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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)
DP1
PGD2 15d-PGJ2
Allergic asthma Allergic airway inflammation Colon carcinogenesis Impaired ovulation and fertilization Salt-sensitive hypertension
PGI2
EP3AD
PGE2
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
Secondary Ligands
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
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
Postreceptor Mechanism
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
H2
H3
R- Thioperamide, Methylhistami iodophenpropit, ne, imetit, clobenpropit1 immepip Clobenpropit, Thioperamide imetit, clozapine
H4
Gi, cAMP
Distribution
Postreceptor Partially Selective Partially Mechanism Agonists Selective Antagonists Gi , cAMP 8-OH-DPAT Sumatriptan, CP93129 WAY100635
5-HT1A 5-HT1B
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
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
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.
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).
Receptor2 Action
...
... M3 M3
...
...
Contracts
Ciliary muscle
[Relaxes]
Contracts
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
... ...
... ...
... ... M 3, M 55 M3
Relaxes
Contracts
Contracts
M3 M3 M3
Sphincters
Contracts
Relaxes
Secretion
...
...
Increases
Receptor2 Action
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,
...
...
3 1
... ...
... ...
1Less
important actions are shown in brackets. receptor type: = alpha, = beta, M = muscarinic.
2Specific
3Vascular 4The
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.
Receptor Name
Cholinoceptors
Typical Locations
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
Receptor Name
Typical Locations
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
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
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
Where Found
Blocked By
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
P/Q CaV2.1
CaV2.3