611, 625, 639, 643-644, 651, 102, 108, 111-113, 117, 125, 127, 142-144,
Cytochromes, 3, 6, 11 657, 683, 706 146, 159, 191-193, 195-197, 206-208, 213,
Cytokines, 6, 123, 228, 693, 721, 723 nervous system, 3, 10, 194, 232-233, 325, 215, 218, 221, 222-225, 229-230, 234-235,
Cytokinesis, 232, 235 342-343, 374, 395, 471, 587, 611 238, 240, 244-245, 247, 261-262, 264-265,
Cytology, 143 organ systems, 28 270-272, 299, 305, 307, 310, 314, 322-323,
Cytoplasm, 6, 17, 20, 53, 55, 58, 73-75, 77, 81, 87, 90, overview, 28, 113, 374, 426, 657, 702 328, 376, 378-380, 382, 384, 391, 399-400,
92, 95, 99-100, 105-106, 119, 125, 131, postnatal, 732, 734 436, 460, 468, 479-480, 489-490, 501,
136-143, 145-147, 159, 176, 182, 185, 188, reproductive system, 127, 707, 709 505-506, 512-513, 548, 564-565, 574, 584,
199, 205, 211, 214, 222, 234, 247, 255-256, respiratory system, 6, 499, 526 587, 598, 600, 603, 610, 613, 616, 628,
259, 264, 270, 405-406, 411, 502, 509, 514, skull, 342 638-639, 641, 665, 667-668, 702, 704,
519, 523-524, 530, 543, 567, 569, 579, spinal cord, 342-343, 374 706-707, 713-714
593-594, 677, 680-681, 685, 703, 710-711, tissue, 3, 10, 13, 28, 33-34, 80, 125, 159, 162, 249, cellular, 28, 30, 33, 42, 45, 67, 96, 111, 113, 117,
715 262, 265, 342, 389, 471, 525, 555, 575, 143-144, 159, 191, 193, 222-225,
cytosol, 6, 74 577, 581, 587, 600, 611, 625, 651, 683, 229-230, 234-235, 238, 240, 244-245,
Cytoskeletal elements, 98, 223 710, 715, 720, 723, 732 247, 261-262, 264-265, 270-272,
Cytoskeleton, 6, 9, 12-14, 67, 90-92, 98-102, 111, 117, vision, 3, 328 512-513, 598, 600, 613, 628, 668, 702
187, 224-225, 233, 238, 261, 263, 269-271, Dextrinase, 563 Diverticula, 576, 578
291-292, 509-511, 513-514, 539, 542, 574, Diabetes mellitus, 6, 153 DNA (deoxyribonucleic acid), 7
581, 687 insulin-dependent, 6 Dominant follicle, 2, 723
Cytosol, 6, 74, 555 non-insulin-dependent, 6 Dopamine, 3, 7, 128, 152, 210, 213, 217, 479
Cytotoxic T cells, 428, 692 Diabetic retinopathy, 389 Dorsal aorta, 690
Diacylglycerol, 6, 17, 79-80, 146, 214, 286, 311, 593 Dorsal root, 7, 340, 342
D Diaphragm, 7, 341, 387, 467, 469-470, 488, 495, 613 Dorsal root ganglia, 342
Daughter cells, 228 respiratory, 467, 469-470, 488, 495 Dorsal root ganglion, 7, 340
Dead space, 2, 6, 18, 471-472, 694 Diarrhea, 486 Double covalent bond, 49
Deafness, 306 Diastole, 7-8, 394, 396, 402-403, 409-411, 415, 417, Down-regulation, 7, 23, 133, 135
Defecation, 6 432-433 Drowsiness, 561
Dehydration, 8, 85, 220, 501, 505-507, 520, 526, 537, Diastolic pressure, 7, 417, 424, 433 Dual innervation, 354, 358, 360
540, 543, 548-550, 713, 719 Dicrotic notch, 409 Ductless glands, 29
Dehydrogenases, 75, 81, 83 Diencephalon, 9, 343, 346 Duodenal glands, 585
Delivery, 32, 36, 75, 255, 260, 385, 389, 399, 415, contents, 9 Duodenum, 7, 12, 19, 566, 579, 583, 585-586, 590
427, 430, 469, 473, 476, 479, 482, 486, development, 343 Dura mater, 342
490-491, 506, 526, 536, 543, 616, 620-623, development of, 343 spinal, 342
654, 733 epithalamus, 346 Dynamic equilibrium, 528
Dementia, 571 functions, 343 Dyspnea, 7, 449
Dendrites, 6, 15, 171-172, 174-178, 180-181, 184, Diet, 4, 8, 12, 18, 38, 47, 70, 73, 76, 155, 357, 503, Dystrophin, 233
191-193, 209, 217, 219, 228, 277, 287, 342 505, 516-517, 523, 544-545, 559, 561-563,
Dendrodendritic synapses, 209 569, 571-572, 575, 578-580, 584, 589, 591, E
Dentin, 575, 578 598, 600-602, 604, 616, 618, 652, 676, 721, Ear, 5, 12, 14, 16-18, 20-21, 23, 243, 254, 279,
Deoxyhemoglobin, 6 728 294-297, 299-301, 303-306, 328-332, 346,
Deoxyribose, 1, 16-17, 20, 103 Differentiation, 15, 243-245, 264, 323, 428-429, 511, 363, 366, 572, 583
in DNA, 103 555, 703 development, 243, 305, 328
Depolarization, 6, 19-20, 96, 98, 157, 172-187, 195, Diffusion, 1, 7, 9-10, 17-18, 47-48, 53, 59-60, 84, external, 12, 14, 16, 20-21, 294, 299, 303
197-198, 201, 206, 209-210, 218, 244, 90-92, 111, 118-119, 121, 123-124, 146, 206, inner, 5, 12, 14, 16-17, 20-21, 23, 243, 299-301,
250-259, 266-267, 270, 274, 277, 285, 223, 377-378, 380-381, 385, 387, 390, 394, 303-306, 328-329, 331-332, 346
288-290, 297-298, 306, 312, 319-320, 328, 431, 442-448, 450-451, 454, 460-461, 466, middle, 12, 14, 16, 21, 23, 299, 301, 303-304, 328,
362, 367, 369, 400, 403-410, 433, 438, 526, 468-469, 473, 481, 491, 494, 496, 498, 503, 363
539, 592 523, 525, 529-530, 532, 542, 555, 565-567, structure of, 5, 21, 294, 296, 299, 303, 306, 332
action potential and, 195, 252, 258 620-623, 628, 674, 741 Ectoderm, 7, 342, 579-580
in cardiac muscle, 250, 252, 256, 258 neurotransmitter, 1, 7, 9, 118-119, 121, 206 formation, 7, 580
neuron, 6, 19, 172-187, 195, 197-198, 201, 206, Digastric, 7, 582 Ectopic pacemaker, 7
209-210, 218, 253-254, 266-267, 274, Digestion, 3, 7, 9-10, 17-18, 21, 37, 122, 135, 162, Edema, 7, 422-425, 433-434, 491, 526, 693
277, 285, 289-290, 297-298, 362, 367, 232, 238, 325, 353, 378, 400, 496, 505-506, cerebral, 425
369, 592 511, 523, 558-564, 566-604, 620, 666, 670, Effector, 3, 7, 18, 22, 148, 151, 192-193, 208, 336,
of heart, 404, 409-410 683, 688, 727 341, 352, 354-363, 372-373
Depth perception, 320-321 chemical, 3, 7, 9-10, 17-18, 21, 122, 135, 162, 505, Effector cells, 360
Desmosome, 6 558-561, 569-570, 582-583, 588, Effector organs, 151, 192-193, 208, 336, 341, 352,
Development, 3, 6, 10, 13, 28, 32-34, 38, 42, 80, 105, 600-602, 683 354, 357, 362, 372
109, 113, 117, 125, 127, 139, 141, 151, in stomach, 37 Efferent arteriole, 528-530, 536, 539-540
159-160, 162, 164, 166, 194, 220, 228, mechanical, 9-10, 560, 577, 583, 600 Efferent arterioles, 7, 528-529, 543
232-233, 243-245, 248-249, 261-262, 265, physiology of, 511, 558, 569, 589, 602 Efferent ductules, 716
270, 305, 315, 325, 328, 342-343, 374, 377, Digestive enzymes, 1, 7, 9, 153, 563, 572, 579, Efferent lymphatic vessels, 422
747
Efferent pathways, 336, 352-353, 372-373 Enzymes, 1-2, 5-7, 9-11, 13-14, 20, 24, 59-67, 72-74, 527, 549, 597, 616-617, 619-620, 623,
Eicosanoids, 7, 130, 145-146 76, 79, 81-83, 85, 87-88, 90, 97, 101, 646-647, 654, 657, 684, 688, 721
Ejaculate, 734 104-107, 110-113, 123-125, 127, 131, Exergonic reactions, 48
Ejaculation, 21, 355, 718 134-140, 142, 144, 153, 163, 190, 234, 262, Exhalation, 9, 418, 463-466, 472-473
Ejaculatory duct, 716 269, 310, 389, 426, 428, 484, 490, 502, Exocrine glands, 9, 121-122, 210, 583
Elastin, 40, 101, 386, 470, 592 508-510, 520-525, 535, 546, 553, 555, multicellular, 9, 583
Elbow, 249, 626 559-560, 563-564, 572, 575-576, 579, structure, 9, 121-122, 210
Electrical energy, 7, 47 582-586, 589-591, 596-597, 600, 603, 616, Exocrine pancreas, 153, 355
Electrical gradient, 7, 14, 48, 93-94 619, 625, 629, 647, 658, 673, 676-679, 684, Exocytosis, 1, 9, 100, 102, 123-124, 129, 131, 153,
Electrical signaling, 93, 96, 191, 216 704, 716, 720, 722-723, 728-729 157, 163-164, 166, 187-188, 209, 216, 224,
Electrical stimulation, 349, 610, 612 pancreatic, 153, 585-586 234, 255, 263, 297, 529, 566, 676-677, 728
Electrical synapses, 206-207, 209, 218, 320 seminal fluid, 716 Exons, 2, 104-105, 107
Electrolyte balance, 125, 325, 729 Enzyme-substrate complex, 61 Expiration, 9, 464, 470, 473, 495
Electromagnetic spectrum, 306-307 Eosinophil, 8, 428-429 muscles used in, 464
Electromyography, 612 Eosinophils, 426-427 Expiratory reserve volume, 472-473, 497
Electron cloud, 50 Ependymal cells, 8, 194, 343 Extension, 9, 19, 23, 98, 150, 172, 231, 234-235, 300,
Electron transport chain, 6, 16, 19 Epicardium, 396-397, 432 341, 343, 572, 614, 628, 631, 717
Electronegativity, 93 Epicardium (visceral pericardium), 397 Extensor muscles, 613-614, 627-628, 656, 658
Elements, 21, 49, 89, 92, 98, 108, 137, 199, 223-224, Epidermis, 512-513, 572-573, 609, 687 External intercostal, 469-470, 495
231, 236, 238-239, 244, 250, 258, 261-262, cell types, 513 External intercostal muscles, 469-470, 495
264, 268, 527, 551, 562, 596, 625-627, 651, color, 572 External respiration, 9, 20, 442
669, 679, 700, 702 layers, 513, 609 Exteroceptors, 278
Elevation, 11, 131, 266, 269, 371, 523, 597, 653, 672, structure, 512, 572-573 Extracellular fluid, 12-13, 52, 54, 75, 93, 95, 100,
692, 731 Epididymis, 8, 23, 716 119-126, 129, 134-143, 145, 147, 176, 182,
Embolism, 526 Epileptic seizures, 348 185, 196, 199, 211, 214, 256, 297-298, 356,
Embryo, 1, 7-8, 14, 18, 32-33, 245, 377, 576-578, 581, Epinephrine, 1-2, 4-5, 8, 22, 128, 132, 155-156, 380, 405-406, 411, 413, 442, 444, 460,
702, 709-710, 719-720, 723-725, 732 158-159, 162, 164-165, 210, 213, 355, 500-502, 504, 509, 511, 514-515, 526, 628,
Embryogenesis, 245, 262, 713, 719 357-360, 371, 400, 405, 410-411, 414, 419, 677, 711
Embryonic development, 3, 6, 10, 33, 233, 243, 248, 433, 471, 586, 593, 620 Extracellular matrix, 3-5, 9-10, 12-13, 24, 67, 90,
342-343, 388, 471, 555, 576, 579, 702, blood pressure and, 433 101-102, 107, 111, 238, 266, 292, 386, 511,
719-720, 725, 734 Epinephrine (E), 213 528, 575, 592, 623-625, 654, 710-711, 723
Emotions, 13, 345-346, 348-349, 360, 372 Epineurium, 338 cartilage, 3-5, 9, 101, 623, 625
Emphysema, 449, 470 Epithalamus, 346-347, 350 connective tissue, 3, 9, 13, 102, 238, 292, 625
Enamel, 575, 578 Epithelial cells, 3-4, 12, 15, 122, 277, 290, 296, 305, Extraembryonic membranes, 713, 720, 725, 732
Encephalitis, 571 310, 327, 337, 386, 396, 458, 460, 502, Extrinsic salivary glands, 583
End diastolic volume, 8 513-514, 516, 518-519, 527, 529, 531-535, Eye, 1, 5-6, 9, 12-13, 16, 19, 21, 24, 114, 203, 248,
End systolic volume, 8 552, 567, 572-573, 583-584, 624, 693, 725, 254, 264-265, 275-276, 278-279, 281, 283,
Endergonic reactions, 48-49 728-729 292, 309, 311-317, 320-322, 324, 326,
Endocardium, 8, 396-397, 432 Epithelial tissue, 8, 500, 511, 513, 723 328-329, 332, 341, 348, 354-355, 389, 518,
Endocrine glands, 19, 121-122, 152, 158, 160, 193, development, 723 554, 560, 583, 670, 688
326 glandular, 723 accessory structures, 276, 292
Endocrine pancreas, 355 Epithelium, 4-5, 7-8, 16, 20, 165, 238, 284-286, 291, chambers, 24, 583
Endocrine system, 8, 116-117, 119, 121, 148-149, 153, 312, 314, 317-318, 324, 327, 349, 467, 491, development, 6, 13, 248, 265, 315, 328, 389, 554
155, 157, 160-161, 166, 326, 347, 370-372, 502, 512, 517, 519, 527, 529, 561, 565, 575, layers of, 1, 5, 13, 292, 314, 317, 329
410, 429, 431, 433 581, 583, 585, 597, 600, 693, 714, 735 muscles, 13, 24, 203, 248, 254, 264-265, 292, 314,
development, 117, 160, 166 intestinal, 4, 238, 519, 581, 585, 600 316, 341, 355, 560, 670
Endocrinology, 155, 166-167, 714, 729, 734 respiratory, 4, 20, 238, 467, 491, 693 structure, 1, 5-6, 9, 16, 19, 21, 203, 264, 292, 309,
Endocytosis, 8, 17-18, 100, 102, 135, 230, 255, 529, Equator, 672 311, 313-315, 328, 332, 355
541, 566-567, 676-677, 711 Equilibrium, 7-8, 14-15, 17, 54, 56-57, 60-61, 63, Eyes, 3, 16, 20, 274, 277-278, 293, 301, 307-316,
Endoderm, 8, 579-580 94-97, 111, 126, 128, 173-174, 179, 320-321, 325, 328, 331-332, 338, 345-346,
formation, 8, 580 181-183, 187, 282, 294-296, 299-300, 328, 348, 355
Endolymph, 303-304, 306 341, 444, 450, 469, 475-479, 482-487, 489,
Endometrium, 8, 723-726 495, 503, 510, 518, 528 F
Endoneurium, 338 Erection, 131, 355, 414, 717 Face, 36, 41, 44-45, 68, 94-95, 163, 264, 301, 306,
Endoplasmic reticulum, 8, 10, 20, 98-100, 123-125, Erythroblasts, 8 320, 341, 344, 351, 412, 452, 484, 491, 506,
145-146, 171-172, 209, 255, 542, 569, 676, Erythropoiesis, 8 517, 549, 587, 598, 601, 618, 634, 637, 643,
681, 704 Erythropoietin, 8, 11, 162, 428, 476, 491, 526 645, 680, 682, 685, 702
rough, 123-124, 209 Esophagus, 8, 20, 37, 122, 254, 288, 338, 341, 560, muscles of, 341
smooth, 125, 146, 569 577, 579, 582-584, 633 Facilitated diffusion, 1, 9, 17-18, 90-92, 503, 523,
Endorphins, 133, 210 blood supply, 584 529-530, 532, 566-567
Endosome, 100 functions, 341 Fainting, 360, 424, 438, 497
Endosomes, 99-100 in digestion, 582 Fascicle, 338
Endothelium, 8, 23, 386-389, 396-397, 413-414, 432, Essential amino acids, 563, 597, 600 Fascicles, 338
438, 502, 587, 622, 694 Essential nutrients, 561-562 Fat cells (adipocytes), 1
Energy, 1-10, 12-15, 17-19, 21-24, 36, 39, 43, 44, Estradiol, 8, 81, 126, 704-705, 709, 712, 721 Fat-soluble vitamins, 562, 568
46-53, 55, 59-61, 64, 66-67, 70-88, 90-93, adrenal, 704 Fatty acids, 13, 17, 20, 23-24, 76-81, 86-89, 110, 125,
98-99, 109-112, 148, 153, 158-159, 170, Estrogen, 8, 125-126, 137, 160, 165, 721-727, 732 442, 513, 561, 563-564, 568-569, 579, 582,
172, 198-199, 209, 228, 232, 234-236, 240, Estrogens, 6, 8, 125, 152, 160, 162, 325-326, 591, 595-596, 599-600, 616, 618-620,
255-256, 261, 264, 268-271, 276, 279, 303, 704-706, 712, 718-719, 721, 724-726, 732 675-677, 685, 687
307-308, 310, 317, 319, 327-328, 335-336, functions, 704, 706 essential, 89, 561, 563, 600
353, 392, 396, 402, 417, 423-424, 443, 449, secretion, 6, 152, 325-326, 705, 726 omega-3, 563, 600
452, 458, 470-471, 481, 489-490, 494, 506, Estrone, 704-705, 721 oxidation of, 77, 81, 86-87, 110, 616, 685
508, 513-514, 516-517, 520-522, 525-526, Eupnea, 8, 449 Feces, 2, 6, 9, 505-506, 561-562
530-531, 536, 552, 559-561, 563-565, Excitability, 172, 195, 197, 436 Feedback, 9, 15, 18, 28, 34, 36-37, 40-42, 74, 140,
569-570, 572, 575, 586-588, 593, 595-598, muscle cell, 172 148-154, 156-157, 161, 164-165, 175,
600-604, 608, 614-619, 627-636, 639, 644, neuron, 172, 195, 197 181-183, 306, 326, 359-360, 364, 366, 389,
646-653, 655-658, 661-667, 669-670, 674, Excitable, 1, 7-9, 12, 16-17, 20, 22, 34, 93, 95, 413, 415, 420-421, 471, 487-488, 491, 537,
676-677, 679, 683-684, 689, 694-696, 698, 169-170, 172-173, 198, 217, 220, 253, 526 539-541, 543, 614, 648, 704, 721, 723-724,
700-701, 715, 727, 730-731, 738, 741 Excitation-contraction coupling, 9, 244, 272, 410, 624, 726, 730
activation, 1-2, 4, 6, 9, 23, 48-49, 59, 61, 77, 110, 684, 726 Female reproductive system, 707
148, 159, 234, 255-256, 264, 268-270, Excitatory neurotransmitters, 210 development, 707
310, 630, 674, 676, 679 Excitatory postsynaptic potentials (EPSPs), 210 Femur, 628
diffusion and, 17, 494 Excreta, 525 Fenestrated, 387, 528
from ATP, 64, 235 Excretion, 2, 86, 378, 421, 501-504, 506, 511, Fenestrated capillaries, 387
