Adrenergic receptor

Epinephrine

Norepinephrine

The adrenergic receptors (or adrenoceptors) are aclass of G protein-coupled receptors that are targetsof the catecholamines, especially norepinephrine (nora-drenaline) and epinephrine (adrenaline).Many cells possess these receptors, and the binding ofa catecholamine to the receptor will generally stimulatethe sympathetic nervous system. The sympathetic ner-vous system is responsible for the fight-or-flight response,which includes widening the pupils of the eye, mobiliz-ing energy, and diverting blood flow from non-essentialorgans to skeletal muscle.

1 History

Raymond Ahlquist, Professor of Pharmacology at Med-ical College of Georgia, published a paper concerningadrenergic nervous transmission in 1948[1] but its sig-nificance was largely ignored at that time. However, in1954 he was able to incorporate his findings in a textbook,Drill’s Pharmacology in Medicine, and thereby firmly es-tablish the essential role played by α and β receptor sitesin the adrenaline/nor-adrenaline cellular mechanism. Hisdiscovery would revolutionise advances in pharmacother-apeutic research, allowing the selective design of spe-cific molecules to target medical ailments rather than relyupon traditional research into the efficacy of pre-existingherbal medicines.

2 Categories

There are two main groups of adrenergic receptors, α andβ, with several subtypes.

• α receptors have the subtypes α1 (a G cou-pled receptor) and α2 (a Gᵢ coupled receptor[2]).Phenylephrine is a selective agonist of the α recep-tor.

• β receptors have the subtypes β1, β2 and β3. Allthree are linked to G proteins (although β2 also cou-ples to Gᵢ),[3] which in turn are linked to adenylatecyclase. Agonist binding thus causes a rise in theintracellular concentration of the second messen-ger cAMP. Downstream effectors of cAMP includecAMP-dependent protein kinase (PKA), which me-diates some of the intracellular events following hor-mone binding. Isoprenaline is a non-selective ago-nist.

The mechanism of adrenergic receptors. Adrenaline or nora-drenaline are receptor ligands to either α1, α2 or β-adrenergicreceptors. α1 couples to Gq, which results in increased intracel-lular Ca2+ and subsequent smooth muscle contraction. α2, on theother hand, couples to Gi, which causes a decrease in neurotrans-mitter release, as well as a decrease of cAMP activity and a re-sulting and smooth muscle contraction. β receptors couple to Gs,and increases intracellular cAMP activity, resulting in e.g. heartmuscle contraction, smooth muscle relaxation and glycogenolysis.

2.1 Roles in circulation

Epinephrine (adrenaline) reacts with both α- and β-adrenoreceptors, causing vasoconstriction and vasodila-

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tion, respectively. Although α receptors are less sensi-tive to epinephrine, when activated, they override the va-sodilation mediated by β-adrenoreceptors because thereare more peripheral α1 receptors than β-adrenoreceptors.The result is that high levels of circulating epinephrinecause vasoconstriction. At lower levels of circulatingepinephrine, β-adrenoreceptor stimulation dominates,producing vasodilation followed by decrease of periph-eral vascular resistance.

2.2 Subtypes

Smooth muscle behavior is variable depending onanatomical location. Smooth muscle contrac-tion/relaxation is generalized below. One importantnote is the differential effects of increased cAMP insmooth muscle compared to cardiac muscle. IncreasedcAMP will promote relaxation in smooth muscle, whilepromoting increased contractility and pulse rate incardiac muscle.[5]

†There is no α₁C receptor. At one time, there was a sub-type known as C, but was found to be identical to one ofthe previously discovered subtypes. To avoid confusion,naming was continued with the letter D.

2.3 α receptors

α receptors have several functions in common, but alsoindividual effects. Common (or still unspecified) effectsinclude:

• Vasoconstriction of veins[6]

• Decrease motility of smooth muscle ingastrointestinal tract[7]

2.3.1 α1 receptor

Main article: Alpha-1 adrenergic receptor

α1-adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, aheterotrimeric G protein, G , activates phospholipaseC (PLC). The PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2), which in turn causes an increasein inositol triphosphate (IP3) and diacylglycerol (DAG).The former interacts with calcium channels of endoplas-mic and sarcoplasmic reticulum, thus changing the cal-cium content in a cell. This triggers all other effects.Specific actions of the α1 receptor mainly involve smoothmuscle contraction. It causes vasoconstriction in manyblood vessels, including those of the skin, gastrointestinalsystem, kidney (renal artery)[8] and brain.[9] Other areasof smooth muscle contraction are:

• ureter

• vas deferens

• hair (arrector pili muscles)

• uterus (when pregnant)

• urethral sphincter

• urothelium and lamina propria[10]

• bronchioles (although minor due to the relaxing ef-fect of β2 receptor on bronchioles)

• blood vessels of ciliary body (stimulation causesmydriasis)

Further effects include glycogenolysis andgluconeogenesis from adipose tissue[11] and liver,as well as secretion from sweat glands[11] and Na+reabsorption from kidney.[11]

Antagonists may be used primarily in hypertension,anxiety disorder, and panic attacks.

2.3.2 α2 receptor

Main article: Alpha-2 adrenergic receptor

The α2 receptor couples to theGᵢ/ₒ protein.[2] It is a presy-naptic receptor, causing negative feedback on, for ex-ample, norepinephrine. When NA is released into thesynapse, it feeds back on the α2 receptor, causing lessNA release from the presynaptic neuron. This decreasesthe effect of NA. There are also α2 receptors on the nerveterminal membrane of the post-synaptic adrenergic neu-ron.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.[11]

• induction of glucagon release from the pancreas.

• contraction of sphincters of the gastrointestinal tract

• negative feedback in the neuronal synapses - presy-naptic inhibition of noradrenalin (NA) release inCNS

• increased thrombocyte aggregation

2.4 β receptors

2.4.1 β1 receptor

Main article: Beta-1 adrenergic receptor

Specific actions of the β1 receptor include:

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• Increase cardiac output by increasing heart rate(positive chronotropic effect), conduction velocity(positive dromotropic effect), and stroke volume (byenhancing contractility—positive inotropic effect).

• Increase renin secretion from juxtaglomerular cellsof the kidney.

• Increase ghrelin secretion from the stomach.[12]

2.4.2 β2 receptor

Main article: Beta-2 adrenergic receptorSpecific actions of the β2 receptor include the following:

Beta-2 adrenergic receptor (PDB 2rh1), which stimulates cellsto increase energy production and utilization. The membrane isshown schematically with a gray stripe.

• Smooth muscle relaxation, e.g. in bronchi,[11] GItract (decreased motility).

• Lipolysis in adipose tissue.[13]

• Anabolism in skeletal muscle.[14][15]

• Relax non-pregnant uterus

• Relax detrusor urinae muscle of bladder wall

• Dilate arteries to skeletal muscle

• Glycogenolysis and gluconeogenesis

• Inhibits insulin secretion

• Contract sphincters of GI tract

• Thickened secretions from salivary glands.[11]

• Inhibit histamine-release from mast cells

• Increase renin secretion from kidney

• Relaxation of Bronchioles (salbutamol, a β2 agonistrelieves bronchiole constriction)

• Involved in brain - immune communication[16]

2.4.3 β3 receptor

Main article: Beta-3 adrenergic receptor

Specific actions of the β3 receptor include:

• Enhancement of lipolysis in adipose tissue. β3 ac-tivating drugs could theoretically be used as weight-loss agents, but are limited by the side effect oftremors.

3 See also• Beta adrenergic receptor kinase

• Beta adrenergic receptor kinase-2

4 References[1] Ahlquist R.P. A Study of the Adenotrophic Receptors,

Am. J. Physiol. 1948 153:586-600

[2] Kou Qin, Pooja R. Sethi and Nevin A. Lambert (August2008). “Abundance and stability of complexes containinginactive G protein-coupled receptors and G proteins”. TheFASEB Journal 22 (8): 2920–2927. doi:10.1096/fj.08-105775. PMC 2493464. PMID 18434433.

[3] Chen-Izu Y, Xiao RP, Izu LT, ChengH, KuschelM, Spur-geon H, Lakatta EG (November 2000). “G(i)-dependentlocalization of beta(2)-adrenergic receptor signaling toL-type Ca(2+) channels”. Biophys. J. 79 (5): 2547–56. Bibcode:2000BpJ....79.2547C. doi:10.1016/S0006-3495(00)76495-2. PMC 1301137. PMID 11053129.

[4] Nisoli E, Tonello C, Landi M, Carruba MO (1996).“Functional studies of the first selective β3-adrenergic re-ceptor antagonist SR 59230A in rat brown adipocytes”.Mol. Pharmacol. 49 (1): 7–14. PMID 8569714.

