Alpha-2C adrenergic receptor explained

The alpha-2C adrenergic receptor (α_2C adrenoceptor), also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.

Receptor

Alpha-2-adrenergic receptors include 3 highly homologous subtypes: alpha_2A, alpha_2B, and alpha_2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. Studies in mice revealed that both the alpha_2A and alpha_2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons; the alpha_2A subtype inhibited transmitter release at high stimulation frequencies, whereas the alpha_2C subtype modulated neurotransmission at lower levels of nerve activity.^[1]

Gene

This gene encodes the alpha2C subtype, which contains no introns in either its coding or untranslated sequences.^[2]

Ligands

Agonists

• (R)-3-Nitrobiphenyline (also weak antagonist at α_2A and α_2B)^[3]

Antagonists

• BMY 7378 (also α_1D antagonist)^[4]
• JP-1302: selective over α2A, α2B, α2C^[5]
• N--2-phenoxy-nicotinamide^[6]
• Quetiapine^[7]
• Risperidone
• Mirtazapine
• Spiroxatrine
• Yohimbine derivatives 9 and 10: >43 fold selectivity over α2A, α2B and α1 subtypes^[8]
• Brexpiprazole

See also

• Adrenergic receptor

Further reading

• Coupry I, Duzic E, Lanier SM . Factors determining the specificity of signal transduction by guanine nucleotide-binding protein-coupled receptors. II. Preferential coupling of the alpha 2C-adrenergic receptor to the guanine nucleotide-binding protein, Go . J. Biol. Chem. . 267 . 14 . 9852–7 . 1992 . 10.1016/S0021-9258(19)50172-7 . 1349607 . free .
• Chhajlani V, Rangel N, Uhlén S, Wikberg JE . Identification of an additional gene belonging to the alpha 2 adrenergic receptor family in the human genome by PCR . FEBS Lett. . 280 . 2 . 241–4 . 1991 . 1849485 . 10.1016/0014-5793(91)80301-I . 26642747 . free .
• Regan JW, Kobilka TS, Yang-Feng TL, Caron MG, Lefkowitz RJ, Kobilka BK . Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype . Proc. Natl. Acad. Sci. U.S.A. . 85 . 17 . 6301–5 . 1988 . 2842764 . 281957 . 10.1073/pnas.85.17.6301 . 1988PNAS...85.6301R . free .
• Eason MG, Liggett SB . Human alpha 2-adrenergic receptor subtype distribution: widespread and subtype-selective expression of alpha 2C10, alpha 2C4, and alpha 2C2 mRNA in multiple tissues . Mol. Pharmacol. . 44 . 1 . 70–5 . 1993 . 7688069 .
• Riess O, Thies U, Siedlaczck I, Potisek S, Graham R, Theilmann J, Grimm T, Epplen JT, Hayden MR . Precise mapping of the brain alpha 2-adrenergic receptor gene within chromosome 4p16 . Genomics . 19 . 2 . 298–302 . 1994 . 8188260 . 10.1006/geno.1994.1061 .
• Klein U, Ramirez MT, Kobilka BK, von Zastrow M . A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation factor 2B . J. Biol. Chem. . 272 . 31 . 19099–102 . 1997 . 9235896 . 10.1074/jbc.272.31.19099 . free .
• Schaak S, Devedjian JC, Cayla C, Sender Y, Paris H . Molecular cloning, sequencing and functional study of the promoter region of the human alpha2C4-adrenergic receptor gene . Biochem. J. . 328 . 2 . 431–8 . 1998 . 9371698 . 1218938 . 10.1042/bj3280431.
• DeGraff JL, Gagnon AW, Benovic JL, Orsini MJ . Role of arrestins in endocytosis and signaling of alpha2-adrenergic receptor subtypes . J. Biol. Chem. . 274 . 16 . 11253–9 . 1999 . 10196213 . 10.1074/jbc.274.16.11253 . free .
• Prezeau L, Richman JG, Edwards SW, Limbird LE . The zeta isoform of 14-3-3 proteins interacts with the third intracellular loop of different alpha2-adrenergic receptor subtypes . J. Biol. Chem. . 274 . 19 . 13462–9 . 1999 . 10224112 . 10.1074/jbc.274.19.13462 . free .
• Hein L, Altman JD, Kobilka BK . Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission . Nature . 402 . 6758 . 181–4 . 2000 . 10647009 . 10.1038/46040 . 1999Natur.402..181H . 205047992 .
• Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB . A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors . J. Biol. Chem. . 275 . 30 . 23059–64 . 2000 . 10801795 . 10.1074/jbc.M000796200 . free .
• Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Blake H, Chiu F, Wang E, Farwell K, Darakjy S, Baker R, Dietz G, Saucier G, MacMurray JP . Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder . Clin. Genet. . 58 . 1 . 31–40 . 2001 . 10945659 . 10.1034/j.1399-0004.2000.580106.x . 43815350 .
• Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB . Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure . N. Engl. J. Med. . 347 . 15 . 1135–42 . 2002 . 12374873 . 10.1056/NEJMoa020803 . free .
• Chotani MA, Mitra S, Su BY, Flavahan S, Eid AH, Clark KR, Montague CR, Paris H, Handy DE, Flavahan NA . Regulation of alpha(2)-adrenoceptors in human vascular smooth muscle cells . Am. J. Physiol. Heart Circ. Physiol. . 286 . 1 . H59–67 . 2004 . 12946937 . 10.1152/ajpheart.00268.2003 .
• Small KM, Mialet-Perez J, Seman CA, Theiss CT, Brown KM, Liggett SB . Polymorphisms of cardiac presynaptic alpha2C adrenergic receptors: Diverse intragenic variability with haplotype-specific functional effects . Proc. Natl. Acad. Sci. U.S.A. . 101 . 35 . 13020–5 . 2004 . 15319474 . 516511 . 10.1073/pnas.0405074101 . 2004PNAS..10113020S . free .
• Chotani MA, Mitra S, Eid AH, Han SA, Flavahan NA . Distinct cAMP signaling pathways differentially regulate alpha2C-adrenoceptor expression: role in serum induction in human arteriolar smooth muscle cells . Am. J. Physiol. Heart Circ. Physiol. . 288 . 1 . H69–76 . 2005 . 15345481 . 10.1152/ajpheart.01223.2003 . 32149099 .
• Belfer I, Buzas B, Hipp H, Phillips G, Taubman J, Lorincz I, Evans C, Lipsky RH, Enoch MA, Max MB, Goldman D . Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene . J. Hum. Genet. . 50 . 1 . 12–20 . 2005 . 15592690 . 10.1007/s10038-004-0211-y . free .
• Neumeister A, Charney DS, Belfer I, Geraci M, Holmes C, Sharabi Y, Alim T, Bonne O, Luckenbaugh DA, Manji H, Goldman D, Goldstein DS . Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans . Pharmacogenet. Genomics . 15 . 3 . 143–9 . 2005 . 15861038 . 10.1097/01213011-200503000-00002 . 479475 .
• Neumeister A, Drevets WC, Belfer I, Luckenbaugh DA, Henry S, Bonne O, Herscovitch P, Goldman D, Charney DS . Effects of an alpha 2C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression . Neuropsychopharmacology . 31 . 8 . 1750–6 . 2006 . 16407897 . 10.1038/sj.npp.1301010 . free .
• Park JS, Zhang SY, Jo SH, Seo JB, Li L, Park KW, Oh BH, Park YB, Kim HS . Common adrenergic receptor polymorphisms as novel risk factors for vasospastic angina . Am. Heart J. . 151 . 4 . 864–9 . 2006 . 16569551 . 10.1016/j.ahj.2005.06.009 .