in cardiac muscle, 256 518-522, 524-527, 535-538, 541, 543-545, Fertilization, 2, 24, 233-234, 245, 377, 576, 702, 704,
Energy balance, 159 547, 549, 551-552, 554-555 708, 710-711, 713, 716, 718-720, 722-724,
Enterocytes, 566-567, 581, 584-585, 594, 600 Exercise, 4, 8, 38-39, 75, 83, 96, 155, 242, 245, 732, 734
Enteroendocrine cells, 584-585, 587, 591 248-249, 262, 413-414, 429-431, 435, Fetus, 151, 248, 262, 496, 714, 724-726
Enzyme inhibitors, 553 437-438, 449, 470, 479, 486, 488, 495, 499, Fever, 9, 19, 363, 427, 669, 692-694, 697
748
Fibers, 4-5, 9, 15, 19, 23, 98-99, 101, 196, 198, 203, Gastric pits, 11, 583-584 cerebellum, 340, 344
223-224, 232-233, 240, 245, 248, 254, Gastric ulcer, 11 characteristics, 340
262-264, 267, 270, 293, 296, 314, 321, 386, Gastrin, 162, 584, 586, 590-591, 593 medulla oblongata, 349
408, 470, 564, 609-611, 613, 616, 621-622, Gastrocnemius, 614, 647 organization, 340, 342, 344, 347, 349, 351
625, 629, 651, 683 Gastrula, 702, 719 pons, 349
connective tissue, 9, 293, 314, 610-611, 625, 651 Gastrula stage, 719 spinal cord, 7, 340, 342
Fibrillation, 409 Gastrulation, 579, 702 Green cones, 322
Fibrinogen, 728 Gated channels, 91, 180-181, 184, 196-197, 199-200, Growth, 2, 6, 10, 26, 32-33, 36, 76, 87, 113, 117, 127,
Fibroblasts, 3, 9, 15, 101-102, 238, 625, 723 203, 216, 218, 298 139-141, 150-152, 155, 159-162, 164-165,
Fibrosis, 514 Generator potential, 10, 277, 282, 285, 327, 329 224, 226-229, 232-233, 239, 244-245, 263,
Fibrous layer, 338 Gene(s), 647 325-326, 371, 389, 516, 543, 561-563, 575,
Filtrate, 9-10, 19, 23, 528-529, 531, 536-538, 548 Genome, 5, 10, 15, 33, 37, 40, 104-105, 108-109, 111, 597, 606, 622, 625, 657, 668, 671, 678,
Filtration, 10, 12, 18, 23, 421-423, 527-530, 537-539, 113, 137, 143, 216, 221, 223, 285, 290, 323, 680-683, 685, 695, 700-701, 703, 706, 710,
541, 543-547, 549-552 330, 702, 719 715, 719-720, 724, 726-727, 729-730
glomerular, 10, 12, 528, 530, 537-539, 541, Genotype, 10, 17, 19, 28, 34, 37-38, 40-41, 701, Growth hormone (GH), 152, 161, 325
543-544, 547, 549, 551-552 707-709, 732 Guanosine triphosphate (GTP), 10
Filtration slits, 18, 529-530, 543 Germ layers, 7, 14, 719 Guanylyl cyclase, 546, 593
Fingerprinting, 718 Gestation, 10, 597, 702, 725-726 Gustatory receptors, 288, 290, 329, 560, 570, 583
Fingers, 682 Gland cells, 157, 481, 572-573 Gustducin, 10, 289-290
First law of thermodynamics, 46, 60 Glands, 7-9, 17, 19, 21, 29, 121-122, 146, 151-152, Gyri, 10, 350
First polar body, 703, 708 158-160, 193, 210, 212, 215, 325-326, 336,
Fissures, 565 341, 354-355, 358, 505-506, 517-518, 551, H
Flagella, 3, 7, 9, 224, 230-232, 269, 447, 544-545 560, 567-568, 577, 583, 585, 601, 687, 690, Hair, 3, 10, 12-13, 16, 18, 21, 36, 292-294, 296-306,
Flexion, 9, 613-614, 627 706, 716, 724, 726-729, 732 328-329, 331-332, 355, 358, 562, 661,
Flexor muscles, 614 skin, 17, 122, 215, 355, 358, 506, 517, 690, 727 667-668, 687, 694-696, 706, 715, 724, 727
Floor, 235, 300, 456, 462-464, 607 structure, 7-9, 19, 21, 29, 121-122, 159, 193, 210, color, 3, 328, 331, 668, 696
Fluid balance, 347, 421, 467 212, 215, 355, 358, 551, 577, 727-729 functions, 3, 10, 18, 299, 302-304, 562, 694, 706
Fluid compartments, 502, 504 Glial cells, 2-3, 10, 14, 184, 194-195 production, 3, 10, 12-13, 16, 18, 21, 36, 562, 667,
Fluid mosaic model, 9, 88-89 Globin, 10-11, 474-475, 477-478, 492 687, 694-695, 706, 727
Folic acid, 562 Globulins, 125, 426 structure, 3, 10, 16, 18, 21, 292-294, 296, 299, 301,
Follicle cells, 710-712, 721, 723 Glomerular capillaries, 528, 530 303, 306, 328, 331-332, 355, 358, 562,
ovarian, 711, 721 Glomerular capillary pressure, 541 661, 668, 695, 715, 727
Follicle-stimulating hormone (FSH), 9, 325, 704 Glomerular filtrate, 537-538 types, 3, 10, 12, 16, 18, 293, 304, 306, 328-329,
Food, 3, 9, 13-14, 17, 20, 36-37, 39, 45, 47, 78, 109, Glomerular filtration, 10, 12, 537-539, 541, 544, 547, 331, 694
117-118, 122, 153, 162, 209, 238, 258, 261, 549, 551-552 Hair cells, 3, 12-13, 16, 21, 296-297, 299-306,
283-284, 288-291, 357, 359, 371, 381, 453, Glomerular filtration rate, 10, 12, 537-538, 544, 547, 328-329, 331-332, 668
490, 505-506, 508, 516-517, 519, 549, 558, 549, 552 Hair follicle, 292, 668, 687
560-561, 563-565, 569-578, 580-583, Glomeruli, 10, 548, 554 structure, 292, 668
585-586, 588-593, 596-598, 600-601, 604, Glomerulus, 1, 4, 7, 9-10, 14-15, 18-19, 527-531, Hair loss, 562, 668
606, 608, 639, 652-653, 678, 691, 701, 707 536-540, 543, 547-549, 551-552, 554 Hair shaft, 294, 687
regulation of, 153, 162, 209, 238, 258, 261, 359, Glottis, 10, 463-464 Haldane effect, 10, 483-484
549, 590, 601, 604 Glucagon, 10, 12, 17, 37, 153-156, 158, 162, 164-165, Half-life, 10, 124, 130
Foot, 37, 337-338, 389, 453, 528, 530, 543, 597, 614, 523, 586, 593, 595, 601, 619-620 hormone, 10, 124
639, 664, 690 Glucoamylase, 563 Hand, 45, 235, 292, 348, 626, 640, 660, 664, 678, 697
muscles, 37, 614, 639, 690 Glucocorticoids, 10, 125-126, 159-160, 163, 371, 523, bones, 626
Foot processes, 528, 530, 543 595, 619, 729-731 joints, 292, 626
Forearm, 613 Gluconeogenesis, 10, 72-73, 85-87, 110, 595, 599, muscles, 235, 292, 626, 678
Forebrain, 5, 9, 11-12, 16, 19, 343-347, 349-350, 617 Haploid, 10, 703, 707-708
372-373, 576 Glucose, 4, 6, 10-12, 15, 37, 54, 63, 70-75, 78, 81, 85, Head, 4, 6, 17, 19, 38-39, 79-80, 88-89, 123, 230,
Foregut, 566, 579, 581 87-88, 92-93, 110, 125, 152-159, 162, 234-237, 239, 241-242, 246, 250-251, 264,
Fornix, 349 164-165, 283, 342, 371, 378, 508, 529-532, 269, 271, 287, 295, 299-303, 305-306,
limbic system, 349 553, 564, 566-567, 589, 595-596, 599, 320-321, 324, 329-330, 334, 338, 341, 366,
Fovea, 9, 315, 317-318, 320 601-603, 615-620, 622, 647, 684, 728, 730 381, 383, 419, 423-425, 437, 456, 506, 518,
retina, 9, 315, 317-318, 320 absorption of, 162 536, 573, 576-577, 595, 603, 667, 675
Free nerve endings, 292-293, 324 conservation of, 6 pancreas, 17, 577
Frontal lobe, 351-352 gluconeogenesis in, 595 Headache, 493
Fructose, 11, 70, 72-73, 87, 566-567, 589, 684, 716 metabolism of, 153 Healing, 131, 389
Fulcrum, 626-627 molecular weight of, 15 Hearing, 5, 10, 12, 16, 21, 23, 278-279, 287, 291,
Functional groups, 50, 259, 582, 613 oxidation in, 619 294-296, 299-301, 303, 328-329, 332, 341,
Functional residual capacity, 473 sources of, 78 346
transport of, 75, 92-93, 532, 567, 596 cochlea, 5, 16, 299-300, 328
G Glucose transporters, 531, 595, 619 development, 10, 328
G cells, 590-591 Glycerol, 13, 15, 17, 23, 74, 78-80, 92, 508, 564, loss, 12, 23
Galactose, 70, 73, 566-567, 728 568-569, 616, 655, 682 sound detection, 301
Gallbladder, 3, 9, 353, 585-586, 591, 601 oxidation of, 74, 616, 655 Heart, 2-4, 6-10, 12, 14-15, 17, 19, 21-24, 29, 35,
functions, 3, 353 Glycine, 3, 56-57, 75, 209-210, 508, 521-522 39-40, 77, 81, 84, 87, 121, 140, 149, 155,
Gametes, 9-10, 16, 258, 702-704, 710, 713, 732 Glycogen, 4, 10, 29, 71-75, 81, 85, 110, 146, 371, 553, 158-159, 162, 212-213, 215, 238, 242-243,
in females, 704 564, 566, 586, 595-596, 600, 616-620, 622, 248-249, 252-253, 255, 270, 292, 334, 341,
in males, 10, 703-704 646, 653, 682 345-346, 352-355, 357, 359-361, 370-373,
Gametogenesis, 10, 702-705, 733 Glycogen phosphorylase, 71-72, 595-596 376-380, 382-390, 392, 394-413, 415-420,
Gamma-aminobutyric acid (GABA), 209, 593 Glycogen synthase, 72 422-425, 430-436, 438, 476, 480, 494,
Ganglia, 1, 3-4, 10, 18, 22, 203, 336-339, 342, 346, Glycogenesis, 10, 71 519-520, 537, 541, 543, 546, 549-551, 592,
356, 358, 360, 362-363, 366, 372 Glycogenolysis, 10, 71, 85 595, 598-600, 617, 621, 629, 678, 696
autonomic, 1, 3, 18, 22, 356, 358, 360, 362, 372 Glycolipids, 70, 80, 88-90, 727 anatomy of, 29, 398-399, 401
Ganglion cells, 317-320, 322, 325-326, 329 Glycoproteins, 91, 101-102, 682, 727 blood vessels, 2-4, 8, 23-24, 35, 149, 159,
Ganglionic neurons, 212 Glycosaminoglycans, 71, 101 212-213, 215, 238, 292, 345, 376-377,
Gap junctions, 12, 118-121, 163-164, 169, 195, Glycosuria, 10 379-380, 382-389, 392, 394-395, 397,
206-207, 218, 253, 259, 320, 337, 403, Goblet cells, 15, 584-585 400, 403, 413, 416-419, 422, 424-425,
406-408, 433, 592 Golgi apparatus, 10, 98-101, 124, 542, 568-569, 728 431-433, 438, 476, 543, 599, 696
Gas exchange, 2, 6-7, 10, 12-13, 18, 22-23, 390, Golgi tendon organs, 293 blood volume in, 420, 551
442-443, 447-452, 454-456, 458-469, Gonadotropin-releasing hormone (GnRH), 705, 721 cardiac output and, 418, 431, 433
471-472, 486, 490-491, 493-499, 507, 511, Gonadotropins, 9-10, 704-706, 721, 723, 732 chambers of, 3, 24, 377, 390, 394-397, 403, 432
633, 639, 690, 720 Gonads, 10, 16, 152, 326, 702-706, 720-721 development, 3, 6, 10, 159, 162, 243, 248-249,
Gas transport, 385, 442-443, 459, 473, 477, 495, 498 Graded contraction, 266 270, 377, 388-389, 395, 436, 438, 600
Gases, 6, 9-10, 17, 34, 92, 122, 130, 223, 443-445, Graded potentials, 8, 20-22, 175-180, 184, 186, 190, endocrine functions, 599
448, 450, 460, 472-473, 481, 493-494, 582, 193, 202, 216-218, 283 Frank-Starling law of, 412
620, 628, 632-633, 639, 712, 720 Granulocytes, 426-427 functions, 3-4, 10, 29, 39, 155, 159, 215, 243, 334,
as neurotransmitters, 122, 130 Granulosa cells, 10, 22, 710, 722-724 341, 345, 352-353, 360-361, 372-373,
partial pressures of, 6, 17, 443 Gray matter, 3, 7, 10, 24, 340, 342, 344, 347, 349, 351 395, 399, 401, 409, 434, 476, 541, 599
749
internal anatomy, 401 157, 159, 161, 164, 209, 262-263, 347, pituitary gland, 150
orientation, 21, 249, 396 534, 541, 599, 652-653, 704, 706, 734 Inhalation, 12, 418, 464-466, 470, 472-473, 488
perfusion of, 494, 621 overview, 118, 608, 657, 702 Inhibin, 721, 723-724
physiology of, 435-436, 629 receptors, 2, 5, 14-15, 19, 90, 118-119, 121, Inhibitory interneurons, 612
position, 14, 19, 23-24, 242, 292, 371, 400, 412, 124-125, 128-130, 134, 137, 151, Inhibitory postsynaptic potentials (IPSPs), 210
422-425, 433, 480, 629 153-154, 156-160, 163-164, 166-167, Initiation, 3, 9, 12, 105-106, 185, 221, 434
valves, 12, 377-379, 383, 388, 396, 399-403, 409, 189, 225, 228, 263, 325-326, 371, 415, in translation, 106
418, 422, 425, 433 471, 509, 541, 544, 587, 590-591, Inner cell mass, 724-725
valves of, 396, 400 593-594, 622, 653, 704, 723, 730-732 Inner ear, 5, 12, 14, 16-17, 20-21, 23, 243, 299-301,
wall of, 23, 249, 389, 394, 480, 543, 546 types, 3, 5-6, 10, 12, 80, 85, 118, 121-122, 137, 303-306, 331-332, 346
Heart failure, 551 150, 153-155, 158, 163-164, 209, 225, Inner hair cells, 12, 16, 304-306
Heart rate, 3-4, 7, 14, 158, 213, 253, 345-346, 228, 235, 238, 245, 260-262, 270, 272, Inner mitochondrial membrane, 8, 82-84, 97, 674, 685
352-353, 355, 357, 359-360, 371-373, 342, 523, 526, 546, 552, 575, 584-585, Innervation, 240, 254, 267, 354, 358-360, 657
405-407, 409-412, 417, 419-420, 425, 430, 608, 652, 654, 678, 704, 722 Inositol trisphosphate (IP3), 12, 146, 286
433-436, 438, 494, 546, 549-550 Human body, 29, 33, 37, 353, 423, 607, 669 Inspiration, 12, 22, 464, 469-470, 473, 496
cardiac output and, 433 Humerus, 614-615, 627 muscles used in, 464
regulation of, 4, 346, 352, 359, 410-412, 419-420, Hyaluronan, 101-102 Inspiratory capacity, 472-473
433, 436, 549-550 Hydrochloric acid, 55-56 Inspiratory reserve volume, 472-473, 497
Heart sounds, 409-410 Hydrochloric acid (HCl), 55 Insulator, 95, 201, 206
Heart valves, 377, 433 Hydrogen, 2-3, 11, 24, 49-54, 67-69, 83, 86, 103, 109, Insulin, 6, 12, 17, 37, 111, 140-141, 153-156, 158, 160,
Heat, 4-12, 14-22, 35-37, 46-49, 52, 60, 66, 70, 82, 130, 304, 335, 471, 477-478, 490, 492, 513, 162, 164-165, 167, 263, 325-326, 355, 523,
84, 86, 110, 113, 264-265, 274, 324, 378, 565, 673, 739 595, 599-601, 619, 622, 706, 719
479, 506-507, 536, 561-562, 570, 600, 604, isotopes of, 86 metabolism and, 599
629, 647, 660-671, 677, 679-681, 683-692, Hydrogen bonds, 2-3, 24, 50-53, 67-69, 103, 109, Integral proteins, 89-90, 100, 225
694-697, 721, 741 477-478, 513, 673 Integration, 84, 109, 170-172, 192, 239, 356, 361, 370,
loss of, 4, 6, 86, 110, 506, 664, 668, 688, 690, 721 Hydrogen ions, 11 372, 499, 553, 607, 614, 652, 657, 728
metabolic rate and, 86, 604 Hydrostatic pressure, 11, 63, 421-425, 469, 480, 528, motor, 170-172, 192, 372, 614, 657
muscles in, 37 537, 539-540, 550, 552, 628, 633, 717 sensory, 170, 192, 361, 370, 372, 614
production of, 8, 10, 12, 16-17, 21, 86, 110, 265, glomerular, 528, 537, 539-540, 552 Integrins, 12, 102, 389, 624
506, 686, 721 Hypercapnia, 11-12, 485, 489 Interatrial septum, 399
Heat exchange, 6, 663-666, 670, 683, 687-689, 694, Hyperglycemia, 11, 156-157, 599 Intercalated cells, 532, 535
696 Hypernatremia, 526 Intercostal muscles, 341, 464-465, 469-470, 488, 495
Heat of vaporization, 10, 52, 665 Hyperpnea, 11, 449 external, 469-470, 488, 495
Heavy chains, 15, 230, 238, 240, 260 Hyperpolarization, 1, 11, 20, 96, 98, 172-174, 179, internal, 341, 469-470, 488
Helicobacter pylori, 584 181, 183, 195, 210, 218, 251, 253, 311-312, Interleukin, 599-600, 693-694
Helper T cells, 428 406 Intermediate filaments, 6, 12, 98-99, 224
Hematocrit, 11, 427, 476, 489, 491, 629 action potential and, 195 Internal intercostal, 470
Hematopoietic, 428-429 neuron, 1, 172-174, 179, 181, 183, 195, 210, 218, Internal intercostal muscles, 470
Hematopoietic stem cells, 428-429 253, 311 Interneurons, 192, 195, 280, 314, 317-318, 336-337,
Heme, 11, 18, 474-475, 477-478, 563, 622 Hypertension, 245, 526, 553-554, 599 342, 344, 362-363, 366-367, 487, 612, 614
Hemoglobin, 2-6, 8, 10-11, 14-15, 20, 29, 32, 426-427, Hyperthermia, 11, 671, 692, 694, 697 Internodal pathways, 408
469, 474-479, 481-482, 484, 488-493, Hypertonic, 11, 54-55, 517, 546, 681 Internodes, 184, 206
495-496, 565, 616, 621, 633, 679 Hypocapnia, 11, 489, 492 Interoceptors, 278
abnormal, 6 Hypodermis, 624 Interstitial cells, 592, 705, 715, 722
carbon dioxide transport in, 484 Hypoglycemia, 11 of Cajal, 592
fetal, 496 Hypokalemia, 526 Interstitial fluid, 12, 17, 380-381, 384, 387, 419,
in urine, 2 Hyponatremia, 526 421-422, 425-427, 459, 461, 477, 484, 502,
low content of, 476 Hypotension, 424, 526 509, 514, 517-519, 528-530, 532-537,
Hemoglobin (Hb), 474 Hypothalamic nuclei, 326 544-545, 567, 693
Hemophilia, 562 Hypothalamic-pituitary portal system, 11, 151-152, 159 Interstitial spaces, 421
