Table 562. The Cytokines.

Cytokine Interferon- (IFN- ) Interferon- (IFN- ) Interferon- (IFN- ) Properties Antiviral, oncostatic, activates NK cells Antiviral, oncostatic, activates NK cells Antiviral, oncostatic, secreted by and activates or up-regulates TH1 cells, NK cells, CTLs, and macrophages T cell activation, B cell proliferation and differentiation T cell proliferation, TH1, NK, and LAK cell activation Hematopoietic precursor proliferation and differentiation TH2 and CTL activation, B cell proliferation Eosinophil proliferation, B cell proliferation and differentiation HCF, TH2, CTL, and B cell proliferation CTL, NK, LAK, and B cell proliferation, thymic precursor stimulation Neutrophil chemotaxis, proinflammatory T cell proliferation TH1 suppression, CTL activation, B cell proliferation Megakaryocyte proliferation, B cell differentiation TH1 and CTL proliferation and activation Macrophage function modulation, B cell proliferation B cell proliferation and differentiation TH1, CTL, and NK/LAK activation, expansion of T cell memory pools T lymphocyte chemotaxis, suppresses HIV replication Stromal cell cytokine production Induces TH1 responses

Interleukin-1 (IL-1) Interleukin-2 (IL-2) Interleukin-3 (IL-3) Interleukin-4 (IL-4) Interleukin-5 (IL-5) Interleukin-6 (IL-6) Interleukin- 7 (IL-7) Interleukin-8 (IL-8) Interleukin-9 (IL-9) Interleukin-10 (IL-10) Interleukin-11 (IL-11) Interleukin-12 (IL-12) Interleukin-13 (IL-13) Interleukin-14 (IL-14) Interleukin-15 (IL-15) Interleukin-16 (IL-16) Interleukin-17 (IL-17) Interleukin-18 (IL-18)

Cytokine

Properties

Interleukin-19 (IL-19) Interleukin-20 (IL-20) Interleukin-21 (IL-21) Interleukin-22 (IL-22) Interleukin-23 (IL-23) Interleukin-24 (IL-24) Interleukin-27 (IL-27)

Proinflammatory Promotes skin differentiation Promotes proliferation of activated T cells, maturation of NK cells Regulator of TH2 cells Promotes proliferation of TH1 memory cells Induces tumor apoptosis, induces TH1 responses Stimulates naive CD4 cells to produce IFNp28 subunit of IL-27 Contributes to type I hypersensitivities and TH2 responses Involved in inflammation Oncostatic, macrophage activation, proinflammatory Oncostatic, proinflammatory, chemotactic Granulocyte production Granulocyte, monocyte, eosinophil production Monocyte production, activation Red blood cell production Platelet production

Interleukin-28 and 29 (IL-28, IL-29) Antiviral, interferon-like properties Interleukin-30 (IL-30) Interleukin-31 (IL-31) Interleukin-32 (IL-32) Tumor necrosis factor- (TNF- ) Tumor necrosis factor- (TNF- ) Granulocyte colony-stimulating factor Granulocyte-macrophage colony stimulating factor Macrophage colony-stimulating factor Erythropoietin (epoetin, EPO) Thrombopoietin (TPO)

Table 181. Eicosanoid Receptors.

Receptor Endogenous Ligand Secondary Ligands G protein, Second Messenger Major Phenotype(s) in Knockout Mice

DP1

PGD2 15d-PGJ2

Gs, cAMP Gi, Ca2+i

Allergic asthma Allergic airway inflammation Colon carcinogenesis Impaired ovulation and fertilization Salt-sensitive hypertension

DP2,CRT PGD2 H2 EP1 EP2 PGE2 PGE2

PGI2

Gq, Ca2+i Gs, cAMP

EP3AD

PGE2

Gi, cAMP Gs, cAMP Gq, PLC

Resistance to pyrogens Acute cutaneous inflammation

EP4

PGE2

Gs cAMP

Patent ductus arteriosus Bone mass/density in aged mice Bowel inflammatory/immu ne response Colon carcinogenesis