[5] english

[6] Elliott J (1997). “Alpha-adrenoceptors in equine dig-ital veins: evidence for the presence of both α1- andα2-receptors mediating vasoconstriction”. J. Vet. Phar-macol. Ther. 20 (4): 308–17. doi:10.1046/j.1365-2885.1997.00078.x. PMID 9280371.

[7] Sagrada A, Fargeas MJ, Bueno L (1987). “Involvementof α1 and α2 adrenoceptors in the postlaparotomy intesti-nal motor disturbances in the rat”. Gut 28 (8): 955–9. doi:10.1136/gut.28.8.955. PMC 1433140. PMID2889649.

4 6 EXTERNAL LINKS

[8] Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA(1981). “Renal α1 and α2 adrenergic receptors: bio-chemical and pharmacological correlations”. J. Pharma-col. Exp. Ther. 219 (2): 400–6. PMID 6270306.

[9] Circulation & Lung Physiology I M.A.S.T.E.R. LearningProgram, UC Davis School of Medicine

[10] Moro, C; Tajouri, L; Chess-Williams, R (January 2013).“Adrenoceptor function and expression in bladder urothe-lium and lamina propria”. Urology. 81 (1): 211.e1–7.doi:10.1016/j.urology.2012.09.011. PMID 23200975.

[11] Fitzpatrick, David; Purves, Dale; Augustine, George(2004). “Table 20:2”. Neuroscience (Third ed.). Sunder-land, Mass: Sinauer. ISBN 0-87893-725-0.

[12] Zhao, T. J.; Sakata, I.; Li, R. L.; Liang, G.; Richard-son, J. A.; Brown, M. S. et al. (2010). “Ghrelinsecretion stimulated by {beta}1-adrenergic recep-tors in cultured ghrelinoma cells and in fastedmice”. Proc Natl Acad Sci U S A 107 (36):15868–15873. Bibcode:2010PNAS..10715868Z.doi:10.1073/pnas.1011116107. PMC 2936616. PMID20713709.

[13] Large V, Hellström L, Reynisdottir S et al. (December1997). “Human beta-2 adrenoceptor gene polymorphismsare highly frequent in obesity and associate with alteredadipocyte beta-2 adrenoceptor function”. J. Clin. In-vest. 100 (12): 3005–13. doi:10.1172/JCI119854. PMC508512. PMID 9399946.

[14] Kline WO, Panaro FJ, Yang H, Bodine SC (February2007). “Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol”. J. Appl. Physiol. 102 (2):740–7. doi:10.1152/japplphysiol.00873.2006. PMID17068216.

[15] Kamalakkannan G, Petrilli CM, George I et al. (April2008). “Clenbuterol increases lean muscle mass butnot endurance in patients with chronic heart fail-ure”. J. Heart Lung Transplant. 27 (4): 457–61.doi:10.1016/j.healun.2008.01.013. PMID 18374884.

[16] Elenkov, I. J., R. L. Wilder et al. (2000). “The sympa-thetic nerve--an integrative interface between two super-systems: the brain and the immune system”. PharmacolRev 52 (4): 595–638. PMID 11121511.

5 Further reading

• Rang HP, Dale MM, Ritter JM, Moore PK (2003).“Chapter 11: Noradrenergic transmission”. Phar-macology (5th ed.). Elsevier Churchill Livingstone.ISBN 0-443-07145-4.

• Rang HP, Dale MM, Ritter JM, Flower RJ (2007).“Chapter 11: Noradrenergic transmission”. Rangand Dale’s Pharmacology (6th ed.). ElsevierChurchill Livingstone. pp. 169–170. ISBN 0-443-06911-5.

6 External links• Alpha receptors illustrated

• The Adrenergic Receptors

• “Adrenoceptors”. IUPHAR Database of Receptorsand Ion Channels. International Union of Basic andClinical Pharmacology.

• Basic Neurochemistry: α- and β-Adrenergic Recep-tors

• Brief overview of functions of the β3 receptor

• Theory of receptor activation

• Desensitization of β1 receptors

• UMich Orientation of Proteins in Membranesprotein/pdbid-2rh1 - 3D structure of β2 adrenergicreceptor in membrane

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7 Text and image sources, contributors, and licenses

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