Adrenergic receptor

Epinephrine

Norepinephrine

The adrenergic receptors (or adrenoceptors) are a class of metabotropic 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.

Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic (or sympathomimetic) response (e.g. 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 G_q coupled receptor) and α₂ (a G_i 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 G_s proteins (although β₂ also couples to Gi),^[1] 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.

The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α₁, α₂ or β-adrenergic receptors. α₁ couples to G_q, which results in increased intracellular Ca²⁺ which results in smooth muscle contraction. α₂, on the other hand, couples to G_i, which causes a decrease of cAMP activity, resulting in e.g. smooth muscle contraction. β receptors couple to G_s, 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

Smooth muscle behavior is variable depending on anatomical location. Smooth muscle contraction/relaxation is generalized below. One important note is the differential effects of increased cAMP in smooth muscle compared cardiac muscle. Increased cAMP will promote relaxation in smooth muscle, while promoting increased contractility and pulse rate in cardiac muscle.

Receptor	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 DAG, rise in calcium	(Alpha-1 agonists) Noradrenaline Phenylephrine Methoxamine Cirazoline Xylometazoline Midodrine	(Alpha-1 blockers) Alfuzosin Doxazosin Phenoxybenzamine Phentolamine Prazosin Tamsulosin Terazosin (TCA:s) Amitriptyline Clomipramine Doxepin Trimipramine
α2: A, B, C	Epinephrine ≥ norepinephrine >> isoprenaline	Smooth muscle mixed effects and neurotransmitter inhibition & Cardiac muscle relaxation	Gi: adenylate cyclase inactivated, cAMP down	(Alpha-2 agonists) Dexmedetomidine Medetomidine Romifidine Clonidine Brimonidine Detomidine Lofexidine Xylazine Tizanidine Guanfacine Amitraz	(Alpha-2 blockers) Phentolamine Yohimbine Idazoxan Atipamezole
β1	Isoprenaline > epinephrine = norepinephrine	Heart muscle contraction	Gs: adenylate cyclase activated, cAMP up	Dobutamine Isoprenaline Noradrenaline	(Beta blockers) Metoprolol Atenolol
β2	Isoprenaline > epinephrine >> norepinephrine	Smooth muscle relaxation	Gs: adenylate cyclase activated, cAMP up (also Gi, see β2)	(Short/long) Salbutamol (Albuterol in USA) Bitolterol mesylate Formoterol Isoprenaline Levalbuterol Metaproterenol Salmeterol Terbutaline Ritodrine	(Beta blockers) Butoxamine Propranolol
β3	Isoprenaline = norepinephrine > epinephrine	Enhance lipolysis, promotes relaxation of detrusor muscle in the bladder	Gs: adenylate cyclase activated, cAMP up	L-796568[2] Amibegron Solabegron	SR 59230A

^†There is no α_1C 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).^[3]
• Vasoconstriction of veins^[4]
• Decrease motility of smooth muscle in gastrointestinal tract^[5]

α₁ receptor

Main article: Alpha-1 adrenergic 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-bisphosphate (PIP2), which in turn causes an increase in inositol triphosphate (IP3) and diacylglycerol (DAG). The former interacts with calcium channels of endoplasmic and sarcoplasmic reticulum, thus changing the calcium content in a cell. This triggers all other effects.

Specific actions of the α₁ receptor mainly involve smooth muscle contraction. It causes vasoconstriction in many blood vessels, including those of the skin, gastrointestinal system, kidney (renal artery)^[6] and brain.^[7] Other areas of smooth muscle contraction are:

• ureter
• vas deferens
• hair (arrector 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^[8] and liver, as well as secretion from sweat glands^[8] and Na⁺ reabsorption from kidney.^[8]

Antagonists may be used in hypertension.

α₂ receptor

Main article: Alpha-2 adrenergic 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 the pancreas.^[8]
• induction of glucagon release from the pancreas.
• contraction of sphincters of the gastrointestinal tract
• negative feedback in the neuronal synapses - presynaptic inhibition of noradrenalin release in CNS
• increased thrombocyte aggregation

β receptors

β₁ receptor

Main article: Beta-1 adrenergic receptor

Specific actions of the β₁ receptor include:

• Increase cardiac output, by raising heart rate (positive chronotropic effect), increasing impulse conduction, and increasing contraction, thus increasing the volume expelled with each beat (increased ejection fraction).
• Increase renin secretion from juxtaglomerular cell of kidney.
• Increase ghrelin secretion from the stomach^[9]

β₂ receptor

Main article: Beta-2 adrenergic receptor

Specific actions of the β₂ receptor include the following:

• Smooth muscle relaxation, e.g. in bronchi,^[8] GI tract (decreased motility).
• Lipolysis in adipose tissue.^[10]
• Anabolism in skeletal muscle.^[11][12]
• Relax non-pregnant uterus
• Relax detrusor urinae muscle‎ of bladder wall
• Dilate arteries to skeletal muscle
• Glycogenolysis and gluconeogenesis
• Stimulates insulin secretion
• Contract sphincters of GI tract
• Thickened secretions from salivary glands.^[8]
• Inhibit histamine-release from mast cells
• Increase renin secretion from kidney
• Relaxation of Bronchioles (salbutamol, a beta 2 agonist relieves bronchiole constriction)
• Involved in brain - immune communication^[13]

β₃ receptor

Main article: Beta-3 adrenergic receptor

Specific actions of the β₃ receptor include:

• Enhancement of lipolysis in adipose tissue. Beta-3 activating drugs could theoretically be used as weight-loss agents, but are limited by the side effect of tremors.

See also

• Beta adrenergic receptor kinase
• Beta adrenergic receptor kinase-2

References

1. ^ Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (November 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophys. J. 79 (5): 2547–56. doi:10.1016/S0006-3495(00)76495-2. PMC 1301137. PMID 11053129. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1301137. 
2. ^ 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. 
3. ^ 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. 
4. ^ 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. 
5. ^ 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. PMC 1433140. PMID 2889649. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1433140. 
6. ^ 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. 
7. ^ Circulation & Lung Physiology I M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
8. ^ ^{a b c d e f} Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0. 
9. ^ Zhao, T. J.; Sakata, I.; Li, R. L.; Liang, G.; Richardson, J. A.; Brown, M. S. et al. (2010). "Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice". Proc Natl Acad Sci U S A 107 (36): 15868–15873. doi:10.1073/pnas.1011116107. PMID 20713709. 
10. ^ 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:10.1172/JCI119854. PMC 508512. PMID 9399946. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=508512. 
11. ^ 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:10.1152/japplphysiol.00873.2006. PMID 17068216. 
12. ^ 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:10.1016/j.healun.2008.01.013. PMID 18374884. 
13. ^ Elenkov, I. J., R. L. Wilder, et al. (2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.". Pharmacol Rev 52 (4): 595–638. PMID 11121511. 

Further reading

• Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Chapter 11: Noradrenergic transmission". Pharmacology (5th ed.). Elsevier Churchill Livingstone. ISBN 0-443-07145-4. 
• Rang HP, Dale MM, Ritter JM, Flower RJ (2007). "Chapter 11: Noradrenergic transmission". Rang and Dale's Pharmacology (6th ed.). Elsevier Churchill Livingstone. pp. 169–170. ISBN 0-443-06911-5. 

External links

• Alpha receptors illustrated
• The Adrenergic Receptors
• "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1274. 
• 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