Heparin, 101 Hypothalamus, 11, 18, 150-152, 158-159, 161, 322, Intestinal juice, 584
Hepatic portal vein, 569 325-326, 342-343, 346-349, 358-359, Intestinal villi, 6
Hepatocytes, 585 371-372, 488, 541, 544, 549-551, 587, 590, Intima, 386-388, 432
Heterogeneous mixture, 560 592, 647, 686-688, 690-691, 693-695, 697, Intrafusal fibers, 293
Heterozygous, 323 706, 711, 715, 721, 723-724, 730, 732 Intrapleural pressure, 23, 467-470, 496
Higher centers, 373, 587 development of, 343 Intrinsic salivary glands, 583
Hindbrain, 5, 11, 20-21, 343, 345-346, 356, 358, functions, 18, 150-151, 159, 161, 343, 347-348, Introns, 104-105
372-373 372, 541, 694, 706 Involuntary, 3, 259, 343, 353, 360-361, 373, 536
Hindgut, 5, 545-546, 552, 579, 581-582 limbic system and, 349 Involuntary nervous system, 353, 373
Hinge joints, 626 Hypothermia, 11, 85, 671, 694, 698 Iodine, 22, 129
Hippocampus, 11, 335, 346, 348-349, 368-369, 371, Hypotonic, 11, 54, 509 Ion channels, 1, 10, 12, 16, 20, 91-92, 98, 111,
373, 375 Hypoxia, 2, 12, 75, 85, 87, 248, 389, 414, 441, 136-138, 142, 144, 157, 163, 173-178, 180,
in memory, 369 475-476, 482, 487-492, 495-496, 498, 571, 189, 195, 197, 204, 211-212, 217-218,
Histamine, 3, 11, 129, 413-414, 471, 590-591, 593 608, 621-622, 697-698 220-221, 252, 254-255, 262, 276, 281, 285,
Histidine, 12, 56-58, 63, 129, 483, 520, 563, 593, 676 Hypoxia-inducible factor, 389 288, 294, 296-297, 305, 324, 327-328, 331,
Histones, 103-105, 715, 719 357, 369, 405, 436, 514, 539
Holocrine secretion, 11 I action potential and, 195, 252
Homeostasis, 11, 28-29, 34, 36-37, 40-41, 133, 135, Identical twins, 38 gated, 1, 12, 16, 91-92, 136-138, 163, 173-174,
148, 153-154, 159, 161, 164, 336, 347, Ileum, 12, 579, 583 176-178, 180, 189, 195, 197, 204, 211,
354-355, 372-373, 389, 490, 501-503, 526, Iliopsoas, 614 217-218, 220-221, 254, 285, 288, 297,
535, 549, 555, 671, 677, 730 Immune response, 3, 8-9, 12, 19, 426, 428, 509, 357, 369, 405
Homeothermic, 3, 22-23, 604, 669, 671 692-694, 697 Ion pumps, 113, 247, 257-258, 262, 500, 555
Homologous, 6, 108, 261, 327, 573, 613 Immune system, 13, 15-16, 125, 131, 162, 190, 194, Ionic bonds, 24, 50-51
Homozygous, 323 371, 414, 426, 428, 692-693, 731 Ions, 3, 5, 7, 10-13, 21, 35, 48, 51-55, 90-98, 120,
Homunculus, 353 cells of, 13, 194, 414, 693 138, 142, 172-176, 180-184, 189-190, 195,
motor, 353 Immunity, 13, 426, 428, 694, 731 197, 199, 204, 206-207, 211, 216, 218, 244,
sensory, 353 specific, 13, 426, 428 250, 252, 256, 274, 288-289, 292, 297, 369,
Hormones, 2-6, 8, 10-12, 14-15, 17, 19, 21, 23, 29, 37, Immunocompetence, 731 387, 405-406, 425, 434, 474-475, 481,
80-81, 85, 90, 110, 118-119, 121-125, Implantation, 6, 14, 719, 723-725 483-484, 486, 501-504, 508-511, 514-518,
127-130, 134, 137, 150-167, 189, 209, 225, Incisors, 575, 578 525-526, 529, 532, 534-535, 548, 551, 554,
228, 232, 235, 238, 244-245, 253, 260-263, Incus, 12, 14, 299, 304 560-561, 684, 689
270, 272, 325-326, 342, 347, 371, 375, 415, Incus (anvil), 12, 304 Iris, 12, 314-315
420, 471, 509, 519, 523, 526-527, 534-535, Infection, 9, 427-428, 693 Iron, 11, 14, 18, 59, 334, 474-475, 478, 526, 563, 653
537, 540-541, 543-544, 546, 552, 575, Inferior, 346, 401, 679 dietary, 563
584-587, 590-595, 599, 601, 603-604, 608, Inferior colliculi, 346 in hemoglobin, 474
619-620, 622, 652-654, 657, 668, 678, 695, Inferior vena cava, 401 Irritability, 357
702, 704-707, 709, 711, 715, 719, 721-726, Inferior venae cavae, 401 Ischemia, 12, 600
728-735 Infundibulum, 150 coronary, 600
functions, 3-4, 10, 29, 123, 129, 150-151, 153, 155, hypothalamus, 150 Isoleucine, 68, 563, 593
750
Isometric contraction, 12, 249, 261 Lipases, 13, 79, 110, 563, 582, 591, 601, 620 Malleus, 14, 299, 304
Isotonic, 12, 54-55 gastric, 591 Malleus (hammer), 14, 304
Isotonic contraction, 12 Lipid, 1, 3, 5, 9-11, 13-14, 17-18, 24, 78-80, 85, 87-91, Maltase, 564
Isotopes, 86 95, 100, 109, 111, 113, 119, 125, 130, 157, Mammary glands, 151, 325, 706, 724, 726-728, 732
Isotropic, 12, 241 163, 184, 342, 387, 512-513, 553, 562, 566, Mass, 3, 8, 10-11, 13-15, 18, 20, 26, 35, 43, 52, 56,
568-570, 587, 596, 599, 616, 618-620, 60-61, 63, 66, 73-74, 85, 90, 97, 111,
J 632-633, 646, 652, 654-655, 667, 674, 687, 126-127, 133, 135, 163, 238, 245, 300-301,
Jejunum, 12, 579, 583, 586 698, 727-728, 732 314, 338, 347, 378, 393-394, 443, 445, 477,
Joints, 4, 101, 292-294, 385, 493, 624-628, 656, 658 Lipid profile, 88, 90 483, 493, 506-507, 516, 527, 569, 591,
movements, 292, 294, 624, 627-628 Lipid rafts, 89-90, 513, 674 596-599, 602, 604, 606, 611, 614, 618, 628,
Juxtaglomerular cells, 10, 13, 539-540, 543, 549, 551 Lipogenesis, 13, 79 636-637, 641, 643-646, 649-656, 658, 664,
Juxtamedullary nephrons, 527-528, 534 Lipolysis, 13, 79 666, 692, 694, 724-725, 727, 737, 741
Lipoprotein lipase, 13, 569, 620 Mast cells, 11, 414
Lipoproteins, 467, 566, 569, 600, 619 Mastication, 14
K Liver, 3, 9, 11, 18, 29, 78-79, 85, 88, 97, 134-135, 146, Matrix, 3-5, 9-10, 12-13, 24, 67, 74, 82-83, 90, 97, 99,
Keratin, 13, 99, 101, 511-512, 574, 687 152-153, 156, 162, 325-326, 354, 371, 387, 101-102, 107, 111, 238, 266, 292, 300-301,
Keratinocytes, 511-512 422, 428, 465, 480, 523, 525, 553, 566, 386, 389, 467, 511-512, 528, 575, 592, 616,
Keratohyalin, 511 568-570, 572, 577, 579, 585, 591, 595-600, 623-625, 654, 710-711, 713, 723
Ketogenesis, 13, 78, 88 617-620, 647, 682, 711 bone, 3, 9, 101, 623, 625
Ketone bodies, 13, 78, 81, 88, 110, 596, 601 cholesterol and, 568 cartilage, 3-5, 9, 101, 467, 623, 625
Kidney, 1, 4-9, 12-15, 19-20, 23, 29, 123, 125, functions, 3, 18, 29, 88, 97, 146, 153, 428, 599, connective tissue, 3, 9, 13, 102, 238, 292, 625
134-135, 140, 146, 155, 158-160, 162, 682 extracellular, 3-5, 9-10, 12-13, 24, 67, 90, 97,
325-326, 354-355, 358, 387, 413, 415, 420, lipid transport and, 569 101-102, 107, 111, 238, 266, 292, 386,
428, 430, 486, 491, 502, 511, 516, 523, veins, 29, 387, 422 511-512, 528, 575, 592, 623-625, 654,
526-529, 531, 533-541, 543-555, 597, 600, Liver cells (hepatocytes), 585 710-711, 723
689, 729 Load, 13, 519, 591, 630, 731 hair, 3, 10, 12-13, 292, 300-301
failure, 123, 155, 486, 551 Lobes, 16, 169, 346, 351-352, 372, 518, 727 mitochondria, 4-5, 9-10, 74, 82-83, 97, 99, 111,
nerves, 6-7, 29, 123, 526, 553, 597 cerebral, 351, 372 616, 623, 654
overview, 502 Long bones, 625, 651 mitochondrial, 74, 82-83, 97, 99, 616, 623, 654
Kidney failure, 155, 486 Loop of Henle, 6, 13, 19, 527-528, 531-536, 540, Matter, 1, 3, 7, 9-10, 24, 179, 276, 329, 340, 342, 344,
Kidneys, 10, 29, 149, 160, 215, 358, 377, 415, 547-548, 552, 689 347-351, 399, 461, 463, 489, 565, 600, 655,
419-421, 430, 433, 480, 486, 489, 494, 511, Loudness, 283, 306 697, 737
526-527, 544-549, 552-554, 598 Lumbar nerves, 340 composition of, 351
Kinesins, 230 Lumbar regions, 356 Mean arterial pressure, 14, 417, 419-420, 424-425,
Kinetic energy, 10, 13-14, 47-48, 676, 741 Lumen, 7, 10, 13, 15, 19, 92, 238, 386-387, 480, 514, 431, 433, 436, 540-541, 549, 551
Kinocilium, 13, 296-298, 302 518-519, 527-536, 538-540, 543-546, 548, Mechanical digestion, 560
Knee joint, 613 560, 564, 566-568, 576, 578-580, 582-583, Mechanical energy, 14, 47, 235
Krebs cycle, 13 585, 590, 592, 713, 716 Mechanoreceptors, 263, 276, 278, 281, 291-292,
blood vessel, 386, 518, 530, 539, 568 294-296, 300-301, 324, 327, 329, 336, 363,
L Lunate, 629, 642 419, 429-431, 488, 495, 591-592
Lacrimal glands, 355 Lung, 5, 17, 22, 132, 212, 354, 390, 423, 449, 452, in digestion, 591
Lactase, 564 454-455, 459, 462-468, 470-473, 491, Medulla, 1, 4-5, 14, 18, 23, 158-160, 162, 212, 343,
Lactation, 13, 597, 727-730, 734 494-496, 499, 507, 511, 521, 633 345-346, 349, 354-355, 358-360, 363-365,
prolactin and, 728-729 development, 471, 499, 633 370-371, 405-406, 414, 419-420, 430,
Lacteals, 568 functions, 467 486-490, 495, 527-529, 533-536, 540-541,
Lactose, 70, 73, 564, 566, 727-728 surfaces, 449, 452, 455, 466-467, 471-472, 494, 543, 548-550, 555, 689
Lamellae, 97, 292, 307, 458-459 511 hair, 18, 355, 358
Laminar flow, 13, 634-636, 654 Lung compliance, 470, 495 renal, 5, 23, 527-529, 535-536, 540, 543, 549, 555
Language, 348, 352 Lungs, 2-4, 6, 11, 13, 18-19, 22-23, 29, 38, 122, 159, thymus, 162
Large intestine, 5, 12, 354, 577, 579, 583 213, 215, 354-355, 357, 371, 377, 388-390, Medulla oblongata, 4, 14, 345-346, 349, 359-360, 419,
cecum, 579, 583 398-401, 403, 418, 423, 433, 435, 443, 445, 430, 488, 541, 543, 549-550
colon, 5, 579 449-450, 452, 455, 459, 462-473, 479, 482, functions, 4, 345, 360, 541
rectum, 354, 579 484-485, 488-489, 491, 493-497, 499, 598, structure, 4, 14, 345-346, 349
regulation, 577 632 Medullary osmotic gradient, 536
Large vein, 386 Luteinizing hormone (LH), 152, 325, 704 Medullary respiratory centers, 488
Larynx, 288, 341, 467 Lymph, 13, 23, 380, 422-423, 425, 431, 509, 568-569 Meiosis, 16-17, 21, 107, 703-704, 708, 732, 734
functions, 341, 467 transport of, 13 Melanin, 668
Latch state, 13, 261, 270 Lymph nodes, 13, 422-423 Melanocyte, 150
Lateral inhibition, 13, 280-281, 283, 318-319, 322 Lymphatic capillaries, 422 Melanocyte-stimulating hormone (MSH), 150
Lateral rectus muscle, 341 Lymphatic ducts, 422 Melanopsin, 310, 325, 331
Lecithin, 568, 585 right, 422 Melatonin, 14, 18, 128, 161, 167, 213, 226, 325-326,
Left atrium, 390, 398-401, 404, 410, 433 Lymphatic system, 13, 380, 422-423, 431, 433-434 331, 346, 350
Left ventricle, 399-401, 403-404, 409-410, 415-416, functions of, 434 Membrane lipids, 14, 89, 444, 673
423, 433 lymph nodes in, 422 Membrane potential, 1, 6-12, 14, 17-22, 24, 35, 48, 82,
Length-tension relationship, 13, 411 Lymphatic vessels, 422, 585 91, 93-98, 111, 120, 125, 138, 142, 145, 153,
Lens, 5, 12-13, 222, 312-317, 326, 328, 341 Lymphocyte, 428-429 170-183, 186-187, 191, 194-195, 197,
Leptin, 162, 587, 590, 599 Lymphocytes, 13, 21, 422, 426, 428-429, 584, 692 200-202, 210-211, 215, 217-220, 251-253,
Leucine, 68, 563 functions, 426, 428, 692 255, 257-258, 266-267, 275-278, 282, 288,
Leukotrienes, 130, 563 production, 13, 21, 428, 692 291-294, 297, 302-303, 307-308, 327-328,
Levels of organization, 30 structure, 21, 584 330, 336, 404-405, 407, 433, 516, 526, 552,
Levers, 623, 625-626, 631 types, 426, 428, 584, 692 739
Ligaments, 314, 316, 396, 624-625 Lymphoid stem cells, 429 Membrane potentials, 95, 172-173
coronary, 396 Lysine, 67, 75, 105, 563 resting, 95, 172-173
elastic, 396 Lysosomes, 13, 98-100, 596 Membrane proteins, 8, 13, 33, 89-91, 99-100, 102,
Ligands, 92, 131-133, 137-138, 143, 163, 255 Lysozyme, 564, 566, 728 111, 228, 233, 255, 389, 513, 674, 684
Light, 3, 5, 9, 12-13, 15, 18-21, 23, 47, 116-117, 143, Membrane receptors, 102, 147, 228, 233-234, 624
191, 216, 235, 238-239, 260-262, 270, M Membrane transport, 46, 90-91, 100, 109, 113, 123,
276-279, 281-283, 292, 307, 309-323, Macromolecules, 4, 14, 16, 23, 34, 44, 50-51, 59, 555
325-329, 331, 344, 348, 427, 461, 570, 572, 70-71, 82, 88, 101, 109, 112, 153, 503, active, 90-91, 123
592, 594, 630, 652, 665, 675, 717, 741 505-508, 516, 528, 560-561, 563, 582, facilitated diffusion, 90-91
properties of, 5, 47, 235, 238-239, 260, 262, 270, 600-601, 623, 625, 673, 682-683, 693, 711, passive, 90-91
276, 310, 313, 320, 327 720, 727-728 Membranes, 1, 4-5, 10-12, 14, 17-18, 22, 35, 40, 48,
visible, 18, 292, 307, 665 Macrophages, 194, 224, 426-428, 693 51, 53, 76, 79-80, 83, 88-93, 95-98, 100,
Light chains, 15, 235, 238-239, 260-262 Macula densa, 13, 539-541, 543, 551 109-111, 119, 122-123, 125, 149, 159, 170,
Light energy, 19, 317 Maculae, 300-301 173, 175, 196, 200-202, 206, 209, 220,
Limbic system, 2, 13, 348-349, 359-360, 365, Magnesium, 59, 369 256-257, 263, 270, 277, 291, 342, 405, 484,
370-373, 488 Major nutrients, 575 502, 508, 513-514, 517, 521, 523, 529, 532,
Linker proteins, 475 Male reproductive system, 709 534, 551, 563, 616-617, 632, 673-677, 681,
Linoleic acid, 76, 563 development, 709 684-685, 695, 713, 720, 725, 732
751
mucous, 17 Molarity, 15-16, 54 Muscle metabolism, 264, 618, 622, 647
Membranous organelles, 99 Molars, 575, 578 Muscle spindle, 15, 293
endoplasmic reticulum, 99 Molecular biology, 41, 113, 220-221, 271, 331, 375, Muscle spindles, 293
lysosomes, 99 499, 554, 603, 734-735 Muscle stretch, 15, 627
mitochondria, 99 Molecular chaperones, 11, 69-70, 679, 681, 697 Muscle tissue, 621
nucleus, 99 Molecular weight, 15, 445, 655 Muscle tone, 592, 688
Memory, 13, 144, 215, 335, 343, 346, 348-349, 351, Monocyte, 15, 428-429 Muscle twitch, 407
366, 368-373, 375, 428, 653 Monocytes, 426-428 Muscle weakness, 190, 526
Menarche, 14, 724 Monoglycerides, 568-569 Muscles, 7, 13, 15, 17-18, 23-24, 35-40, 78, 84, 88,
Meninges, 5, 14, 342 Monosaccharides, 7, 11, 18, 70-71, 73, 290, 564, 98, 123, 131, 148, 157-159, 168, 170-171,
cranial, 342 566-567, 579, 601 190-191, 193, 203-204, 210, 213, 222-272,
spinal, 5, 342 Monosynaptic reflex, 361-362, 366 292-293, 305, 314, 316, 336, 341, 346, 353,
Menses, 14, 721 Motilin, 586, 593 355, 357-358, 360, 363-366, 371, 378-379,
Menstrual cycle, 14, 388, 720-721 Motor end plate, 15, 253-254, 270, 360, 429, 628, 683 381, 395, 401, 406, 413-415, 417-418, 425,
Menstruation, 14, 735 Motor neuron, 15-16, 170-172, 174, 180, 187, 429-431, 456-457, 460, 464-466, 469-471,
Mesangial cells, 14, 529-530, 539, 543 191-192, 195, 206-207, 215, 217, 220, 474, 476, 479, 486-488, 493-496, 526-527,
glomerular, 530, 539, 543 253-254, 266-267, 271, 285, 360, 363, 553, 560, 574, 591, 607-632, 639, 641,
Mesencephalon, 14, 343 366-368, 429, 592, 612, 628 643-645, 647-651, 654, 656-658, 670-671,
development, 343 Motor neurons, 1, 157, 171-172, 174, 184, 188, 678, 683-684, 687, 690, 706, 726, 731
functions, 343 191-194, 198, 206, 208, 217, 253-254, 262, arrector pili, 355, 358
structure, 14, 343 266, 351, 360, 362-367, 371, 429, 469-470, ciliary, 232, 314, 316
Mesencephalon (midbrain), 343 487-488, 537, 608, 611-612, 654, 683 diaphragm, 7, 341, 469-470, 488, 495, 613
Mesoderm, 5, 14, 579-580 Motor output, 363-364, 366 digastric, 7
formation, 5, 580 Motor unit, 15 gastrocnemius, 614, 647
Messenger RNA (mRNA), 102 Motor units, 266, 683 iliopsoas, 614
