Signaling Molecules and Their Receptors

Many diIIerent kinds oI molecules transmit inIormation between the cells oI multicellular organisms. Although all
these molecules act as ligands that bind to receptors expressed by their target cells, there is considerable variation in
the structure and Iunction oI the diIIerent types oI molecules that serve as signal transmitters. Structurally, the
signaling molecules used by plants and animals range in complexity Irom simple gases to proteins. Some oI these
molecules carry signals over long distances, whereas others act locally to convey inIormation between neighboring
cells. In addition, signaling molecules diIIer in their mode oI action on their target cells. Some signaling molecules
are able to cross the plasma membrane and bind to intracellular receptors in the cytoplasm or nucleus, whereas most
bind to receptors expressed on the target cell surIace. The sections that Iollow discuss the major types oI signaling
molecules and the receptors with which they interact. Subsequent discussion in this chapter Iocuses on the
mechanisms by which cell surIace receptors then Iunction to regulate cell behavior.
Modes of Cell-Cell Signaling
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Cell signaling can result either Irom the direct interaction oI a cell with its neighbor or Irom the action oI secreted
signaling molecules (Figure 13.1). Signaling by direct cell-cell (or cell-matrix) interactions plays a critical role in
regulating the behavior oI cells in animal tissues. For example, the integrins and cadherins (which were discussed in
the previous chapter) Iunction not only as cell adhesion molecules but also as signaling molecules that regulate cell
proliIeration and survival in response to cell-cell and cell-matrix contacts. In addition, cells express a variety oI cell
surIace receptors that interact with signaling molecules on the surIace oI neighboring cells. Signaling via such direct
cell-cell interactions plays a critical role in regulating the many interactions between diIIerent types oI cells that take
place during embryonic development, as well as in the maintenance oI adult tissues.

igure 13.1
Modes oI cell-cell signaling. Cell signaling can take place either through direct cell-cell contacts or through the
action oI secreted signaling molecules. (A) In endocrine signaling, hormones are carried through the circulatory
system to act on distant (more...)
The multiple varieties oI signaling by secreted molecules are Irequently divided into three general categories based
on the distance over which signals are transmitted. In endocrine signaling, the signaling molecules (hormones) are
secreted by specialized endocrine cells and carried through the circulation to act on target cells at distant body sites.
A classic example is provided by the steroid hormone estrogen, which is produced by the ovary and stimulates
development and maintenance oI the Iemale reproductive system and secondary sex characteristics. In animals,
more than 50 diIIerent hormones are produced by endocrine glands, including the pituitary, thyroid, parathyroid,
pancreas, adrenal glands, and gonads.
In contrast to hormones, some signaling molecules act locally to aIIect the behavior oI nearby cells. In paracrine
signaling, a molecule released by one cell acts on neighboring target cells. An example is provided by the action
oI neurotransmitters in carrying signals between nerve cells at a synapse. Finally, some cells respond to signaling
molecules that they themselves produce. One important example oI such autocrine signaling is the response oI cells
oI the vertebrate immune system to Ioreign antigens. Certain types oI T lymphocytes respond to antigenic
stimulation by synthesizing a growth Iactor that drives their own proliIeration, thereby increasing the number oI
responsive T lymphocytes and ampliIying the immune response. It is also noteworthy that abnormalautocrine
signaling Irequently contributes to the uncontrolled growth oI cancer cells (see Chapter 15). In this situation,
a cancer cell produces a growth Iactor to which it also responds, thereby continuously driving its own unregulated
proliIeration.
Steroid Hormones and the Steroid Receptor Superfamily
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As already noted, all signaling molecules act by binding to receptors expressed by their target cells. In many cases,
these receptors are expressed on the target cell surIace, but some receptors are intracellular proteins located in the
cytosol or the nucleus. These intracellular receptors respond to small hydrophobic signaling molecules that are able
to diIIuse across the plasma membrane. Thesteroid hormones are the classic examples oI this group oI signaling
molecules, which also includes thyroid hormone, vitamin D3, and retinoic acid (Figure 13.2).