FPA,B IP

PGF2 PGI2

isoPs PGE2

Gq, PLC Gs, cAMP

Parturition failure Thrombotic response Response to vascular injury

Receptor Endogenous Ligand

Secondary Ligands

G protein, Second Messenger

Major Phenotype(s) in Knockout Mice

Atherosclerosis Cardiac fibrosis Salt-sensitive hypertension Joint inflammation TP , TXA2 isoPs Gq, Gi, G12/13, G16, PLC Bleeding time

Response to vascular injury Atherosclerosis Survival after cardiac allograft BLT1 LTB4 G16, Gi Some suppression of inflammatory response

BLT2

LTB4

12S-HETE

Gq-like, Gi-like, ? Gz-like

12R-HETE CysLT1 LTD4 LTC4/LTE4 Gq, PLC Innate and adaptive immune vascular permeability response Pulmonary inflammatory and fibrotic response CysLT2 LTC4/LTD4 LTE4 Gq, PLC Pulmonary inflammatory and fibrotic response

Table 161. Histamine Receptor Subtypes.

Receptor Distribution Subtype

Postreceptor Mechanism

Partially Selective Agonists

Partially Selective Antagonists

H1

Smooth muscle, Gq, IP3, DAG endothelium, brain Gastric mucosa, Gs, cAMP cardiac muscle, mast cells, brain Presynaptic: brain, myenteric plexus, other neurons Eosinophils, neutrophils, CD4 T cells Gi, cAMP

Histaprodifen Mepyramine, triprolidine Amthamine Ranitidine, tiotidine

H2

H3

R- Thioperamide, Methylhistami iodophenpropit, ne, imetit, clobenpropit1 immepip Clobenpropit, Thioperamide imetit, clozapine

H4

Gi, cAMP

Table 163. Serotonin Receptor Subtypes.

Distribution

Postreceptor Partially Selective Partially Mechanism Agonists Selective Antagonists Gi , cAMP 8-OH-DPAT Sumatriptan, CP93129 WAY100635

5-HT1A 5-HT1B

Raphe nuclei, hippocampus

Substantia Gi , cAMP nigra, globus pallidus, basal ganglia Gi , cAMP Gi , cAMP Gi , cAMP Go, slow EPSP

5-HT1Da,b Brain 5-HT1E 5-HT1F 5-HT1P Cortex, putamen Cortex, hippocampus Enteric nervous system

Sumatriptan

LY334370 5-Hydroxyindalpine Renzapride

5-HT2A

Platelets, Gq, IP3 smooth muscle, cerebral cortex Stomach fundus Gq, IP3

-Methyl-5-HT

Ketanserin

5-HT2B 5-HT2C

-Methyl-5-HT -Methyl-5-HT

SB204741 Mesulergine

Choroid, Gq, IP3 hippocampus, substantia nigra Area postrema, Receptor is a sensory and Na+-K+ ion enteric nerves channel CNS and Gs, cAMP myenteric neurons, smooth muscle Brain Brain cAMP Gs, cAMP

5-HT3

2-Methyl-5-HT, mGranisetron, chlorophenylbiguani ondansetron, de tropisetron 5Methoxytryptamine, renzapride, metoclopramide

5-HT4

5-HT5A,B 5-HT6,7

Clozapine
HT7)

(5-

Table 61. Some of the Transmitter Substances Found in Autonomic Nervous System (ANS), Enteric Nervous System (ENS), and Nonadrenergic, Noncholinergic Neurons.1

Substance
Acetylcholine (ACh)

Probable Roles
The primary transmitter at ANS ganglia, at the somatic neuromuscular junction, and at parasympathetic postganglionic nerve endings. A primary excitatory transmitter to smooth muscle and secretory cells in the ENS. Probably also the major neuron-to-neuron ("ganglionic") transmitter in the ENS. Acts as a transmitter or cotransmitter at many ANS-effector synapses. Found with substance P in cardiovascular sensory nerve fibers. Present in some secretomotor ENS neurons and interneurons. A cardiac stimulant.