Metabolic acidosis, 1, 14, 486, 490, 535 Mouth, 4, 8, 24, 122, 286, 290, 337-338, 341, 353, intercostal, 341, 464-465, 469-470, 488, 495
Metabolic alkalosis, 1, 486, 496 381, 452-457, 462-464, 466-467, 489, 506, lateral rectus, 341
Metabolic rate, 1, 3-4, 7-9, 11-14, 20-22, 31, 35, 38, 527, 545, 565-566, 568, 570, 572-574, papillary, 401
75, 84-86, 112, 130, 153, 325, 413, 415, 447, 577-584, 595, 603, 661, 691, 727 pectoralis, 614-615
476, 489-490, 494, 496, 507, 513-514, 561, Movement, 1-5, 7-11, 13-14, 16-24, 29, 36, 45, 47-48, rectus femoris, 614
593, 596-597, 602, 604, 621, 623, 646-650, 53-54, 82, 84, 89-94, 96, 98-99, 101, 109, sartorius, 243
655-656, 661, 670-671, 673-674, 677, 679, 120, 169, 171, 173-175, 178, 181-182, 187, soleus, 613-614, 651
683-685, 692, 695-698, 740 211, 222-272, 278, 282, 292-295, 297, 300, stapedius, 243
basal, 1, 3, 20-22, 86, 597, 602, 647, 671 306, 341, 345, 351, 353, 363-366, 387, superior oblique, 341
heat production and, 695 391-392, 405, 420-421, 434, 444-445, 447, superior rectus, 265
neuron, 1, 3, 7, 9, 12-13, 21-22 449, 454, 456, 464, 466, 481, 502, 504, teres major, 627
Metabolism, 1, 6, 8, 10, 14, 22-23, 35, 43, 45, 59, 63, 508-509, 511, 513-514, 516-517, 519, 521, tibialis, 614
66-67, 70-72, 78-79, 81, 84-88, 110, 113, 532, 534, 536-537, 539, 546, 566, 570, 572, tongue, 341, 560
117, 125, 141, 148, 150, 152-153, 155, 157, 585, 606-614, 619-620, 624, 626-632, tympanic, 23
161-162, 167, 209, 240, 264, 325, 371, 429, 634-641, 643-644, 646, 648-652, 654-656, Muscular system, 272, 429
441-442, 446, 449, 461, 469, 474, 483-486, 663, 667, 673, 682-684, 692, 694, 712, 716, movement and, 272
489-490, 492, 494, 507, 520-524, 526, 535, 724, 729, 735 Myasthenia gravis, 190, 219
551, 554-555, 559, 564, 569, 575, 587, 593, Movements, 92-95, 117, 142, 174-175, 195, 216, 223, Myelencephalon, 343
595-600, 604, 608, 614-618, 621-622, 225, 230, 234, 255-256, 267, 292, 294, 297, Myelin, 12, 15-16, 20, 171-172, 184, 186, 194-196,
628-629, 633, 639, 647, 650, 652-653, 299, 301, 321, 337, 339, 341, 343, 346, 350, 205-206, 221, 338, 342
655-658, 660, 663, 666, 670, 673, 677-679, 360, 363-366, 373, 379, 383, 388, 401, 418, Myelin sheath, 12, 15-16, 171-172, 184, 186, 194-196,
683-684, 692, 695, 698, 704, 706, 709, 716, 449, 454-455, 459-461, 463-465, 478, 486, 205-206, 338
722, 729-730 489, 510-511, 513-514, 519, 534-537, 539, Myelinated, 20, 184, 186, 196, 198, 205-206, 218-219,
anabolism and catabolism, 87-88, 153 542, 553, 611, 614, 623-624, 627-629, 631, 338
ATP synthesis, 66, 88, 618, 677, 683 634, 638, 640-641, 643, 649, 652-655, 657, Myelination, 15, 196, 198, 203, 205-206
muscle, 1, 6, 8, 14, 22-23, 67, 79, 84-85, 148, 153, 665, 684, 729 Myeloid stem cells, 429
240, 264, 429, 483, 526, 555, 559, types, 92-93, 195, 223, 225, 230, 255-256, 321, Myoblasts, 15, 244-245, 265
595-597, 599-600, 608, 614-618, 379, 489, 513, 611, 623-624, 629, 631, Myocardial infarction, 526
621-622, 628-629, 633, 647, 650, 655, 652, 654-655 Myocardium, 15, 396-399, 403, 407-408, 414, 420,
657-658, 670, 677-678, 683-684 Mucin, 15 432-433
nutrient, 8, 71, 85, 564, 575, 587, 597-599, 618, Mucous cells, 15 Myoepithelial cells, 223, 727-728
622, 653, 670, 716 Mucous neck cells, 583-584 Myofibrils, 6, 84, 99, 240, 243, 247-248, 257-258,
thermoregulation and, 490 Mucus, 9, 15-16, 122, 231-232, 284-285, 501-502, 264-266, 268, 404
Metanephros, 547 511, 515, 525, 560, 572, 582-585, 590, 601, Myoglobin, 15, 240, 262, 474-477, 491, 493, 616,
Metencephalon, 343 693, 716, 724 622-623, 629, 654, 657-658, 679
Methionine, 68, 106, 563 Multicellular exocrine glands, 583 Myometrium, 8, 15, 723, 725
Micelles, 568 Multipolar neuron, 193 Myosin, 1, 6, 9, 15, 18, 21-24, 99-100, 223-224, 231,
Microcirculation, 151, 437 Multipolar neurons, 15, 192-193, 294 233-242, 244-251, 257-258, 260-262,
Microfilaments, 1, 6, 14, 98-100, 224, 231-235, Muscarine, 212 264-265, 268-272, 410-411, 429, 592, 594,
237-239, 259, 269-270 Muscarinic receptors, 5, 211-212, 357, 406, 414, 611, 613, 651, 678, 717
Microglia, 14, 194 593-594 Myosin ATPase, 236, 246-247, 249, 257-258, 261-262,
Microtubule-organizing center (MTOC), 14, 225 Muscle cell, 4, 15-16, 20, 171-172, 187, 190, 222, 240, 269, 410, 429
Microtubules, 3, 6-7, 13-14, 19, 23, 98-100, 209, 242-243, 245, 247-248, 250, 252-253, 255, Myosin heads, 15, 239, 241-242, 250-251, 271
224-232, 238, 269, 271, 296, 715 258-259, 262-263, 265-267, 360, 413-414, Myotome, 15, 611-612
in cilia, 3, 231 460, 594, 622
polar, 3, 229 Muscle contraction, 9, 13, 15-16, 20, 123, 146, 190, N
Microvilli, 4, 14, 233, 238, 288, 296, 313-314, 519, 203, 213, 235, 238, 244, 247-250, 254, 257, Nail, 577
531-532, 546, 567-568, 573, 581, 584-585, 260-261, 266, 268, 270, 379, 384, 425, Nails, 13
600 429-430, 463, 528, 592, 607, 609, 611-612, body, 13
Micturition, 14, 527, 536, 547 615, 623, 626-628, 654, 684, 726 Nares (nostrils), 463
Midbrain, 14, 16, 22, 343-346, 349-350, 352, 372, 487, cardiac muscle, 238, 247-250, 254 Nasal cavity, 284, 286, 467, 691
576 end of, 20, 379, 626 Nasal septum, 286
Middle ear, 12, 14, 16, 21, 23, 299, 303-304, 328 energy for, 235, 628 Nebulin, 241-242
Mineralocorticoids, 14, 125-126, 163, 534, 537, 541 movement and, 235, 238, 244, 247-250, 254, 257, Neck, 4, 39, 230, 234-236, 239, 249, 269, 338, 341,
Minor calyces, 527 260-261, 266, 268, 270 422, 424, 506, 547, 574-575, 578, 583-584,
Minute ventilation, 472 skeletal muscle, 15-16, 20, 190, 238, 244, 247-249, 668
Mitochondria, 4-6, 9-10, 14-16, 20, 45, 59, 73-75, 77, 254, 257, 261, 266, 270, 379, 425, 430 muscles of, 341
81-84, 87, 92, 97-99, 110-111, 125, 148, 159, smooth muscle, 13, 15, 146, 238, 260-261, 266, of bone, 574
172, 189, 240, 264, 271, 404, 427, 442-443, 268, 270, 430, 528, 592, 726 tooth, 575, 578
461, 481, 513-515, 518-519, 523-524, 531, Muscle contractions, 190, 384, 453, 464, 683, 711 urinary bladder, 547
546, 610, 615-616, 619-623, 629, 654-655, Muscle fatigue, 190, 407 veins of, 422
678, 681, 685-686, 715 Muscle fibers, 4, 9, 15, 19, 23, 203, 245, 262, 293, Negative feedback, 9, 15, 34, 37, 40-42, 74, 140, 148,
Mitosis, 16, 21, 232, 707 609-611, 616, 621-622, 629 151-154, 156-157, 161, 164-165, 175, 183,
Mixed nerves, 338 Muscle force, 250, 626, 651 359-360, 389, 413, 415, 420-421, 471,
752
487-488, 491, 537, 539-541, 543, 721, synaptic communication, 121, 194 412-413, 415, 420, 422, 428, 430-431, 435,
723-724 Neurophysiology, 168, 204, 220, 374 462, 494, 499, 544, 554, 572, 579, 598,
Nephron, 5, 15, 19-20, 527-531, 535, 537, 542-544, Neurotransmitters, 3, 16, 22, 121-123, 128, 130-131, 669-670, 706, 713, 716, 732
547-549, 551-552 135, 144, 163, 188-191, 194, 197, 206, Orthostatic hypotension, 424
juxtamedullary, 527-528 209-210, 213, 215, 217-218, 230, 245, 253, Osmol, 54
proximal convoluted tubule, 531 266, 305, 356-357, 360, 373, 527, 552, 561, Osmolarity, 5, 11-13, 16, 20, 54-55, 112, 501, 504-505,
structure and function, 527, 544, 551-552 575, 587, 590, 592, 603, 683 507-511, 518-519, 525-526, 532-536, 541,
Nephrons, 10, 527-529, 531, 534-535, 547-548, 552 definition, 16 544, 546-551, 553
Nerve endings, 150, 292-293, 324, 493 functions, 3, 123, 131, 191, 197, 209, 215, 360, Osmoreceptors, 541, 544, 551
free, 292-293, 324, 493 373 Osmosis, 16
Nerve fibers, 196, 314 Neutrophil, 428-429 Osmotic pressure, 1, 5, 16, 52-55, 421, 423, 502, 504,
Nerves, 6-7, 16, 18, 21, 29, 40, 123, 131, 157, 168, Neutrophils, 16, 426-428 509, 517, 537, 539, 682
228, 260, 264, 268, 279, 305, 320, 338, Nicotine, 189, 212, 288, 373 Ossification, 625, 654
340-341, 396, 526, 553, 560, 575, 585-586, Nicotinic receptors, 190, 211-212, 357 Osteoblasts, 101, 625, 654
591-592, 594, 597, 610, 612, 614, 622, 670, Nictitating membrane, 341 Osteoclasts, 625
685, 687-688, 690, 695, 714, 717 Night blindness, 562 Osteocytes, 3, 625, 654
radial, 610 Nipple, 714 Otolith, 16, 301
thoracic, 7, 340-341, 670 Nitric oxide (NO), 130, 209, 717 Otoliths, 300-302
vestibular, 21 Nitric oxide synthase, 130, 546, 717 Outer hair cells, 12, 16, 304, 306, 329, 331
Nervous system, 1-4, 7-10, 14-18, 21-22, 24, 116, 119, Nitrogen, 2, 5, 16-17, 23, 169, 443, 446, 469, 493-494, Outer mitochondrial membrane, 84, 97
121, 149, 154, 157-158, 168, 171, 180, 499, 501-502, 520-525, 551, 554, 597, 601 Oval window, 16, 304
192-195, 197, 203-205, 207-213, 217-218, Nitrogenous wastes, 13, 23, 520-522, 525-526, Ovaries, 10, 162, 703, 706, 708, 712, 724
221, 232-233, 266, 275, 277-278, 291, 554-555 Ovary, 10, 16, 706, 710, 712, 720-726, 729, 732,
293-296, 299, 311, 325, 327, 336-343, 347, Nociceptors, 278, 324, 327 734-735
352-362, 364, 366, 370-375, 387, 395-396, Nodes of Ranvier, 184, 186, 196, 206, 220-221 Overview, 28, 46, 113, 118, 170, 221, 224, 276, 336,
410-412, 414-415, 418-420, 428-431, Noradrenaline, 16, 213 374, 378, 385, 426, 442, 497, 502, 560, 608,
433-434, 471, 486, 488, 493, 540, 544, 552, Norepinephrine, 1-2, 4, 16, 22, 128, 158-159, 162, 657, 662, 702
583, 587, 591-592, 608, 611, 647, 669, 210, 213-215, 217, 219, 357-358, 370-372, Overweight, 598-599
685-688, 711, 730 405, 410-411, 414-415, 418, 420, 431, 433, Oviduct, 710-713, 716, 718, 725
anatomical organization, 611 592-593, 620, 685 Ovulation, 16, 702, 708, 710, 714, 721-724, 726
autonomic, 1, 3, 8, 17-18, 22, 208, 210-212, 347, blood pressure and, 433 Ovum, 1-3, 5-6, 9, 13-14, 16, 19, 23-24, 702-703, 708,
352-356, 358-362, 370, 372-374, 420 receptors for, 1, 213 710-713, 716, 718-720, 722-724, 732
central, 2-4, 7, 9-10, 14-18, 21, 24, 171, 180, 192, Nose, 2, 19, 30, 42, 284-285, 351-353, 506, 642, 691 Oxidation, 3, 13, 16, 19-20, 66, 74, 77-78, 81-83,
194, 203-204, 208, 210, 212-213, 293, Nostrils, 15, 286, 463, 517 85-88, 110, 112, 524, 565, 595, 616-620,
325, 336, 340-343, 352-353, 355-356, Nucleases, 106, 564, 582, 586, 591, 601 655-656, 685
358, 360, 364, 372-375, 387, 419-420, Nucleic acids, 1, 10, 16, 44, 59, 70, 102-103, 586 beta, 595
486, 488, 544, 552, 587, 591, 608, 611, Nucleoside, 1, 6, 10, 16, 131 Oxidative phosphorylation, 4, 9, 14, 16, 23, 82-84,
647, 669, 686-687, 711, 730 Nucleosome, 105 87-88, 97, 262, 264-265, 508, 615-617, 623,
development, 3, 10, 194, 232-233, 325, 342-343, Nucleus, 6, 10, 21, 45, 49, 51, 98-99, 104-105, 111, 646, 654, 683
374, 395, 471, 587, 611 131, 137, 141-142, 159, 171-172, 186, 196, Oxygen, 1-3, 6, 8-12, 14, 17, 19-20, 24, 29, 32, 36, 44,
divisions of, 343, 353 225, 228, 230, 233, 243, 259, 263, 296, 309, 49-51, 54, 73-75, 82-88, 110-112, 130, 148,
enteric, 3, 8, 154, 353, 372, 591-592 320-321, 325-326, 368, 389, 428, 532, 542, 158, 278, 283, 335, 376-378, 381, 385, 389,
motor pathways, 360, 373 544, 587, 590, 613, 680, 685, 713, 719, 728, 397, 399, 409, 413-415, 423, 425-432, 434,
overview, 221, 336, 374, 608 734 440-450, 452-453, 458-463, 466, 468-471,
peripheral, 3, 17-18, 21-22, 195, 208, 210, 213, Nutrition, 555, 559, 565, 587, 596, 598, 657, 710, 473-479, 481-483, 486-487, 489-498,
336, 340, 352-353, 355-356, 372, 374, 732-733 506-507, 565, 607-608, 616-618, 620-623,
418-420, 431, 433, 488, 540, 686-688, 629, 632-633, 639, 644, 646, 648, 654-655,
711 O 678-679, 697
somatic, 9-10, 21-22, 352, 360, 372-373, 488, 711 Obesity, 155, 363, 587, 590, 598-600, 604 alveolar, 469-471, 491, 496
Nervous tissue, 571, 596 Occipital lobe, 351-352 solubility of, 11, 444-445, 452, 474, 476, 481
Neural circuits, 359 Odorants, 5, 16, 284, 286-287, 290, 327, 330 toxicity of, 75
Neural crest, 576-577, 604 Olfactory bulbs, 348 transport of, 9, 75, 111, 426, 448, 473
Neural tissue, 157, 474 Olfactory cells, 193 Oxytocin, 17-18, 150-151, 161, 164, 325-326, 726,
neurons, 157, 474 Olfactory cortex, 352 732
Neural tube, 342-343 Olfactory epithelium, 284-286, 291, 324, 327, 349, 714
Neuroeffector junctions, 208 Olfactory organs, 287 P
Neuroendocrine cells, 590, 707 Olfactory receptors, 286, 290, 327, 570, 714 P wave, 19, 408-409
Neurohormones, 16, 122, 150-152, 160, 164 Oligodendrocytes, 194 Pacemaker, 7, 17, 253, 362, 404-410, 412, 433, 436,
Neurohypophysis, 18, 150 Oligosaccharides, 564, 727 487, 592
Neurokinin A, 593 Oocyte, 10, 16, 19, 33, 703, 708, 710-712, 719-720, ectopic, 7
Neuromodulators, 131 723 Pacemaker cells, 17, 253, 362, 404-410, 412, 433,
Neuromuscular junction, 15-16, 129, 131, 171, Oogenesis, 16, 703-704, 708, 710-712 592
187-188, 190-191, 207, 209, 211, 215, 221, Oogonia, 16, 19, 710 Pain, 16, 130, 133, 278, 324, 327-328, 493
253, 360 Opsins, 310-311, 323 Pain receptors (nociceptors), 327
Neurons, 1-4, 6-8, 10, 12-13, 15-17, 19, 30, 35, 91, Optic chiasm, 16, 320-321, 348 Palate, 286, 288, 661
95-96, 121, 144, 149-151, 154, 156-158, Optic nerve, 279, 315, 317-319, 321, 326 soft, 288
161, 168-175, 177-179, 184, 186-188, Oral cavity, 8, 14, 20, 286, 583, 727 Pancreas, 10-12, 17, 153-156, 158, 162, 353-355,
190-198, 201, 203-210, 212, 214-221, 225, salivary glands, 583 558-559, 568, 577, 579, 585-586, 591,
253-254, 262, 265-267, 277, 279-282, tongue, 286, 583 598-599, 601
284-288, 290-292, 294-297, 299, 301-302, Oral cavity (mouth), 8 endocrine, 11-12, 17, 153-156, 158, 162, 355, 599
305-306, 309, 313, 317, 320-321, 323-325, Organ of Corti, 12, 16, 304 endocrine functions, 153, 599
327, 329, 332, 336-342, 344, 346, 349-352, Organ system, 28 in digestion, 17, 585, 591, 598
355-374, 396, 405-406, 410, 414-415, Organ systems, 28, 31 regulation, 153-156, 158, 162, 577, 601
418-420, 429, 431, 469-471, 474, 486-488, development, 28 Pancreatic amylase, 566
526, 537, 540-541, 543-544, 549, 587, overview, 28 Pancreatic duct, 585
590-592, 601, 608, 611-612, 654, 678, 683, Organelles, 3, 9, 13-14, 35, 88, 92, 97, 99, 116, 172, Pancreatic islets, 154
686-687, 694-696, 705, 707, 717, 732 222, 225, 234, 237, 404, 427, 434 Pancreatic polypeptide (PP), 586
functions, 1, 3-4, 10, 150-151, 157, 161, 172-173, Organic compounds, 479 Paneth cells, 584-585
178, 191-193, 195, 197, 209, 215, 262, Organism, 2-3, 5, 8-10, 14, 17, 23, 28, 30-33, 36, 38, Papillary ducts, 528
287, 299, 302, 336, 341, 344, 350-352, 41, 59, 85, 121, 157-158, 191, 195, 197-198, Papillary muscles, 401
360-361, 372-374, 541, 694 271, 275, 277, 279, 325, 337, 350, 353, 362, Paracrines, 121-122, 128, 131, 163, 419, 430
