Adrenergic receptor
The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline (norepinephrine) and adrenaline (epinephrine). Although dopamine is a catecholamine, its receptors are in a different category. Dopamine has been used as a neurotransmitter since the beginning of nerve system evolution. One possible natural selection pathway is that random mutations in receptor DNA eventually created receptors that allowed some beneficial fine tuning of the dopamine system, the adrenergic receptors sensed the metabolites of dopamine - noradrenaline in early vertebrates, and octopamine in arthropods. Further mutation of vertebrate adrenergic receptor DNA made some of them more sensitive to noradrenaline's degradation product adrenaline. But still they have some sensitivity to dopamine - a fact that is sometimes used in medicine.
Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic response (i.e. the fight-or-flight response). For instance, the heart rate will increase and the pupils will dilate, energy will be mobilized, and blood flow diverted from other non-essential organs to skeletal muscle.
Subtypes
There are two main groups of adrenergic receptors, α and β, with several subtypes.
- α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor). Phenylephrine is a selective agonist of the α receptor.
- β receptors have the subtypes β1, β2 and β3. All three are linked to Gs proteins, which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP (cyclic adenosine monophosphate). Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a selective agonist.
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Roles in circulation
Adrenaline reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodilation, respectively. Although α receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated by β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. At lower levels of circulating epinephrine, β-adrenoreceptor stimulation dominates, producing an overall vasodilation.
Comparison
| Receptor type | Agonist potency order | Selected action of agonist |
Mechanism | Agonists | Antagonists |
|---|---|---|---|---|---|
| α1: A, B, D† |
epinephrine ≥ norepinephrine >> isoproterenol | smooth muscle contraction | Gq: phospholipase C (PLC) activated, IP3 and calcium up | (Alpha-1 blockers) | |
| α2: A, B, C |
norepinephrine ≥ epinephrine >> isoproterenol | smooth muscle contraction and neurotransmitter inhibition | Gi: adenylate cyclase inactivated, cAMP down | (Alpha-2 blockers) | |
| β1 | isoprenaline > epinephrine = norepinephrine | heart muscle contraction | Gs: adenylate cyclase activated, cAMP up | (Beta blockers) | |
| β2 | isoprenaline > epinephrine >> norepinephrine | smooth muscle relaxation | Gs: adenylate cyclase activated, cAMP up | (Short/long) | (Beta blockers) |
| β3 | isoprenaline = norepinephrine > epinephrine | Enhance lipolysis | Gs: adenylate cyclase activated, cAMP up |
|
†There is no α1C receptor. At one time, there was a subtype known as C, but was found to be identical to one of the previously discovered subtypes. To avoid confusion, naming was continued with the letter D.
α receptors
α receptors have several functions in common, but also individual effects. Common (or still unspecified) effects include:
- Vasoconstriction of arteries to heart (coronary artery).[2]
- Vasoconstriction of veins[3]
- Decrease motility of smooth muscle in gastrointestinal tract[4]
α1 receptor
Alpha1-adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC). The PLC cleaves phosphatidylinositol 4,5-biphosphate (PIP2) which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of endoplasmic and sarcoplasmic retuculum thus changing the calcium content in a cell. This triggers all other effects.
Specific actions of the α1 receptor mainly involves smooth muscle contraction. It causes vasoconstriction in many blood vessels including those of the skin & gastrointestinal system and to kidney (renal artery)[5] and brain[6]. Other areas of smooth muscle contraction are:
- ureter
- vas deferens
- hair (erector pili muscles)
- uterus (when pregnant)
- urethral sphincter
- bronchioles (although minor to the relaxing effect of β2 receptor on bronchioles)
- blood vessels of ciliary body (stimulation causes mydriasis)
Further effects include glycogenolysis and gluconeogenesis from adipose tissue[7] and liver, as well as secretion from sweat glands[7] and Na+ reabsorption from kidney.[7]
Antagonists may be used in hypertension.
α2 receptor
There are 3 highly homologous subtypes of α2 receptors: α2A, α2Β, and α2C.
Specific actions of the α2 receptor include:
- inhibition of insulin release in pancreas.[7]
- induction of glucagon release from pancreas.
- contraction of sphincters of the gastrointestinal tract
- negative feedback in the neuronal synapses
- platelet aggregation
β receptors
β1 receptor
Specific actions of the β1 receptor include:
- Increase cardiac output, by raising heart rate (positive chronotropic effect) and increasing impulse conduction and increasing contraction thus increasing the volume expelled with each beat (increased ejection fraction).