igure 13.2
Structure oI steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid. The steroids include the sex
hormones (testosterone, estrogen, and progesterone), glucocorticoids, and mineralocorticoids.
The steroid hormones (including testosterone, estrogen, progesterone, the corticosteroids, and ecdysone) are all
synthesized Iromcholesterol. Testosterone, estrogen, and progesterone are the sex steroids, which are produced by
the gonads. The corticosteroidsare produced by the adrenal gland. They include the glucocorticoids, which act on a
variety oI cells to stimulate production oI glucose, and the mineralocorticoids, which act on the kidney to regulate
salt and water balance. Ecdysone is an insect hormone that plays a key role in development by triggering the
metamorphosis oI larvae to adults.
Although thyroid hormone, vitamin D3, and retinoic acid are both structurally and Iunctionally distinct Irom the
steroids, they share a common mechanism oI action in their target cells. Thyroid hormone is synthesized Irom
tyrosine in the thyroid gland; it plays important roles in development and regulation oI metabolism. 'itamin
D3 regulates Ca
2
metabolism and bone growth. Retinoic acid and related compounds (retinoids) synthesized Irom
vitamin A play important roles in vertebrate development.
Because oI their hydrophobic character, the steroid hormones, thyroid hormone, vitamin D3, and retinoic acid are
able to enter cells by diIIusing across the plasma membrane (Figure 13.3). Once inside the cell, they bind to
intracellular receptors that are expressed by the hormonally responsive target cells. These receptors, which are
members oI a Iamily oI proteins known as the steroid receptor superIamily, are transcription Iactors that contain
related domains Ior ligand binding, DNA binding, and transcriptional activation.Ligand binding regulates their
Iunction as activators or repressors oI their target genes, so the steroid hormones and related molecules directly
regulate gene expression.

igure 13.3
Action oI steroid hormones. The steroid hormones diIIuse across the plasma membrane and bind to nuclear
receptors, which directly stimulate transcription oI their target genes. The steroid hormone receptors bind DNA as
dimers.
Ligand binding has distinct eIIects on diIIerent receptors. Some members oI the steroid receptor superIamily, such
as the estrogenand glucocorticoid receptors, are unable to bind to DNA in the absence oI hormone. The binding oI
hormone induces a conIormational change in the receptor, allowing it to bind to regulatory DNA sequences and
activate transcription oI target genes. In other cases, the receptor binds DNA in either the presence or absence oI
hormone, but hormone binding alters the activity oI the receptor as a transcriptional regulatory molecule. For
example, thyroid hormone receptor acts as a repressor in the absence oI hormone, but hormone binding converts it to
an activator that stimulates transcription oI thyroid hormone-inducible genes (Figure 13.4).

igure 13.4
Gene regulation by the thyroid hormone receptor. Thyroid hormone receptor binds DNA in either the presence or
absence oI hormone. However, hormone binding changes the Iunction oI the receptor Irom a repressor to an
activator oI target gene transcription.(more...)
itric Oxide and Carbon Monoxide
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The simple gas nitric oxide (NO) is a major paracrine signaling molecule in the nervous, immune, and circulatory
systems. Like thesteroid hormones, NO is able to diIIuse directly across the plasma membrane oI its target cells. The
molecular basis oI NO action, however, is distinct Irom that oI steroid action; rather than binding to a receptor that
regulates transcription, NO alters the activity oI intracellular target enzymes.
Nitric oxide is synthesized Irom the amino acid arginine by the enzyme nitric oxide synthase (Figure 13.5). Once
synthesized, NO diIIuses out oI the cell and can act locally to aIIect nearby cells. Its action is restricted to such local
eIIects because NO is extremely unstable, with a halI-liIe oI only a Iew seconds. One well-characterized example oI
NO action is signaling the dilation oI blood vessels. The Iirst step in this process is the release oI neurotransmitters,
such as acetylcholine, Irom the terminus oI nerve cells in the blood vessel wall. These neurotransmitters act on
endothelial cells to stimulate NO synthesis. NO then diIIuses to neighboring smooth muscle cells where it reacts
with iron bound to the active site oI the enzyme guanylyl cyclase. This increases enzymatic activity, resulting in
synthesis oI the second messenger cyclic GMP (discussed later in this chapter), which induces muscle cell relaxation
and blood vessel dilation. For example, NO is responsible Ior signaling the dilation oI blood vessels that leads to
penile erection. It is also interesting to note that the medical use oI nitroglycerin in treatment oI heart disease is
based on its conversion to NO, which dilates coronary blood vessels and increases blood Ilow to the heart.

igure 13.5
Synthesis oI nitric oxide. The enzyme nitric oxide synthase (NOS) catalyzes the Iormation oI nitric oxide Irom
arginine.
Another simple gas, carbon monoxide (CO), also Iunctions as a signaling molecule in the nervous system. CO is
closely related to NO and appears to act similarly as a neurotransmitter and mediator oI blood vessel dilation. The
synthesis oI CO in brain cells, like that oI NO, is stimulated by neurotransmitters. In addition, CO can stimulate
guanylate cyclase, which may also represent the major physiological target oI CO signaling.
eurotransmitters
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The neurotransmitters carry signals between neurons or Irom neurons to other types oI target cells (such as muscle
cells). They are a diverse group oI small hydrophilic molecules including acetylcholine, dopamine, epinephrine
(adrenaline), serotonin, histamine, glutamate, glycine, and -aminobutyric acid (GABA) (Figure 13.6). The release
oI neurotransmitters is signaled by the arrival oI an action potential at the terminus oI a neuron (see Figure 12.22).
The neurotransmitters then diIIuse across the synaptic cleIt and bind to receptors on the target cell surIace. Note that
some neurotransmitters can also act as hormones. For example, epinephrine Iunctions both as a neurotransmitter and
as a hormone produced by the adrenal gland to signal glycogen breakdown in muscle cells.