regeneration, 194 442, 444, 447, 450, 452, 490, 552, 629 Parallel processing, 361
structure, 1-4, 6-8, 10, 15-16, 19, 91, 121, 168-175, Organs, 5, 10, 12-13, 17-18, 21-22, 28, 30-31, 46, 116, Parasitic infections, 426
177-179, 184, 186-188, 190-198, 201, 121, 127, 151, 154, 157-159, 192-193, 208, Parasympathetic nervous system, 17, 353-354,
203-210, 212, 214-221, 225, 262, 277, 259, 263-265, 269-270, 274, 276-279, 282, 356-357, 372-373, 411, 419, 430
284, 287-288, 292, 294-296, 299, 301, 284, 286-287, 291-297, 299, 305-308, 311, Parathyroid glands, 17
306, 309, 313, 332, 338, 340, 344, 346, 324, 326, 328, 336-338, 341, 347, 352, Parietal cells, 17, 584, 590-591
349-350, 355-356, 358, 362-363, 374, 354-355, 357-358, 360, 362, 370-372, 377, Parietal lobe, 351-352
469-471, 474, 526, 544, 678, 695, 705 379, 382-383, 387, 391, 395, 400, 403, Parietal pericardium, 396-397
753
Parotid gland, 583 739 488, 502, 504, 507, 509-511, 514, 517-519,
Parotid glands, 583 acid, 1, 3-4, 17-18, 20, 55-59, 63, 67, 82, 110, 247, 523, 525, 530-531, 538-539, 541-544,
Partial pressures, 6, 17, 443-444, 477, 741 485, 490, 492, 521, 525-526, 535, 555, 548-550, 553, 566, 594, 600, 620, 677, 685,
Parturition, 17, 151, 702, 724-727, 730, 732 584, 591, 685 711, 731
Passive processes, 689 base, 1, 3-4, 16, 18, 55, 57-58, 490, 526, 535, 555, carbon dioxide transport in, 484
Patella, 312 584, 739 Plasma membrane, 2, 4, 7-9, 13-15, 18, 22-23, 48, 71,
Pathogens, 422, 427-428, 692, 694 normal, 4, 12, 60, 63, 479, 485-487, 489, 496, 553 88, 90, 99-100, 102, 111, 119, 124, 129-130,
Pathways, 2-4, 17-18, 21, 32, 36-37, 41, 45, 59, 61, of blood, 4, 16-17, 20, 484-488, 553, 621-622 137-143, 145-147, 165, 172-173, 175-176,
63, 66-67, 75, 77, 79-81, 84-91, 98, 100-101, of urine, 526 187-189, 212, 214, 222, 224-226, 228, 231,
106, 110, 117-119, 125-126, 129, 131, regulation of, 4, 112, 269, 485-486, 488, 495, 526, 233-234, 236, 244, 257-260, 263, 286,
135-136, 138-139, 141-144, 146-150, 535, 555, 622 509-511, 514, 519, 523, 539, 541-542, 566,
152-155, 158-161, 163, 166, 188, 207, 211, pH scale, 17, 54, 739 594, 620, 677, 711
219, 224, 228, 244-245, 253, 255, 258, Phagocytosis, 8, 17-18, 100, 426-428, 566, 572, 600 structure of, 2, 15, 22, 111, 119, 139, 142, 225, 231,
260-261, 263, 271, 277, 279-280, 285, 290, Pharynx, 10, 290, 341, 381, 395, 455, 467, 577-578, 244, 510
311, 318, 320, 336-337, 342, 345, 352-353, 581 Plasma proteins, 421-422, 553
355-357, 360, 362-363, 365, 368, 370, in digestion, 578 Plasminogen, 599-600
372-373, 407-411, 432-433, 484, 490, muscles, 341, 381, 395 Plasmocytes, 426
509-511, 522-526, 535-537, 539-540, 549, regions, 577, 581 Plasticity, 17-18, 22, 34, 38-39, 41, 43, 215, 271-272,
551, 553, 559, 562, 566, 569, 587, 592-593, Phasic receptors, 283, 292 335, 366, 375, 647
601, 615, 617, 622, 657, 670, 676, 678-679, Phenotype, 17, 28, 34, 37-38, 40-41, 117, 244-245, Platelet plug, 428
683-685, 692, 704, 706, 708, 711, 714, 717, 262, 315, 577, 600, 647, 701 Platelets, 414, 426, 429, 434, 507
719, 723, 728-729, 731, 733 Phenylalanine, 68, 563 Pleura, 467-468
PCO2, 444, 452, 461, 471, 478-479, 481, 483-489, Pheromones, 17, 24, 80, 122, 125, 286-287, 291, 327, Pleural cavity, 18, 468-470
491-492, 495 346, 713-714 Pleural fluid, 468
Pectoralis muscle, 614-615 Phosphatases, 64-65, 72, 100, 110, 146-147, 228, 260 Pneumothorax, 469
Pellagra, 562 Phosphate, 1-2, 6, 10, 16-17, 19, 22, 58, 64-66, 71-74, Podocytes, 528, 530, 543
Pelvic girdle, 465 79-80, 83-84, 87, 103, 110, 162, 214, 226, Poikilothermic, 9, 21
muscles, 465 236, 481, 522-525, 532-533, 555, 562-563, Polar body, 3, 703, 708
Pelvis, 341, 422, 527 575, 625, 683 Polarity, 50, 68, 103, 170, 193-194, 226, 229-230, 238
nerves, 341 regulation of, 6, 22, 73-74, 87, 162, 524, 555 of water, 50
veins, 422 Phosphatidylcholine, 88, 675 Polarized, 18, 510, 675
veins of, 422 Phosphodiesterase (PDE), 311 Polycythemia, 489, 493
Penis, 125, 131, 414, 716-718 Phospholipase C, 144-146, 160, 214-215, 286, 289, Polymerase, 105
Pepsin, 5, 558-559, 567-568, 584, 591, 601, 603 310-311, 327-328, 546, 593-596 DNA, 105
gastric secretion of, 591 Phospholipid bilayer, 89, 675 RNA, 105
Pepsinogen, 590-591 Phospholipids, 13, 17, 76, 79-80, 88-90, 110-111, 130, Polypeptide, 18-19, 23, 68-69, 123-124, 128, 162,
Peptic ulcers, 584 199, 563, 568-569, 585, 673-677, 682, 684 533, 563, 586, 593
Peptidases, 563, 567 in membranes, 89, 675 Polysaccharides, 71, 290, 512, 563-564, 566
Peptide bond, 17, 106, 563 synthesis of, 80, 563 Polysynaptic reflex, 362, 366
Peptide hormones, 10, 123-124, 130, 163, 537, 546, Phosphoric acid, 56-57 Pons, 4, 18, 343, 345-346, 349, 354, 363-364,
706-707, 732 Phosphorus, 563 487-488
Peptides, 122-124, 130, 140, 161-163, 166, 209-210, dietary, 563 development of, 343
543, 546, 568, 718 Phosphorylation, 4, 6, 9, 14, 16-18, 22-23, 64-65, 67, functions, 4, 18, 343, 345
Perception, 3, 47, 130, 276, 279, 284, 288, 290, 318, 72-73, 81-88, 97, 105-106, 110, 135, structure, 4, 18, 343, 345-346, 349, 363
320-321, 330, 347, 351, 543, 571, 600 139-141, 145-147, 163, 228, 235, 260-265, Pores, 12, 91, 111, 118-119, 206, 223, 305, 381, 387,
depth, 320-321 268, 270, 410, 508, 519, 542, 592-593, 421, 427, 448, 452-453, 467, 471, 528, 572
Perfusion, 17, 24, 449, 472-473, 486-487, 491, 494, 615-617, 623, 646, 654, 683, 685 alveolar, 467, 471
620-622, 628 oxidative, 4, 9, 14, 16, 23, 82-85, 87-88, 97, 110, skin, 387, 448
tissue, 17, 24, 491, 620-622, 628 262, 264-265, 508, 615-617, 623, 646, Portal system, 11, 18, 151-152, 159, 326, 705
Pericardial cavity, 397, 403 654, 683 Portal vessels, 706
Pericardial fluid, 397 Photons, 3, 5, 18, 47, 307-308, 332, 665 Positive feedback, 9, 18, 34, 37, 40-41, 148, 151, 157,
Pericardium, 17, 396-397, 403, 432 Photoreceptors, 5, 18, 20, 23, 276, 278, 281, 307-314, 161, 164, 181-183, 704, 723, 726, 730
parietal, 17, 396-397 317-322, 325, 327-329, 331-332, 336 Positive selection, 647
visceral, 396-397 Phototransduction, 5, 16, 310, 312, 322, 331 Posterior, 4, 11-12, 17-18, 150-151, 161, 165, 314,
Pericytes, 389 Physical properties, 34, 52, 54, 79, 85, 102, 113, 445, 326, 337, 341-343, 346, 383-384, 400,
Perilymph, 17, 304-305 452, 494, 497, 512, 568, 575, 608, 625, 637, 414-415, 463-466, 468, 541, 565, 579,
Perineurium, 338 663 609-611, 642, 686, 688, 708, 726
Periosteum, 625 Physiology, 1, 5, 7, 11, 26-30, 32-36, 39-43, 44-114, Posterior chamber, 314, 463
Peripheral nervous system, 3, 17, 21, 208, 213, 336, 116-117, 148, 155, 167, 168, 170, 196, 204, Posterior pituitary, 18, 150-151, 161, 165, 326,
340, 352-353, 372, 374 220-221, 222-223, 229-230, 232, 238, 249, 414-415, 541, 726
cranial nerves, 340 271-272, 274, 276, 325, 330-332, 334, 366, Postsynaptic membrane, 190, 206, 208, 369-370
receptors in, 208 374-375, 376, 434-438, 440, 481, 490, 492, Postsynaptic neuron, 6, 189, 207, 209, 219-220, 361,
spinal nerves, 21, 340 497-499, 500, 507, 511, 524, 554-555, 368
Peripheral nervous system (PNS), 17 558-560, 564, 569, 579, 586-587, 589, 598, Postsynaptic potential, 9, 12, 19, 190, 219, 266
Peripheral proteins, 89-90, 111 602-604, 606-608, 628-629, 631, 639, 643, Postsynaptic potentials, 210, 266, 270
Peripheral thermoreceptors, 323, 686-687 645-648, 652, 655-658, 660-673, 675-698, Potassium, 21, 94-96, 111, 153, 405, 526, 541, 552,
Peristalsis, 17, 379, 592 700, 702, 704-706, 713, 725-726, 729-731, 554
Peritoneal cavity, 578 733-735, 737, 739, 740 regulation and, 554
Peritubular capillaries, 529 cardiovascular, 35, 39, 238, 249, 434-438, 499, Potential energy, 14, 18, 46-48, 82, 93, 109, 170, 199,
Peritubular fluid, 518, 529-531, 533-535 608, 629, 648, 655, 692 392, 396, 423-424, 683, 741
Permeability, 17, 54, 89, 93-97, 110-111, 136, 173-175, renal, 5, 554-555 Prefrontal cortex, 352
178, 180-182, 218-219, 288, 404-407, 480, Pia mater, 342 Preganglionic neurons, 356
510-512, 536, 540, 552, 633, 673, 693 spinal, 342 Pregnancy, 325, 722, 725-728, 732
action potential and, 219 Pigmented layer, 314 Premotor cortex, 352, 364
active transport, 93, 536 Pili, 355, 358 Pressure receptors, 292-293, 343, 359
diffusion, 17, 111 Pineal gland, 18, 161, 325-326, 342 pacinian corpuscles, 292-293
endocytosis, 17 Pinna, 16, 18, 299, 301, 303 Presynaptic neuron, 7, 13, 189, 206-209, 216, 219,
facilitated diffusion, 17 Pinocytosis, 8, 18, 100, 342, 566 361, 368-369
membrane, 17, 54, 89, 93-97, 111, 136, 173-175, Pitch, 642 Primary active transport, 1, 19, 92
178, 180-182, 218-219, 288, 404-405, Pituitary gland, 2, 18, 150, 326, 342, 415, 540, 727 Primary brain vesicles, 343
407, 510-512, 552, 673 Placenta, 5, 18, 162, 471, 578, 724-727, 729, 732 Primary follicle, 19
phagocytosis, 17 Plaque, 1, 259 Primary germ layer, 8
types, 54, 89, 93, 97, 219, 407, 552, 673 Plasma, 1-2, 4, 7-10, 13-15, 18, 20-23, 48, 71, 88, 90, Primary germ layers, 7, 14
Pernicious anemia, 562 92, 96, 99-100, 102, 111, 119, 124, 129-130, Primary motor cortex, 351-352, 365
pH, 1, 3-4, 12, 14, 16-18, 20, 54-60, 63, 67, 82, 110, 137-143, 145-147, 156, 162, 165-166, Primary spermatocyte, 19, 703
112, 120, 247-248, 250, 269, 278, 290, 441, 172-173, 175-176, 187-189, 212, 214, 220, Principal cells, 532, 534-535, 541-542, 545-546
478-479, 481, 483-490, 492, 494-497, 501, 222, 224-226, 228, 231, 233-234, 236, 244, Procarboxypeptidase, 585
514-515, 521, 525-526, 535, 553, 555, 568, 257-260, 263, 286, 342, 380, 392, 414, Progesterone, 81, 125-126, 152, 162, 704-706, 708,
582, 584, 591, 616-617, 621-622, 685, 716, 421-423, 427-428, 474-476, 479, 484-486, 721-727, 732
754
Projection, 3, 293-294, 306 Range of motion, 626 cellular, 5, 117, 159, 232, 575, 598, 702, 715, 719,
Prolactin (PRL), 152, 161, 729 Reabsorption, 123, 146, 161, 421-423, 481, 527-532, 732-734
Promoter, 12, 104-105, 109, 262, 677-678, 680-681 534-536, 538, 540-541, 543, 546-547, Reproductive system, 127, 707, 709
Prone, 423 549-552 development, 127, 707, 709
Pronephros, 19, 547-548 of bicarbonate, 535 Residual volume, 472-473
Proprioceptors, 292-294, 301, 327, 346, 364-366, 614 of sodium, 549 Resistance, 8-9, 17-18, 20, 22, 24, 35, 39, 43, 45, 92,
Prosencephalon, 9, 19, 343 passive, 529 176, 198-200, 202, 204-206, 391-394, 399,
Prosencephalon (forebrain), 343 tubular, 529-531, 543 403, 413, 415-416, 418-420, 422, 424,
Prostacyclin, 414 Receptive field, 19, 279-280, 292, 318-320 431-435, 446, 470-471, 495, 513, 526, 528,
Prostate, 19, 125, 716, 729 Receptor potential, 19, 277, 283, 291, 311, 327-329 533, 539-541, 549, 551, 599-600, 726, 738,
Prostate gland, 19, 716 Receptors, 1-2, 5, 9, 14-16, 18-20, 90, 102, 118-119, 741
Proteasomes, 596 121, 124-125, 128-138, 140-144, 146-147, airway, 22, 471
Protein C, 69 151, 153-154, 156-160, 163-164, 166-167, electrical, 8-9, 20, 35, 176, 198-200, 202, 204, 206,
Protein synthesis, 20, 23, 106, 209, 427, 596 172, 174, 176-177, 188-191, 193, 197, 206, 391-393, 600, 738, 741
transcription, 106 208, 210-214, 217-219, 225, 228, 233-234, in renal circulation, 540
translation, 23, 106 254-255, 263, 276-288, 290-294, 306, Resistin, 155
Proteinases, 129 308-310, 323-330, 336, 343, 356-360, 362, Respiration, 1, 6, 9, 17, 20, 23, 83-84, 86, 232, 264,
Proteins, 1-16, 18-20, 23-24, 33-34, 40, 45, 51, 53, 364, 366, 369-371, 373, 389, 405-406, 378, 436, 442-443, 448-450, 452-454, 461,
57-59, 64, 67-71, 82, 84, 88-92, 98-112, 117, 410-411, 414-415, 418, 429, 431, 434, 471, 463, 468, 481-482, 489-490, 498-499, 506,
119, 122-126, 128, 131-133, 139-142, 487-488, 493, 509, 536, 541, 544, 550-551, 511, 565, 602, 607, 617-618, 639, 648, 661,
144-147, 154-155, 159, 163-164, 166, 172, 560, 569-570, 572, 583, 587, 590-591, 685, 690-691
187, 196, 206, 211-212, 221, 222-235, 593-594, 622, 624, 639, 653, 704, 714, 718, cellular, 83-84, 232, 264, 442, 607, 617
238-239, 241-247, 249, 255, 257, 260-266, 723, 730-732 control of, 436, 490, 499, 685
268-272, 276-277, 281, 284-288, 290-292, gustatory, 286-288, 290-291, 327, 329, 560, 570, external, 1, 6, 9, 20, 378, 442-443, 448-450,
295, 297, 324, 326-328, 331, 357, 368, 370, 583 452-454, 463, 482, 489, 511
380-381, 387, 389, 395, 410-411, 421-422, olfactory, 16, 193, 284-287, 290-291, 324, 327, internal, 1, 20, 442-443, 448-449, 452-453, 489,
425-426, 434, 474-475, 482-485, 495, 498, 330, 343, 570, 714 511, 618
507, 511-514, 520, 524-525, 529-531, 534, sensory, 1-2, 14, 16, 18-19, 157-158, 191, 193, Respiratory alkalosis, 1, 486, 489-491
537, 539-540, 542, 553, 559, 562-563, 219, 225, 276-288, 290-294, 306, Respiratory centers, 488
566-570, 577, 579, 592-593, 596-597, 601, 308-310, 323-330, 336, 343, 360, 362, medullary, 488
608, 613, 616, 618, 623, 625, 632, 673-674, 364, 366, 370-371, 487-488, 560, 570, Respiratory epithelium, 693
678-682, 684, 686, 689, 693, 695, 697-698, 639, 653 Respiratory gases, 223, 445, 628
704-705, 711-712, 715, 717-720, 727-729, Recruitment, 19, 611-612, 643, 651, 654 Respiratory pump, 418-419
731, 734 Rectum, 354, 468, 545, 579 Respiratory system, 6, 19, 21, 24, 258, 264, 456,
carrier, 1, 4, 20, 82, 91-92, 123, 125-126, 128, 133, Rectus femoris, 614 465-467, 472-473, 485-486, 495-496, 499,
163, 166, 381, 426, 474, 514, 566-567 Red blood cells, 8, 11, 21, 93, 419, 426-427, 476, 482, 526, 608
membrane, 1-16, 18-20, 23-24, 33-34, 45, 53, 59, 484, 489-491, 493-495 development, 6, 499, 526
71, 82, 84, 88-92, 98-102, 109, 111-112, Red blood cells (erythrocytes), 427 epithelium, 467
119, 122-125, 128, 131, 139-142, Red cones, 322 functions, 264, 467
144-147, 163, 172, 187, 196, 206, Reflex, 11, 18, 20, 37, 41, 148, 343, 345-346, 359-362, gas exchange and, 486
211-212, 222, 224-226, 228, 231, 364, 366-368, 370, 372-373, 419-420, 424, larynx, 467
233-234, 244, 255, 257, 260, 263, 266, 431, 433-434, 436-437, 488, 536 overview, 608
270, 276-277, 285-286, 288, 291-292, classification, 436 primary bronchi, 466-467
297, 327-328, 370, 387, 389, 410, 484, endocrine, 11, 148, 370, 372, 431, 433 trachea, 465-467, 472
511-514, 529-530, 534, 539, 542, 566, integration, 361, 370, 372 upper, 467
568-569, 593, 616, 623, 673-674, 682, respiratory, 11, 18, 20, 370, 419, 433-434, 436, 488 Respiratory tract, 467, 693