Adenosine triphosphate (ATP) Calcitonin generelated peptide (CGRP)

Cholecystokinin (CCK) May act as a cotransmitter in some excitatory neuromuscular ENS neurons. Dopamine Enkephalin and related opioid peptides Galanin A modulatory transmitter in some ganglia and the ENS. Probably a postganglionic sympathetic transmitter in renal blood vessels. Present in some secretomotor and interneurons in the ENS. Appear to inhibit ACh release and thereby inhibit peristalsis. May stimulate secretion. Present in secretomotor neurons; may play a role in appetite-satiety mechanisms.

GABA ( -aminobutyric May have presynaptic effects on excitatory ENS nerve terminals. Has some acid) relaxant effect on the gut. Probably not a major transmitter in the ENS. Gastrin-releasing peptide (GRP) Extremely potent excitatory transmitter to gastrin cells. Also known as mammalian bombesin.

Neuropeptide Y (NPY) Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and electrolytes by the gut. Causes long-lasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic neurons. Nitric oxide (NO) Norepinephrine (NE) Serotonin (5-HT) A cotransmitter at inhibitory ENS neuromuscular junctions; may be especially important at sphincters. The primary transmitter at most sympathetic postganglionic nerve endings. An important transmitter or cotransmitter at excitatory neuron-to-neuron junctions in the ENS.

Substance P (and Substance P is an important sensory neuron transmitter in the ENS and elsewhere. related "tachykinins") Tachykinins appear to be excitatory cotransmitters with ACh at ENS neuromuscular junctions. Found with CGRP in cardiovascular sensory neurons. Substance P is a vasodilator (probably via release of nitric oxide). Vasoactive intestinal peptide (VIP) Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular cotransmitter. A probable cotransmitter in many cholinergic neurons. A vasodilator (found in many perivascular neurons) and cardiac stimulant.

Table 63. Direct Effects of Autonomic Nerve Activity on Some Organ Systems. Autonomic Drug Effects Are Similar But Not Identical (See Text).

Effect of Sympathetic Activity Organ Action1 Parasympathetic Activity Receptor2

Receptor2 Action

Eye Iris radial muscle Contracts

1

...

... M3 M3

Iris circular muscle

...

...

Contracts

Ciliary muscle

[Relaxes]

Contracts

Heart Sinoatrial node Accelerates

1, 2

Decelerates

M2

Ectopic pacemakers

Accelerates

1, 2

...

...

Contractility

Increases

1, 2

Decreases (atria)

M2

Blood vessels Skin, splanchnic vessels Skeletal muscle vessels Contracts Relaxes
2

... ...

... ...

[Contracts] Relaxes Endothelium M3

... ... Releases EDRF4

... ... M 3, M 55 M3

Bronchiolar smooth muscle

Relaxes

Contracts

Gastrointestinal tract Smooth muscle Walls Relaxes

2 6, 2

Contracts

M3 M3 M3

Sphincters

Contracts

Relaxes

Secretion

...

...

Increases

Effect of Sympathetic Activity Organ Action1 Parasympathetic Activity Receptor2

Receptor2 Action

Genitourinary smooth muscle Bladder wall Relaxes

2

Contracts

M3 M3

Sphincter

Contracts

Relaxes

Uterus, pregnant

Relaxes

...

...

Contracts

Contracts

M3 M

Penis, seminal vesicles Skin Pilomotor smooth muscle Sweat glands Thermoregulatory Apocrine (stress) Metabolic functions Liver

Ejaculation

Erection

Contracts

... ...

... ... ... ...

Increases Increases

... ...

Gluconeogenesis

2,

...

...

Liver

Glycogenolysis

2,

...

...

Fat cells Kidney

Lipolysis Renin release

3 1

... ...

... ...

1Less

important actions are shown in brackets. receptor type: = alpha, = beta, M = muscarinic.