Notes and References

1. Web site: ADRA2C adrenoceptor alpha 2C [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. en. 2018-09-11.
2. Web site: Entrez Gene: ADRA2C adrenergic, alpha-2C-, receptor.
3. Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M . Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist . Journal of Medicinal Chemistry . 50 . 16 . 3964–8 . August 2007 . 17630725 . 10.1021/jm061487a .
4. Cleary L, Murad K, Bexis S, Docherty JR . The alpha (1D)-adrenoceptor antagonist BMY 7378 is also an alpha (2C)-adrenoceptor antagonist . Autonomic and Autacoid Pharmacology . 25 . 4 . 135–41 . 2005 . 16176444 . 10.1111/j.1474-8673.2005.00342.x .
5. Sallinen J, Höglund I, Engström M, Lehtimäki J, Virtanen R, Sirviö J, Wurster S, Savola JM, Haapalinna A . Pharmacological characterization and CNS effects of a novel highly selective alpha2C-adrenoceptor antagonist JP-1302 . Br. J. Pharmacol. . 150 . 4 . 391–402 . 2007 . 17220913 . 2189732 . 10.1038/sj.bjp.0707005 .
6. Patel SD, Habeski WM, Min H, Zhang J, Roof R, Snyder B, Bora G, Campbell B, Li C, Hidayetoglu D, Johnson DS, Chaudhry A, Charlton ME, Kablaoui NM . Identification and SAR around N--2-phenoxy-nicotinamide, a selective alpha2C adrenergic receptor antagonist . Bioorg. Med. Chem. Lett. . 18 . 20 . 5689–93 . 2008 . 18799310 . 10.1016/j.bmcl.2008.08.055 .
7. Bryan Roth . Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL . N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity . Neuropsychopharmacology . 33 . 10 . 2303–12 . September 2008 . 18059438 . 10.1038/sj.npp.1301646 . free .
8. Bavadekar SA, Ma G, Mustafa SM, Moore BM, Miller DD, Feller DR . Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands . J. Pharmacol. Exp. Ther. . 319 . 2 . 739–48 . November 2006 . 16873606 . 10.1124/jpet.106.105981 . 31412932 .