684, 695, 698, 711, 718, 720, 727 spinal, 343, 345, 359-360, 364, 366, 370, 372-373, Respirometer, 607
plasma, 1-2, 4, 7-10, 13-15, 18, 20, 23, 71, 88, 90, 536 Responsiveness, 368, 734
92, 99-100, 102, 111, 119, 124, 139-142, steps, 420 Resting membrane potential, 6, 11, 17, 20, 93-98, 111,
145-147, 166, 172, 187, 212, 222, stretch, 364, 366, 419-420, 488, 536 170, 172-175, 177-183, 187, 194, 219-220,
224-226, 228, 231, 233-234, 244, 257, Reflex arc, 20, 359-362, 366, 536 251, 253, 288, 297, 404-405, 407, 433, 526
260, 263, 286, 380, 421-422, 474-475, Refraction, 20, 315 in neurons, 170, 172
484-485, 507, 511, 514, 525, 530-531, Refractory periods, 186, 197, 218, 282 Reticular formation, 349, 358-359, 365
539, 542, 553, 566, 711, 731 neuron, 186, 197, 218, 282 Retina, 9-10, 13, 20, 277, 309, 311-320, 322, 328-329,
transmembrane, 9, 12-13, 19, 23, 89-91, 123-125, Regeneration, 75, 194, 245, 315 332, 341, 361, 389
128, 131, 139, 142, 147, 163-164, 166, neuronal, 194 development of, 315, 328, 389
514, 566 Relative refractory period, 20, 179, 181, 186-187, 197, Retinal cells, 193
Proteolysis, 19, 568, 596 219 Rhodopsin, 20, 310, 312
Proteolytic enzymes, 106, 123-124 Relaxation, 2, 17, 23, 148, 213, 244, 247-248, 252, Rhombencephalon, 20, 343
Proximal, 7, 13, 19, 305, 418, 527-528, 530-535, 540, 256-258, 260-262, 264, 267-268, 270, 355, Rhombencephalon (hindbrain), 343
543, 547-549, 552, 687, 689 379, 386, 394, 410-411, 416, 418, 432, 465, Rib cage, 464, 469, 495
Proximal convoluted tubule, 531 543, 593-594, 608-609, 614, 624, 630-631, Ribose, 6, 10, 16-17, 20, 103
reabsorption in, 531 690, 717 in RNA, 103
Pseudopodia, 233 smooth muscle, 17, 23, 148, 258, 260-261, 268, Ribosomal RNA (rRNA), 102
Pulmonary arteries, 419 270, 355, 386, 418, 432, 594, 717 Ribosomes, 23, 106, 123-124, 427
Pulmonary capillaries, 497 Renal arteries, 540 in translation, 23, 106
Pulmonary circuit, 19, 388-390, 399, 403-404, 422, Renal artery, 527-529, 537, 551 Ribs, 464-465, 469
462 Renal clearance, 5, 20, 538 Right atrium, 21, 390, 398-401, 404, 416, 419, 422,
Pulmonary circulation, 29, 399-401, 435, 488 Renal cortex, 527-528 432
Pulmonary function tests, 472 Renal medulla, 527-528, 555 Right ventricle, 399-401, 403, 423, 432-433
Pulmonary vein, 388, 398-400 Renal papilla, 527 Rigor mortis, 236
Pulmonary veins, 401, 433 Renal pelvis, 527 RNA polymerase, 105
Pulp, 575, 578 Renal physiology, 554 Rods, 20, 297, 309-310, 317-318, 322, 325, 329
Pupil, 12, 19, 29, 314-315, 341, 355 Renal pyramids, 527 Roof, 284, 346, 661
Purines, 103, 122, 130-131, 209 Renal tubule, 20, 527-528, 537, 552, 554 Root, 7, 10, 20, 152, 292, 340, 342, 380, 445,
Purkinje fibers, 19, 408 Renal tubules, 543 479-482, 496, 575, 578
Pyloric sphincter, 19, 583 reabsorption in, 543 hair, 10, 292
Pyramids, 365, 527 Renal vein, 527 lung, 496
Pyrogens, 693 Renin, 2, 13, 355, 526, 543, 549-552 tooth, 575, 578
blood pressure and, 526, 549-550 Root hair plexus, 292
Q Repair, 20, 245, 389, 574, 625, 679 Rotation, 9, 303, 626, 645
QRS complex, 19, 408-409 tissue, 389, 574, 625 Rough endoplasmic reticulum, 123-124, 209
Repolarization, 20, 23, 96, 172-174, 179-183, 195, Rough ER, 263
218, 251-253, 257-259, 405, 407-409 Round window, 20, 304-305
R in cardiac muscle, 252, 258 Ruffini corpuscles, 293
Radial nerve, 339 Reproduction, 2, 5, 17, 21, 108, 117, 125, 150, 159,
Radiation, 18-19, 30, 47, 103, 307, 498, 573, 664-666, 162, 164, 167, 232, 286, 325, 343, 346, 507,
688, 694, 696 S
561, 575, 587, 594, 596, 598, 601-602, 639, Saccule, 300-301
Radius, 35, 50, 204-205, 391, 394, 432-435, 446-447 653, 671, 700-735 Sacral nerves, 340
755
Saliva, 20, 122, 288, 558-560, 583, 590, 666 Serotonin, 21, 128, 135, 164-165, 213, 219, 268-269, 386-387, 389, 413-415, 418, 420, 422,
Salivary amylase, 566 367-368, 414, 592-593 430-432, 438, 471-473, 528-529, 536-537,
Salivary glands, 146, 341, 354, 583 Serous cells, 583 539, 541, 549-550, 580, 584-585, 589,
Saltatory conduction, 20, 184 Serum, 21, 728 591-592, 594, 597, 601, 603, 622, 633, 688,
Saphenous nerve, 198 Sex hormones, 325, 709, 715, 722, 730 711, 717-718, 723-726, 733
Sarcolemma, 4, 6, 20, 23, 244, 247, 250-251, adrenal, 325, 730 digestive system, 261, 589, 591
253-258, 265-267, 270, 619 Shaft, 46, 294, 667, 687 functions, 4, 131, 146, 151, 541
in cardiac muscle, 250, 256, 258 hair, 294, 667, 687 locations, 13, 132, 258, 270
smooth muscle, 4, 23, 258, 266, 270 Shivering, 21, 37, 597, 683-686, 694 Smooth muscle tone, 688
Sarcomere, 1, 10, 12-13, 15, 20, 22, 24, 240-243, Shock, 11, 15, 70, 265, 275, 342, 367, 631, 647, Sodium, 1, 12-13, 15, 21, 55-56, 96, 125, 162, 221,
250-251, 264, 266, 268-270, 411, 625 679-681, 697, 713 291, 405, 514, 526, 541, 543, 549, 551-552
Sarcomeres, 21, 240, 243, 249, 258-259, 261, circulatory, 11, 342 absorption of, 162
264-266, 269-270, 608, 628 neurogenic, 15 regulation of, 125, 162, 526, 549, 551
cardiac muscle, 243, 249, 258-259 spinal, 342 Sodium channels, 1, 12, 221, 291
skeletal muscle, 21, 243, 249, 258, 261, 264, 266, vascular, 15 Soft palate, 288
270, 608 Shortening velocity, 628, 630 Soleus, 613-614, 651
Sarcoplasm, 20, 264 Shoulder joint, 627 Soleus muscle, 613
Sarcoplasmic reticulum, 4, 6, 20, 22, 254-256, 259, Shunt, 399-400, 481, 688 Soma, 3-4, 21, 171
410-411, 429, 593-595, 615, 624 Sign, 178, 365, 570, 690 Somatic, 9-10, 21-22, 352, 360, 372-373, 469-470,
in cardiac muscle, 256 Signal sequence, 123-124 487-488, 537, 702, 707, 710-711, 720, 732
in skeletal muscle, 254, 256, 595 Simple carbohydrates, 155, 600 Somatic cells, 10, 22, 710
Sartorius, 243 Simple diffusion, 223, 387, 620 Somatostatin, 152, 162, 586, 592-593
Satellite cells, 20, 244-245 Sinoatrial node, 21, 405-406, 410, 412, 420, 436 Sound detection, 301, 304, 572
Saturated fats, 76 Sinoatrial (SA) node, 404, 408 Spatial summation, 21-22, 177-179, 217-218, 361
Scapula, 615 Sinus, 21, 157, 284, 380, 382-383, 398, 401, 403-407, Speech, 303, 345, 347, 351-352
Scar tissue, 470 432, 546 Sperm, 1-2, 4, 8-9, 21, 23-24, 98, 125, 161-162, 223,
Schleiden, Matthias, 29 Skeletal muscle, 15-16, 20-22, 172, 187, 189-190, 230-234, 492-493, 702-703, 707-708,
Schwann cells, 171, 184, 186, 194, 292 192, 212, 238-239, 243-245, 247-249, 712-713, 715-720, 724, 732-735
Schwann, Theodor, 29, 558 252-258, 261-262, 264, 266, 270, 272, 293, Spermatids, 21, 703, 713, 715
Sciatic nerve, 198 360, 373, 379, 406-407, 413-415, 417-419, Spermatocytes, 703
Sclera, 21, 314-315 425, 430-431, 434, 437, 456, 595-596, primary, 703
Scrotum, 669 599-600, 608, 613, 619-621, 646, 657, 683 secondary, 703
Scurvy, 559, 562 actions, 15, 247, 379, 414, 619 Spermatogenesis, 21, 703-705, 713, 715, 732,
Second messengers, 139, 144, 146, 148, 163, 546, blood supply, 262, 608 734-735
593, 718 connective tissue, 238, 293, 434, 608 Spermatogenic cells, 713, 715
Second polar body, 3, 703, 708 contraction, 15-16, 20, 22, 190, 238-239, 243-244, Spermatogonia, 21, 715
Secondary active transport, 1, 19, 21, 92-93, 503, 518, 247-249, 252-258, 261-262, 264, 266, Sphincter, 2, 19, 21, 536-537, 579, 583, 585
566 270, 272, 360, 379, 407, 418, 425, 430, esophageal, 579, 583
Secondary brain vesicles, 343 434, 608, 657, 683 Spinal cord, 4-5, 7, 21, 40, 192, 336, 339-343, 345,
Secondary oocyte, 703, 708, 710 distribution, 413 350, 353, 356, 358-360, 363-366, 370,
Secondary sex characteristics, 715, 724, 731 fibers, 15, 245, 248, 254, 262, 264, 270, 293, 613, 372-374, 487, 536-537, 592, 612-613, 687,
female, 724, 731 621, 683 690
Secondary spermatocytes, 703 functions, 172, 192, 243, 262, 264, 360, 373, 434, development, 342-343, 374
Secondary structure of protein, 2, 21 599 functions, 4, 192, 336, 341, 343, 345, 350, 353,
Second-order neuron, 280 locations, 257-258, 270 360, 372-374
Secretin, 162, 586, 591, 593 names, 249 gray matter of, 342
Secretion, 2, 6, 9, 11, 18, 21, 90, 100, 111, 117, neural control, 437 Spinal meninges, 342
121-123, 127, 146, 150-154, 156-157, 159, organization, 243, 252, 360, 373, 379, 608, 613 Spinal nerves, 7, 21, 340-341
165, 325-326, 346-347, 355, 400, 420, 471, overview, 608, 657 Spindle, 15, 293, 428
481, 511, 517-519, 527-529, 531, 533-535, properties, 172, 212, 238-239, 243-245, 247-249, Spirometer, 472-473
538, 541, 543, 546-547, 549-552, 555, 252-253, 255, 258, 261-262, 264, 270, Spleen, 21, 354, 428, 476, 493-494
583-587, 590-592, 595, 694, 705, 723, 608, 613, 683 Stapes, 14, 21, 299, 304
726-729, 733 types, 16, 20, 22, 172, 192, 212, 238-239, 243, Stapes (stirrup), 21, 304
acid-base balance and, 555 245, 247-248, 252, 254-258, 261-262, Starling forces, 421-422
glandular, 723 264, 270, 272, 293, 379, 407, 434, 600, Steady state, 21, 665
modes of, 541, 555, 733 608, 613 Stellate cells, 545-546
of bicarbonate, 535, 591 Skeletal muscle pump, 418-419, 425, 456 Stellate ganglion, 203
Secretory vesicles, 123-124, 131, 151, 224, 569 Skeletal system, 631 Stereocilia, 21, 296-298, 301-306
Seizures, 348 Skeleton, 3-4, 8, 11, 39, 67, 101, 223, 262, 425, 455, of hair cells, 296-297, 301, 304
Selective permeability, 95 480, 512, 520, 608-609, 623, 625, 627-628, Sternum, 466
Selenium, 59 643, 655 Steroid hormones, 2, 4-5, 8, 10, 14, 21, 80-81, 90,
Semen, 21 appendicular, 643 110, 125, 127, 130, 160, 163, 166, 537, 541,
Semicircular canals, 21, 299-301, 303, 328-329 Skin, 6, 17-18, 52, 99, 117, 122, 215, 225, 277, 652-653, 668, 704, 706, 709, 723, 725, 728,
Semilunar valves, 401-403, 409 279-281, 292-293, 297, 299, 306, 323, 732-733
Seminal fluid, 716 328-329, 339, 355, 358, 362-363, 366-367, Stethoscope, 409
Seminiferous tubules, 21, 713, 716 380, 387, 390, 398, 424-425, 443, 448-450, Stimuli, 2, 10, 16, 143, 157-158, 178-179, 266, 270,
Sensation, 7, 278, 287-288, 290, 293, 324, 331, 341, 454-455, 494, 496, 499, 502, 506, 511-513, 276-284, 291-293, 295, 297, 323, 327,
351 517, 521, 547, 553, 561-562, 573, 610-611, 329-330, 336, 346, 351, 361, 364, 366-367,
Sense organs, 21, 157, 276, 278, 282, 284, 337-338, 614, 629, 636, 638-639, 664-667, 686, 370, 652
341, 370 688-690, 693, 695, 727 Stimulus frequency, 187
Sensitized, 367 development, 6, 117, 328, 499, 547, 611, 639, 727 Stomach, 7-8, 10, 15, 19-21, 37, 92, 162, 338, 354,
Sensory homunculus, 353 disorders, 562 360, 400, 462, 492, 496, 558-559, 566-568,
Sensory input, 21, 345-346, 348, 353, 362, 365, 420 glands, 17, 122, 215, 355, 358, 506, 517, 690, 727 571, 577, 579, 582-588, 590-592, 598, 601,
Sensory integration, 372 structure and function, 215, 292 701
Sensory neurons, 19, 158, 192-195, 277, 284, 287, tactile receptors, 292, 328 blood supply, 584
290, 292, 295-297, 305-306, 324, 327, Skull, 21, 299, 326, 334, 340, 342, 573, 660 functions, 10, 92, 360
336-337, 340, 342, 349, 352, 360, 366-368, development, 342 musculature, 15
488, 537, 608 Small intestine, 3, 7, 12, 354, 566-568, 577, 579, 583, regulation, 7, 19, 162, 577, 590, 601
Sensory receptor, 7-8, 14, 16-19, 21-23, 276-279, 585, 597 Strain, 35, 574
281-283, 288, 296, 325, 329, 361-362, 570 functions, 3 Stratum corneum, 506, 511-513, 693
Sensory receptors, 18, 276-279, 281-283, 293, 327, regions, 7, 566, 577, 579, 585, 597 Stress proteins, 679, 695
329-330, 336, 366, 370 regulation, 7, 577 Stress response, 8, 10, 156-159, 162, 164-165, 167,
general, 276, 279, 327, 330 Smell, 16, 21, 47, 143, 278, 283-284, 290-291, 330, 370, 595, 681, 697, 731
peripheral, 18, 329, 336 346, 349, 370, 560, 591, 653 Stretch receptors, 153-154, 263, 294, 364, 366, 488,
Sensory transduction, 21, 281, 330 Smooth endoplasmic reticulum, 125, 569 536, 541
Septum, 286, 399-401, 456, 465, 545 Smooth ER, 568 Striated, 4, 16, 20-22, 239-245, 247, 250, 252-262,
interatrial, 399 Smooth muscle, 4, 13, 15, 17, 21, 23, 131-132, 146, 265-266, 269-272, 411, 609, 628
nasal, 286 148, 151, 158, 210, 223, 238-240, 258-261, Striations, 16, 239
Serosa, 15, 21 266, 268, 270-271, 314, 354-355, 357, Stroke volume, 4, 22, 360, 409-412, 419-421, 424,
756
430, 434-436, 438 cytotoxic, 428 Thyroid gland, 17, 22, 152, 162, 325-326
regulation of, 4, 22, 410-412, 419-420, 436 helper, 428 development, 162, 325
Strong acid, 56 memory, 428 regulation, 22, 152, 162, 325-326
Strong acids, 56 T wave, 23, 408-409 Thyroid hormone, 22, 129, 262-263, 326, 516, 643,
Strong bases, 56 T4 (thyroxine), 129 729
Sublingual gland, 583 Tachycardia, 22, 410 Thyroid-stimulating hormone (TSH), 325
Sublingual glands, 583 Tactile receptors, 292, 328 Thyrotropin, 593
Submucosa, 22, 584-585, 592, 597 Tail, 38, 105-106, 230-231, 234-235, 239, 263, 269, Thyroxine (T4), 162
esophagus, 584 341, 366-367, 370, 388, 512, 611-613, 617, Tibia, 628
trachea, 22 629, 636, 641-643, 664, 668, 733 Tibialis anterior, 614
tracheal, 22 Target cells, 118-119, 121, 132-133, 148-150, Tidal volume, 22, 471-473, 496-497, 690-691
Substance P, 414 153-155, 157, 159, 163, 170, 172, 189, 206, Tight junction, 22, 387, 513-514
Substrate, 1-2, 5-6, 10, 13-14, 22-23, 48-49, 56, 209, 371 Tight junctions, 17, 113, 342, 387, 513-514, 517, 531,
59-65, 67, 73, 75-78, 81-82, 92, 110, 130, Target organs, 17, 22, 154, 158-159, 354, 358, 362 583
141, 145-146, 155, 159, 337, 522, 524, 530, Tarsals, 645 epithelial, 17, 513-514, 517, 531, 583
535, 609-610, 676-677 Taste, 10, 21-22, 143, 278-279, 284, 287-291, 324, Tissues, 4-6, 8-11, 13-15, 17-18, 23, 28-32, 34-35, 37,
Substrates, 8-9, 14-15, 19, 24, 49, 59, 61, 63-64, 73, 327, 329-330, 341, 591, 653 45-47, 52, 67, 71, 73, 75, 77-81, 85, 88, 92,
75-76, 81, 83, 85-86, 110, 484, 521-522, Taste buds, 288 97, 101-102, 110-111, 116, 121, 125, 127,
526, 620, 676, 684 Taste transduction, 288, 330 135, 148, 151-153, 155-156, 158-160, 165,
Sucrase, 564, 589 Teeth, 400, 455, 560, 575, 578, 600, 660 169, 195, 198, 209, 212-214, 218, 225, 229,
Sucrose, 70, 73, 81, 566, 589, 618 types, 560, 575, 578, 600 234, 238, 242-243, 258, 263-264, 274, 277,
Sugars, 47, 52, 70-71, 101, 153, 155, 288, 290, 507, Telencephalon, 9, 343, 346 315, 325-326, 338, 342, 353, 357, 370-371,
565, 570, 579, 682-683, 727, 729 Temperature, 1-7, 9-14, 18-23, 31-32, 34, 36-37, 39, 376-377, 380, 382-385, 387-390, 394,
simple, 101, 155, 507, 579 47, 49, 51-52, 54-55, 57-58, 60, 63-64, 69, 398-399, 401, 409, 413-416, 419, 422-423,
Sulcus, 22, 350-351 86, 89-90, 94, 109-113, 130, 157, 173, 191, 425, 431, 436, 442-443, 453, 459-460, 462,