2Specific

3Vascular 4The

smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers.

endothelium of most blood vessels releases EDRF (endothelium-derived relaxing factor), which causes marked vasodilation, in response to muscarinic stimuli. However, unlike the receptors innervated by sympathetic cholinergic fibers in skeletal muscle blood vessels, these muscarinic receptors are not innervated and respond only to circulating muscarinic agonists.
5Cerebral 6Probably

blood vessels dilate in response to M5 receptor activation. through presynaptic inhibition of parasympathetic activity.

Table 62. Major Autonomic Receptor Types.

Receptor Name
Cholinoceptors

Typical Locations

Result of Ligand Binding

Muscarinic CNS neurons, sympathetic M1 postganglionic neurons, some presynaptic sites Muscarinic Myocardium, smooth muscle, M2 some presynaptic sites; CNS neurons

Formation of IP3 and DAG, increased intracellular calcium Opening of potassium channels, inhibition of adenylyl cyclase

Muscarinic Exocrine glands, vessels (smooth Like M1 receptorM3 muscle and endothelium); CNS ligand binding neurons Muscarinic CNS neurons; possibly vagal M4 nerve endings Like M2 receptorligand binding

Muscarinic Vascular endothelium, especially Like M1 receptorM5 cerebral vessels; CNS neurons ligand binding Nicotinic NN Postganglionic neurons, some Opening of Na+, K+ presynaptic cholinergic terminals channels, depolarization Nicotinic NM Skeletal muscle neuromuscular endplates Opening of Na+, K+ channels, depolarization

Adrenocep tors Alpha1 Postsynaptic effector cells, especially smooth muscle Formation of IP3 and DAG, increased intracellular calcium Inhibition of adenylyl cyclase, decreased cAMP

Alpha2

Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle

Receptor Name

Typical Locations

Result of Ligand Binding

Beta1

Postsynaptic effector cells, Stimulation of especially heart, lipocytes, brain; adenylyl cyclase, presynaptic adrenergic and increased cAMP cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body epithelium Postsynaptic effector cells, especially smooth muscle and cardiac muscle Stimulation of adenylyl cyclase and increased cAMP. Activates cardiac Gi under some conditions. Stimulation of adenylyl cyclase and increased cAMP1

Beta2

Beta3

Postsynaptic effector cells, especially lipocytes; heart

Dopamine receptors D1 (DA1), D5 D2 (DA2) Brain; effector tissues, especially Stimulation of smooth muscle of the renal adenylyl cyclase and vascular bed increased cAMP Brain; effector tissues, especially Inhibition of adenylyl smooth muscle; presynaptic cyclase; increased nerve terminals potassium conductance Brain Brain, cardiovascular system Inhibition of adenylyl cyclase Inhibition of adenylyl cyclase

D3 D4

Table 412. Glucose Transporters.

Transporter Tissues

Glucose Km (mmol/L)

Function

GLUT 1

All tissues, 12 especially red cells, brain B cells of 1520 pancreas; liver, kidney; gut Brain, kidney, < 1 placenta, other tissues Muscle, adipose Gut, kidney 5 12

Basal uptake of glucose; transport across the bloodbrain barrier Regulation of insulin release, other aspects of glucose homeostasis Uptake into neurons, other tissues Insulin-mediated uptake of glucose Absorption of fructose

GLUT 2

GLUT 3

GLUT 4 GLUT 5

Table 124. Properties of Several Recognized Voltage-Activated Calcium Channels.

Type Channel Name

Where Found

Properties of the Calcium Current

Blocked By

CaV1.1 CaV1.3 CaV3.1 CaV3.3

Muscle, neurons Long, large, high (CaV1.4 is found threshold in retina) Heart, neurons Short, small, low threshold

Verapamil, DHPs, Cd2+ sFTX, flunarizine, Ni2+ -CTX-GVIA, Cd2+ -CTXMVIIC, Aga-IVA SNX-482

CaV2.2

Neurons

Short, high threshold

P/Q CaV2.1

Cerebellar Long, high threshold Purkinje neurons Neurons Pacemaking

CaV2.3