igure 13.6
Structure oI representative neurotransmitters. The neurotransmitters are hydrophilic molecules that bind to cell
surIace receptors.
Because the neurotransmitters are hydrophilic molecules, they are unable to cross the plasma membrane oI their
target cells. ThereIore, in contrast to steroid hormones and NO or CO, the neurotransmitters act by binding to cell
surIace receptors. Manyneurotransmitter receptors are ligand-gated ion channels, such as the acetylcholine receptor
discussed in the preceding chapter (seeFigure 12.23). Neurotransmitter binding to these receptors induces a
conIormational change that opens ion channels, directly resulting in changes in ion Ilux in the target cell.
Other neurotransmitter receptors are coupled to G proteinsa major group oI signaling molecules (discussed later in
this chapter) that link cell surIace receptors to a variety oI intracellular responses. In the case
oI neurotransmitter receptors, the associated G proteins Irequently act to indirectly regulate ion channel activity.
Peptide Hormones and Growth actors
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The widest variety oI signaling molecules in animals are peptides, ranging in size Irom only a Iew to more than a
hundred amino acids. This group oI signaling molecules includes peptide hormones, neuropeptides, and a diverse
array oI polypeptide growth Iactors(Table 13.1). Well-known examples oI peptide hormones include insulin,
glucagon, and the hormones produced by the pituitary gland (growth hormone, Iollicle-stimulating hormone,
prolactin, and others).

Table 13.1
Representative Peptide Hormones, Neuropeptides, and Growth Factors.
europeptides are secreted by some neurons instead oI the small-molecule neurotransmitters discussed in the
previous section. Some oI these peptides, such as the enkephalins and endorphins, Iunction not only
as neurotransmitters at synapses but also asneurohormones that act on distant cells. The enkephalins and
endorphins have been widely studied because oI their activity as natural analgesics that decrease pain responses in
the central nervous system. Discovered during studies oI drug addiction, they are naturally occurring compounds
that bind to the same receptors on the surIace oI brain cells as morphine does.
The polypeptide growth Iactors include a wide variety oI signaling molecules that control animal cell growth and
diIIerentiation. The Iirst oI these Iactors (nerve growth factor, or G) was discovered by Rita Levi-Montalcini in
the 1950s. NGF is a member oI a Iamily oI polypeptides (called neurotrophins) that regulate the development and
survival oI neurons. During the course oI experiments on NGF, Stanley Cohen serendipitously discovered an
unrelated Iactor (called epidermal growth Iactor, or EG) that stimulates cell proliIeration. EGF, a 53-amino-
acid polypeptide (Figure 13.7), has served as the prototype oI a large array oI growth Iactors that play critical roles
in controlling animal cell proliIeration, both during embryonic development and in adult organisms.

igure 13.7
Structure oI epidermal growth Iactor (EGF). EGF is a single polypeptide chain oI 53 amino acids. DisulIide bonds
between cysteine residues are indicated. (AIter G. Carpenter and S. Cohen, 1979. Ann. Rev. Biochem. 48: 193.)
A good example oI growth Iactor action is provided by the activity oI platelet-derived growth Iactor (PDG) in
wound healing. PDGF is stored in blood platelets and released during blood clotting at the site oI a wound. It then
stimulates the proliIeration oI Iibroblasts in the vicinity oI the clot, thereby contributing to regrowth oI the damaged
tissue. Members oI another large group oI polypeptide growth Iactors (called cytokines) regulate the development
and diIIerentiation oI blood cells and control the activities oI lymphocytes during the immune response.
Other polypeptide growth Iactors (membrane-anchored growth Iactors) remain associated with the plasma
membrane rather than being secreted into extracellular Iluids, thereIore Iunctioning speciIically as signaling
molecules during direct cell-cell interactions.
Peptide hormones, neuropeptides, and growth Iactors are unable to cross the plasma membrane oI their target cells,
so they act by binding to cell surIace receptors, as discussed later in this chapter. As might be expected Irom the
critical roles oI polypeptidegrowth Iactors in controlling cell proliIeration, abnormalities in growth Iactor signaling
are the basis Ior a variety oI diseases, including many kinds oI cancer. For example, abnormal expression oI a close
relative oI the EGF receptor is an important Iactor in the development oI many human breast and ovarian cancers.
Eicosanoids
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Several types oI lipids serve as signaling molecules that, in contrast to the steroid hormones, act by binding to cell
surIace receptors. The most important oI these molecules are members oI a class oI lipids called the eicosanoids,
which includes prostaglandins,prostacyclin, thromboxanes, and leukotrienes (Figure 13.8). The eicosanoids are
rapidly broken down and thereIore act locally in autocrine or paracrine signaling pathways. They stimulate a variety
oI responses in their target cells, including blood platelet aggregation, inIlammation, and smooth-muscle
contraction.