cerebrum, 350 219, 228-229, 245, 247-248, 262, 269, 274, 473-482, 484-485, 490, 494-495, 497-498,
Sulfur, 564-565 278-279, 322-324, 327-328, 331, 343, 500-503, 505, 507-508, 511, 513-514,
dietary, 564 346-347, 359, 378, 438, 443-445, 447, 476, 516-521, 523, 526, 531, 536, 541, 544, 547,
Summation, 21-22, 177-180, 186, 202, 217-218, 267, 479, 482, 490, 495, 506, 513, 521, 555, 551, 559-560, 562-567, 569-571, 575, 579,
270, 361 596-597, 601, 618, 655, 660, 662-680, 587, 595-601, 617-619, 623, 633, 646, 651,
spatial, 21-22, 177-179, 217-218, 361 683-684, 686-689, 691-698, 709, 732-733, 664, 671, 678, 680, 682, 684, 686, 688-689,
Superficial, 12, 612, 629, 716 737, 741 693, 696, 700, 702-707, 711, 719, 724, 727,
Superior, 19, 40, 265, 321, 341, 346, 401, 404, 419, Temporal lobe, 351-352 729-730, 732
506, 661, 668, 681, 730 Temporal summation, 22, 178, 180, 202, 217-218 definition, 34
Superior colliculi, 346 Tendon organs, 293 development, 6, 10, 13, 28, 32, 34, 80, 125, 127,
Superior rectus muscle, 265 Tendons, 8, 611, 625, 629, 649, 651 151, 159-160, 243, 315, 325, 342, 377,
Superior vena cava, 401, 404, 419 structure, 8, 625, 651 388-389, 436, 526, 547, 565, 575, 579,
Supporting cells, 15, 284, 291, 297, 317-318 Tension, 13, 22, 52, 149, 251, 254, 270, 272, 276, 587, 600, 633, 651, 700, 702, 704,
olfactory, 284, 291 293, 316, 394, 411, 429, 469-471, 488, 539, 706-707, 719, 727, 729, 732
Suprachiasmatic nucleus, 325-326 592, 639, 649, 741 membranes, 4-5, 10-11, 14, 17-18, 35, 79-80, 88,
Surface tension, 22, 52, 469-471, 639 Teres major, 627 92, 97, 110-111, 125, 159, 209, 263, 277,
alveolar, 469-471 Terminal cisternae, 22, 255-256, 259 342, 484, 502, 508, 513-514, 517, 521,
of water, 52, 639 Testes, 10, 13, 21, 162, 703, 705-706, 708, 713, 715, 523, 551, 563, 617, 684, 732
Surfactant, 22, 471, 496 732 overview, 28, 46, 385, 442, 497, 502, 560, 702
Suspensory ligaments, 314, 316, 396 development, 10, 13, 162, 706, 713, 715, 732 primary types, 195
Swallowing, 123, 341 structure, 10, 21, 705, 715 Titin, 22, 241-242, 268
Sweat, 37, 212, 355, 358, 506, 549, 665-666, Testis, 8, 10, 21, 713, 715, 735 Tongue, 286, 288, 341, 505, 560, 573, 583, 691
689-690, 729 Testosterone, 2, 13, 81, 125-126, 137, 652-653, 668, taste buds on, 288
Sweat glands, 212, 355, 358, 506, 690, 729 704-705, 709, 715, 730-731 Tonic receptors, 283, 292
Sweating, 52, 355, 506, 666, 686, 689-690, 695 adrenal, 704, 730 Tonicity, 22, 54-55, 112, 511
Sympathetic nervous system, 16, 22, 157-158, functions, 652-653, 704 Tooth, 575, 577-578
353-354, 356-357, 370-373, 410, 414-415, in spermatogenesis, 715 crown, 575, 578
418-419, 428, 430-431, 540, 552, 583, 685, secretion, 2, 705 neck, 575, 578
688 Tetraiodothyronine (T4), 129 root, 575, 578
Sympathetic pathways, 356 Thalamic nuclei, 349 Total lung capacity, 22, 472-473
Symptom, 559, 599 limbic system and, 349 Total metabolic rate, 646, 655
Synapse, 3, 5-6, 8, 16, 18-19, 22, 120-121, 135, Thalamus, 22, 343, 346-347, 349-351, 358, 364-366, Touch receptors, 291, 293, 306, 362, 639
171-172, 187-190, 206-208, 215-221, 230, 370 Trabeculae, 22, 397-398, 407
254, 277, 290, 296, 318, 337, 342, 355-357, development of, 343 Trachea, 2, 4, 10, 22, 442-443, 459-460, 465-467,
360-362, 366-367, 369 functions, 343, 347, 350-351 471-472, 488, 512
axoaxonic, 3, 208 Thermoreceptors, 278, 322-324, 327-328, 686-687 Transcription, 12, 22, 102-103, 105-107, 116, 128-129,
axodendritic, 3, 208 peripheral and central, 686 137-138, 141, 146, 159-160, 163, 211,
axosomatic, 3, 208 Thermoregulation, 3, 17, 22, 490, 604, 668, 670, 686, 244-245, 262-263, 315, 368, 371, 389, 395,
neuromuscular, 16, 171, 187-188, 190, 207, 215, 690-692, 694, 696-697, 730 426, 476, 542, 622, 679-680, 704
221, 254, 360 hypothalamus in, 691 Transcription factors, 105, 107, 128, 137-138, 141,
Synapses, 6-7, 15, 18, 22, 187, 191, 194-195, Thick filaments, 1, 10, 239-242, 248, 259-260, 244-245, 263, 395, 426
206-209, 211, 217-218, 279-280, 284-285, 264-265, 269, 271 Transcytosis, 387, 529, 728
306, 317-320, 327, 336-339, 341, 346, Thigh, 243 Transducers, 136
356-358, 361-362, 365-366, 368, 370, 375 Thin filaments, 1, 10, 12, 21-22, 24, 239-244, 247, Transducin, 22, 289, 311-312, 319
Synaptic cleft, 16, 22, 187-189, 207, 360 250, 258-262, 265, 269-270, 717 Transduction, 2, 4, 6, 9, 14, 17, 21-22, 30, 80, 98,
neuromuscular junction, 16, 187-188, 207, 360 Thin skin, 448, 454 117-119, 125, 128, 132, 135-148, 153-156,
Synaptic delay, 206-207 Thirst center, 544 159-160, 163-166, 188, 206, 211, 213-214,
Synaptic vesicles, 22, 187-189, 206, 215-216, 254, Thoracic cavity, 418, 422, 465 216, 219, 276-277, 281, 284-291, 294,
368, 541 Thoracic nerves, 340 296-298, 306-308, 310-311, 324, 327-331,
Synovial fluid, 625 Thorax, 296, 425, 460-461, 465, 467, 469-471, 624, 375, 389, 405-406, 410-411, 698, 714, 729
Systemic blood pressure, 537 670-671, 684 taste, 21-22, 143, 284, 287-291, 324, 327, 329-330
Systemic circuit, 22, 386, 388-390, 398-399, 401, 404, arteries, 425 Transfer RNA (tRNA), 102
422, 425 Threonine, 64, 67, 139-142, 144, 146-147, 563 Translation, 15, 23, 102, 106, 128, 159, 211, 244, 542,
arteries, 386, 388-389, 398, 401, 404, 425 Threshold, 10, 19, 22, 127, 177-181, 183-187, 193, 679
veins, 386, 388, 398, 401, 422, 425 197, 201, 206, 217-220, 229, 232, 253, 255, Transmembrane proteins, 12, 91
Systemic circulation, 399-401, 419, 433, 435, 569 277-278, 281, 329, 332, 404-407, 505, 531, Transport proteins, 91, 498, 531, 534, 542, 689
Systole, 8, 22, 394, 396, 402-403, 410, 415-416, 537, 612, 649, 684, 721 Transport vesicles, 234, 263
432-433 Threshold stimulus, 22, 186-187, 281 Transpulmonary pressure, 23, 469-471
Systolic pressure, 22, 415, 417, 424, 433 Threshold voltage, 253 Transverse tubule, 23
Thrombocytes, 426, 428, 434 Tricuspid valve, 399
T Thumb, 616 Trigger zone, 3, 177, 193, 277-278
T cells, 426, 428, 584, 692 Thymosin, 162 Triglyceride, 13, 23, 78-79, 85, 563, 569-570, 587,
T lymphocytes (T cells), 428 Thymus, 162 595-596, 599, 619-620, 632-633, 655, 685,
activation of, 428 Thyroglobulin, 129 687, 711
757
Triglycerides, 13, 76, 78-79, 110, 563, 568-569, 586, inferior vena cava, 401 development, 3, 328
595, 599 intestinal, 422 overview, 560
Triiodothyronine (T3), 129, 162 jugular, 425 Visual acuity, 313
Trophoblast, 23, 724-725 large, 383, 385-388, 391, 398, 403, 416-419, 425, Visual association areas, 352
Tropic hormones, 2, 23 688-689, 718 Visual cortex, 24, 320-321, 351-352, 365
Tropomyosin, 23, 239, 245-248, 250, 262, 269, 272 liver, 29, 387, 422 Visual processing, 16, 321, 346, 351
Troponin, 23, 239, 245-248, 250, 260, 262, 264, 269, ovarian, 718 Vital capacity, 24, 472-473, 497
272 pelvis, 422 Vitamin D, 563
Trypsin, 563, 567-568, 585, 727 pulmonary, 29, 388, 398, 401, 403, 419, 422, 425, Vitreous humor, 314-315
Trypsinogen, 585, 683 432-433 Voltage, 1, 12, 15, 24, 91-94, 170, 175, 180-188,
Tryptophan, 68, 128, 213, 563 structure of, 29, 386-388, 432-433 195-204, 214, 216-221, 251-253, 255-256,
Tubule lumen, 10, 519, 531, 534-535, 543, 548 superior vena cava, 401, 419 270, 274, 277, 285, 289, 297-298, 306,
Tubulin, 14, 19, 23, 98, 225-230, 269, 271 systemic, 385-386, 388, 398, 401, 419, 422, 425, 367-368, 392, 405-407, 741
Tunica externa, 386-388, 432 433 Voltage-gated sodium channels, 1, 12, 221
Tunica intima, 386-388, 432 systemic circuit, 386, 388, 398, 401, 422, 425 Voluntary, 5, 259, 350, 360-361, 364-365, 372-373,
Tunica media, 386-388, 432 thoracic, 418, 422 494, 499, 536, 647, 657-658
Twins, 38 valves in, 418 Voluntary muscle, 5
identical, 38 venules, 24, 385-388, 401, 416, 418, 432, 690 Voluntary nervous system, 360
Two-neuron chain, 355 Venae cavae, 388, 401
Tympanic membrane, 14, 23, 299, 304 inferior, 401 W
superior, 401 Water, 1-5, 7-20, 22-24, 27, 30, 35-36, 38, 44, 50-56,
U Venous anastomoses, 386 58, 60, 67-68, 75, 82, 85-86, 92, 101,
Ulcer, 11 Venous reserve, 418 110-112, 116-117, 121, 123, 144, 146, 151,
Umami, 287-290, 327 Venous return, 9, 388, 412, 417-419, 424-425, 430, 161, 165, 176, 203, 222, 229, 265, 274, 283,
Unipolar neurons, 192-193, 277 433, 549, 718 295, 297, 299, 301, 305, 307, 316, 322, 325,
Unmyelinated, 184, 186, 196, 206, 218-219, 338 stroke volume and, 424 335, 359, 363, 368, 370, 380-381, 384,
Up-regulation, 7, 23, 133, 135 Venous system, 377, 425, 528, 569, 688 387-388, 391-393, 398, 400, 419, 423, 425,
Urea, 16, 23, 52, 54-55, 92, 502, 507-509, 518-520, Ventilation, 7, 19-20, 24, 223, 442-443, 449-452, 431-432, 436, 441-442, 444-447, 449,
522-526, 531, 536, 546-547, 551-555, 597 455-466, 468-473, 485-492, 494-499, 506, 452-458, 460-463, 468-469, 471, 476-477,
recycling, 597 513, 690-691 480, 482-484, 487, 489, 493-499, 500-556,
Urea cycle, 16, 522-525, 552, 555 alveolar, 469-472, 485, 491, 496 562, 565, 572, 574, 578, 583, 585-586, 592,
Ureter, 23, 527, 545 minute, 472, 486, 497, 691 601, 607, 610, 616, 623, 625, 629, 631-641,
Ureters, 29, 527, 552 Ventral, 196, 338-340, 342, 362, 381-383, 399, 487, 643-645, 649-650, 652-655, 657, 662,
Urethra, 23, 527, 536, 552, 716 642, 708, 727 664-667, 672, 675, 680-683, 688-691,
Uric acid, 1, 23, 502, 520-522, 524-526, 548, 551, 720 Ventral respiratory group, 487 693-695, 712-713, 719, 727, 729, 733-734,
Urinary bladder, 23, 527, 536, 547, 552 Ventral root, 340, 342 741
Urine, 1-2, 7, 9-10, 13-15, 19, 23, 29, 355, 506-507, Ventricles, 3, 8, 19, 343, 347, 398-403, 408, 412 alveolar, 23, 469, 471, 496
523, 526-529, 531, 533-538, 540-544, brain, 3, 8, 343, 347, 400 body, 2-5, 7-20, 22-24, 35-36, 52-53, 58, 86, 117,
546-553, 561-562, 597, 602, 714 development of, 343 121, 123, 151, 176, 229, 295, 297, 299,
formation of, 2, 19, 23, 29, 536 heart, 3, 8, 19, 398-403, 408, 412 301, 325, 335, 359, 363, 368, 380-381,
renal clearance and, 538 Ventricular diastole, 402, 409-410, 433 384, 387-388, 391, 398, 419, 423, 425,
water loss in, 526 Ventricular ejection phase, 403 442, 444, 447, 449, 452-455, 460-462,
Uterine cycle, 723 Ventricular fibrillation, 409 468-469, 477, 482, 487, 493, 500-503,
Uterine wall, 23, 719, 721, 723-725, 732 Ventricular systole, 402-403, 410, 415 505-509, 511, 513, 516, 520-521, 523,
Uterus, 6, 8, 10, 15, 151, 161, 325-326, 355, 388, 706, Ventromedial nucleus, 325-326 526-527, 535, 540, 545-547, 549-551,
710-712, 715, 718-719, 721-726, 729 Venules, 24, 385-389, 401, 416, 418, 432, 690 555, 562, 565, 574, 578, 607, 610, 623,
in pregnancy, 726 Vertebrae, 21, 39 629, 631-633, 635-638, 640-641, 643,
wall, 719, 721, 723-725 structure of, 21, 39 645, 649-650, 653-655, 662, 664-667,
Utricle, 300-302 Vertebral column, 341, 480 680, 682-683, 688-689, 691, 693-695,
movements, 341 712
muscles, 341 in urine, 2, 527, 543
V Vertebrates, 1-6, 9-10, 12-13, 15-24, 30, 67, 71,
Vagina, 711-712, 717-718, 721 output of, 17, 487, 526, 657
78-79, 107-109, 119, 125-129, 131, 150-151, partial pressure of, 444, 446, 461, 469, 493, 521,
Vagus nerve, 354, 359 156, 159-162, 164-167, 192-196, 203, 205,
Vagus nerve (cranial nerve X), 354 666
211, 217, 223, 240, 247-248, 254, 257-259, polarity of, 68
Valine, 68, 563 261, 265, 267, 270-272, 274, 277, 279, 284,
Valves, 12, 377-379, 383, 388, 396, 399-403, 409, Water balance, 2, 19, 117, 151, 165, 359, 419,
286-288, 290-295, 299-301, 306, 308-313, 500-537, 539-556, 583, 727, 729
418, 422, 425, 433, 578, 582 315-317, 323-324, 326-332, 336, 340-346,
heart, 12, 377-379, 383, 388, 396, 399-403, 409, regulation and, 151, 553-554
350, 352, 360, 363-364, 366, 370-372, 374, Water intake, 551
418, 422, 425, 433 376, 379-380, 384-386, 388, 391, 395, 400,
lymphatic vessels, 422 Water-soluble vitamins, 526, 531-532, 562
403-405, 407, 415, 417-418, 422, 426-428, Wavelength, 9, 23, 307, 309, 321-322, 665
venous, 377, 388, 399, 403, 418, 422, 425, 433 430-434, 436-437, 448, 450, 458, 462,
Varicosities, 208, 356, 360, 370 light, 9, 23, 307, 309, 321-322, 665
474-476, 478, 482-487, 492, 494-496, sound, 23
Varicosity, 3, 356 498-499, 503-504, 506, 512, 520, 522, 524,
Vas deferens, 21, 23, 716 Weak acid, 58
526, 544, 546, 552, 554, 560, 565, 570, 573, Weak acids, 56, 58
Vasa recta, 23, 528-529, 536 575, 577-578, 582, 584, 590, 595-596, 598,
Vascular system, 384, 438, 454, 477 Weak bases, 56
603-604, 610, 613-615, 623, 625, 627, 639, White blood cells, 13, 427
Vasoactive intestinal peptide, 519, 586, 591, 593 642, 651, 653, 656, 660, 667, 681, 694, 697,
Vasoconstriction, 23, 215, 360, 386, 391, 413-415, White matter, 10, 24, 340, 342, 344, 347-348, 351
704-707, 710-712, 714, 719-720, 727, cerebellum, 340, 344
419, 422, 430-431, 473, 491, 496, 528, 537, 729-730, 732-734
539-541, 543, 549-551, 586, 599, 686, 688, cerebral, 347, 351
Vesicle, 1, 5, 8-9, 24, 99-100, 123-124, 187-188, 208, cerebrum, 340, 347
690, 694 224-225, 230, 232, 234, 236-238, 242, 250,
blood pressure and, 539, 549-550 midbrain, 344
253, 263, 277, 367, 542, 568, 620, 677, 716, organization, 340, 342, 344, 347-348, 351
Vasodilation, 23, 131, 140, 148, 386, 391, 413-415, 720, 728
419-420, 422, 430-431, 473, 539, 543, 586, spinal cord, 340, 342
Vesicular transport, 235 Whole blood, 11, 392, 427
686 Vestibular apparatus, 21, 24, 299-300, 365-366
Vasomotion, 23, 622 Wrinkles, 10, 123
Vestibular membrane, 304
Veins, 24, 29, 377, 383, 385-388, 391, 398, 401, 403, Viagra, 131, 414, 718
416-420, 422, 425, 432-433, 688-690, 718 Villi, 6, 24, 581, 584, 592, 600 X
abdomen, 383, 422 Viscera, 240, 400, 686 X-rays, 18
blood pressure in, 417, 433 Visceral, 238-239, 395-397, 400, 465, 580, 591-592,
blood volume in, 420 598 Y
brain, 24, 29, 383, 387, 419, 425 Viscosity, 18, 24, 391-392, 419, 426, 445-446, 468, Yolk sac, 720, 732
cardiac, 398, 401, 403, 416-420, 425, 433 475, 490, 493, 634-636, 649
central, 24, 386-387, 419-420 Visible light, 18, 307
cerebral, 425 Z
Visible spectrum, 18 Zinc, 59, 483, 563
coronary, 29, 377, 432 Vision, 3, 5, 9, 20, 23, 47, 145, 278-279, 307, 309-310,
functions, 29, 401 Zona pellucida, 24, 710-711, 724
313-314, 316-317, 321-323, 328-332, 341, Zygote, 15, 24, 702, 707-708
gonadal, 718 364, 560, 714
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Principles of Animal Physiology