- Renin release from juxtaglomerular cells.[7]
- Lipolysis in adipose tissue.[7]
β2 receptor
The 3D crystallographic structure of the β2-adrenergic receptor has been determined (PDB: 2R4R, 2R4S, 2RH1).[8][9][10]
Specific actions of the β2 receptor include:
- Smooth muscle relaxation, e.g. in bronchi.[7]
- Lipolysis in adipose tissue.[11]
- Anabolism in skeletal muscle.[12][13]
- Relax non-pregnant uterus
- Relax detrusor urinae muscle of bladder wall
- Dilate arteries to skeletal muscle
- Glycogenolysis and gluconeogenesis
- Contract sphincters of GI tract
- Thickened secretions from salivary glands.[7]
- Inhibit histamine-release from mast cells
- Increase renin secretion from kidney
- Promotes insulin release from pancreatic beta cells
β3 receptor
Specific actions of the β3 receptor include:
- Enhancement of lipolysis in adipose tissue. However, acitvation of Beta-3 receptors often causes tremors, which is the paramount reason that Beta-3 activating pharmacological agents are not utilized as weight loss agents Clarify
See also
References
- ^ Nisoli E, Tonello C, Landi M, Carruba MO (1996). "Functional studies of the first selective β3-adrenergic receptor antagonist SR 59230A in rat brown adipocytes". Mol. Pharmacol. 49 (1): 7–14. PMID 8569714.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Woodman OL, Vatner SF (1987). "Coronary vasoconstriction mediated by α1- and α2-adrenoceptors in conscious dogs". Am. J. Physiol. 253 (2 Pt 2): H388–93. PMID 2887122.
- ^ Elliott J (1997). "Alpha-adrenoceptors in equine digital veins: evidence for the presence of both α1- and α2-receptors mediating vasoconstriction". J. Vet. Pharmacol. Ther. 20 (4): 308–17. doi:10.1046/j.1365-2885.1997.00078.x. PMID 9280371.
- ^ Sagrada A, Fargeas MJ, Bueno L (1987). "Involvement of α1 and α2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat". Gut. 28 (8): 955–9. doi:10.1136/gut.28.8.955. PMID 2889649.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA (1981). "Renal α1 and α2 adrenergic receptors: biochemical and pharmacological correlations". J. Pharmacol. Exp. Ther. 219 (2): 400–6. PMID 6270306.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Circulation & Lung Physiology I M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
- ^ a b c d e f g h Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007). "Crystal structure of the human β2-adrenergic G-protein-coupled receptor". Nature. 450 (7168): 383–7. doi:10.1038/nature06325. PMID 17952055.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). "High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor". Science. 318 (5854): 1258–65. doi:10.1126/science.1150577. PMID 17962520.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007). "GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function". Science. 318 (5854): 1266–73. doi:10.1126/science.1150609. PMID 17962519.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Large V, Hellström L, Reynisdottir S; et al. (1997). "Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function". J. Clin. Invest. 100 (12): 3005–13. doi:10.1172/JCI119854. PMC 508512. PMID 9399946.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Kline WO, Panaro FJ, Yang H, Bodine SC (2007). "Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol". J. Appl. Physiol. 102 (2): 740–7. doi:10.1152/japplphysiol.00873.2006. PMID 17068216.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Kamalakkannan G, Petrilli CM, George I; et al. (2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure". J. Heart Lung Transplant. 27 (4): 457–61. doi:10.1016/j.healun.2008.01.013. PMID 18374884.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
Further reading
- Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 11". Pharmacology. Elsevier Churchill Livingstone. ISBN 0-443-07145-4.
{{cite book}}: Cite has empty unknown parameters:|coauthors=and|month=(help)CS1 maint: multiple names: authors list (link) - Rang HP, Dale MM, Ritter JM, Flower RJ (2007). "Ch. 11". Rang and Dale's Pharmacology. Elsevier Churchill Livingstone. pp. 169–170. ISBN 0-443-06911-5.
{{cite book}}: Cite has empty unknown parameters:|coauthors=and|month=(help)CS1 maint: multiple names: authors list (link)
External links
- The Adrenergic Receptors
- "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
{{cite web}}: Cite has empty unknown parameter:|coauthors=(help) - Basic Neurochemistry: α- and β-Adrenergic Receptors
- Brief overview of functions of the beta-3 receptor
- Theory of receptor activation
- Desensitization of beta-1-receptors
- UMich Orientation of Proteins in Membranes protein/pdbid-2rh1 - 3D structure of beta-2 adrenergic receptor in membrane