igure 13.8
Synthesis and structure oI eicosanoids. The eicosanoids include the prostaglandins, prostacyclin, thromboxanes, and
leukotrienes. They are synthesized Irom arachidonic acid, which is Iormed by the hydrolysis oI phospholipids
catalyzed by phospholipase(more...)
All eicosanoids are synthesized Irom arachidonic acid, which is Iormed Irom phospholipids. The Iirst step in the
pathway leading to synthesis oI either prostaglandins or thromboxanes is the conversion oI arachidonic acid to
prostaglandin H2. Interestingly, the enzyme that catalyzes this reaction (cyclooxygenase) is the target oI aspirin and
other nonsteroidal anti-inIlammatory drugs. By inhibiting synthesis oI the prostaglandins, aspirin reduces
inIlammation and pain. By inhibiting synthesis oI thromboxane, aspirin also reduces platelet aggregation and blood
clotting. Because oI this activity, small daily doses oI aspirin are Irequently prescribed Ior prevention oI strokes. In
addition, aspirin and nonsteroidal anti-inIlammatory drugs have been Iound to reduce the Irequency oI
coloncancer in both animal models and humans, apparently by inhibiting the synthesis oI prostaglandins that act to
stimulate cell proliIeration and promote cancer development.
Plant Hormones
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Plant growth and development are regulated by a group oI small molecules called plant hormones. The levels oI
these molecules within the plant are typically modiIied by environmental Iactors, such as light or inIection, so they
coordinate the responses oI tissues in diIIerent parts oI the plant to environmental signals.
The plant hormones are generally divided into Iive major classes: auxins, gibberellins, cytokinins, abscisic acid,
and ethylene (Figure 13.9), although several additional plant hormones have recently been discovered. The Iirst
plant hormone to be identiIied was auxin, with the early experiments leading to its discovery having been perIormed
by Charles Darwin in the 1880s. One oI the eIIects oI auxins is to induce plant cell elongation by weakening the cell
wall (see Figure 12.49). In addition, auxins regulate many other aspects oI plant development, including cell
division and diIIerentiation. The other plant hormones likewise have multiple eIIects in their target tissues, including
stem elongation (gibberellins), Iruit ripening (ethylene), cell division (cytokinins), and the onset oI dormancy
(abscisic acid).

igure 13.9
Structure oI plant hormones.
Our understanding oI the molecular mechanisms oI plant hormone action is less advanced than comparable studies
oI animal cells, and the receptors Ior plant hormones are just beginning to be identiIied and characterized. One area
oI noteworthy progress has been in understanding the mechanism by which plant cells respond to ethylene. Using
the small weed Arabidopsis as a model, several oI the genes required Ior ethylene responsiveness have been
identiIied. These include genes encoding the ethylene receptor, which is similar to a Iamily oI receptors commonly
Iound in bacteria and yeast. Additional genes that have been identiIied in the ethylene signaling pathway include a
protein related to the RaI protein kinase, which plays a key role in animal cell signaling pathways (discussed later in
this chapter), and transcription Iactors, which regulate the expression oI ethylene-responsive genes.
By agreement with the publisher, this book is accessible by the search Ieature, but cannot be browsed.
Copyright 2000, GeoIIrey M Cooper.
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The Cell: A Molecular Approach. 2nd edition.
Cooper GM.
Sunderland (MA): Sinauer Associates; 2000.
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n this Page
O Modes oI Cell-Cell Signaling
O Steroid Hormones and the Steroid Receptor SuperIamily
O Nitric Oxide and Carbon Monoxide
O Neurotransmitters
O Peptide Hormones and Growth Factors
O Eicosanoids
O Plant Hormones
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igure 13.2Structure of steroid hormones, thyroid hormone, vitamin D
3
, and retinoic acid
USA.gov

igure 13.3Action of steroid hormones
The steroid hormones diIIuse across the plasma membrane and bind to nuclear receptors, which directly
stimulate transcription oI their target genes. The steroid hormone receptors bind DNA as dimers.
From: Signaling Molecules and Th

igure 13.4Gene regulation by the thyroid hormone receptor
Thyroid hormone receptor binds DNA in either the presence or absence oI hormone. However, hormone binding
changes the Iunction oI the receptor Irom a repressor to an activator oI target gene transcription.

igure 13.5Synthesis of nitric oxide
The enzyme nitric oxide synthase (NOS) catalyzes the Iormation oI nitric oxide Irom arginine