Visit us on the World Wide Web at: www.pearsoned.co.uk

© Pearson Education Limited 2014

ISBN 10: 1-292-02638-3

British Library Cataloguing-in-Publication Data

Printed in the United States of America

Research vessel, Alpha Helix.

spearheaded an initative that would allow teams of interna-

Communities Ecosystems Biosphere

Figure 2 Levels of biological organization Chemists and biochemists study the

dertakes a specific process or behavior. For An organismal characteristic such as meta-

particular groups of animals: thus, there are Physiological subdisciplines can be

BOX 1 METHODS AND MODEL SYSTEMS

cules, or solubility of gases in solution. Physiologists

Table 1 Unifying themes in animal physiology.

Unifying theme Examples

Biochemical and physiological patterns 1000 Elephant

areas buffered against unfa-

patterns to create the appropriate phenotype. For

Figure 5 Phenotypic plasticity and

Although it is easy to be overwhelmed by the di-

For Further Reading

West-Eberhard, M. J. 2003. Developmental Vogel, S. 1988. Life’s devices. Princeton, NJ:

acids in proteins, and the basic pathways of intermediary

Overview entropy, states that the universe is becoming

Energy production Membrane transport

Cellular anatomy Gene expression

hood of endergonic reactions.

Activation Covalent bonds involve shared electrons

OH OH van der Waals interaction Hydrophobic bond

(a) (b) (c) (d)

Hyperosmotic Hyposmotic Hypertonic Isotonic

5 sentially eliminating a weak acid from the body,

4 buffering against a change in pH.

BOX 1 MATHEMATICAL UNDERPINNINGS

action depend on the difference between the mass

The physicochemical environment alters

(c) Covalent activation [S]

with the common names dehydrogenase, reduc- NH2

Primary structure Secondary structure Tertiary structure Quaternary structure

Disulfide bond Ionic bond

Figure 21 Protein secondary structure: The ␣-

residues to come into close proximity, their C C H

HOCH2 HOCH2 refolded or destroyed before it can damage the cell.

C O Animals use monosaccharides for energy

acts with other macromolecules and reducing its OH OH OH OH

susceptibility to degradation. Amylose

Complex carbohydrates perform many ••• •••

important in metabolism and structure are shown ••• •••

animals. Amylose, amylopectin, and glycogen dif- C O C O C O

the nature of the branching pattern. Cellulose, an-

their exoskeletons with chitin, a polysaccharide of OH CH3

N-acetyl-glucosamine. Vertebrates secrete hyaluro-

Glycogen synthase (inactive)

Glycogen synthase (active) Pyruvate

Pyruvate carboxylase GTP

Glycogen Glycogen PEPCK

Glycogen phosphorylase (inactive) Malate

Figure 27 Gluconeogenesis Cells convert pyruvate Glucose 1-phosphate

Gluconeogenesis begins in the mitochondria, Glucose

they have excess energy available. The metabolic

liberated from stored glycogen. This pathway is a

(a) α Glycerophosphate shuttle (b) Malate-aspartate shuttle