Adrenergic receptor
The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines. Adrenergic receptors specifically bind their endogenous ligands, the catecholamines adrenaline and noradrenaline (called epinephrine and norepinephrine in the United States), and are activated by these.
Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic response (ie 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.
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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. 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.
Epinephrine binds its receptor, that associates with an heterotrimeric G protein. The G protein associates with adenylate cyclase that converts ATP to cAMP, spreading the signal (more details...)
The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenergic receptors. α1 couples to Gq, which results in increased intracellular Ca2+ which results in e.g. smooth muscle contraction. α2, on the other hand, couples to Gi, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle contraction. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.
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† |
norepinephrine ≥ epinephrine >> isoprenaline | smooth muscle contraction | Gq: phospholipase C (PLC) activated, IP3 and calcium up |
(Alpha-1 agonists)
|
(Alpha-1 blockers)
|
| α2: A, B, C |
norepinephrine ≥ epinephrine >> isoprenaline | smooth muscle contraction and neurotransmitter inhibition | Gi: adenylate cyclase inactivated, cAMP down |
(Alpha-2 agonists)
|
(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 |
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†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), which causes an increase in IP3 and calcium. 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
- hairs (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
β receptors
β1 receptor
Specific actions of the β1 receptor include:
- Increase cardiac output, both by raising heart rate and 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
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
- Beta adrenergic receptor kinase
- Beta adrenergic receptor kinase-2
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. http://molpharm.aspetjournals.org/cgi/content/abstract/49/1/7.
- ↑ 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. http://ajpheart.physiology.org/cgi/content/abstract/253/2/H388.
- ↑ 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:. 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. PMID 2889649.
- ↑ 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. http://jpet.aspetjournals.org/cgi/content/abstract/219/2/400.
- ↑ Circulation & Lung Physiology I M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third Edition ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
- ↑ 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:. PMID 17952055.
- ↑ 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:. PMID 17962520.
- ↑ 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:. PMID 17962519.
- ↑ Large V, Hellström L, Reynisdottir S, et al (December 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:. PMID 9399946.
- ↑ Kline WO, Panaro FJ, Yang H, Bodine SC (February 2007). "Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol". J. Appl. Physiol. 102 (2): 740–7. doi:. PMID 17068216.
- ↑ Kamalakkannan G, Petrilli CM, George I, et al (April 2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure". J. Heart Lung Transplant. 27 (4): 457–61. doi:. PMID 18374884.
Further reading
- Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 11". Pharmacology. Elsevier Churchill Livingstone. ISBN 0-443-07145-4.
- 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.
External links
- The Adrenergic Receptors
- "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- 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
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