Alpha-2B adrenergic receptor explained

The alpha-2B adrenergic receptor (α_2B adrenoceptor), is a G-protein coupled receptor. It is a subtype of the adrenergic receptor family. The human gene encoding this receptor has the symbol ADRA2B.ADRA2B orthologs^[1] have been identified in several mammals.

Receptor

α₂-adrenergic receptors include 3 highly homologous subtypes: α_2A, α_2B, and α_2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system.

Clinical significance

This gene encodes the α_2B subtype, which was observed to associate with eIF-2B, a guanine nucleotide exchange protein that functions in regulation of translation. A polymorphic variant of the α_2B subtype, which lacks 3 glutamic acids from a glutamic acid repeat element, was identified to have decreased G protein-coupled receptor kinase-mediated phosphorylation and desensitization; this polymorphic form is also associated with reduced basal metabolic rate in obese subjects and may therefore contribute to the pathogenesis of obesity. This gene contains no introns in either its coding or untranslated sequences.^[2]

A deletion variant of the α_2B adrenergic receptor has been shown to be related to emotional memory in Europeans and Africans.^[3] This variant also predisposed people who had it to focus more on negative aspects of a situation.^[4] This predisposition remained present in people with the variant gene who took a single dose of the noradrenergic antidepressant reboxetine, but was weakened in people without the variant.^[5]

Evolution

The ADRA2B gene (sometimes referenced as A2AB) is used in animals as a nuclear DNA phylogenetic marker.^[1] This intronless gene has first been used to explore the phylogeny of the major groups of mammals,^[6] and contributed to reveal that placental orders are distributed into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchontoglires. Comparative analysis of the primary protein sequence of ADRA2B across placentals also showed the high conservation of residues thought to be involved in agonist binding and in G protein–coupling. However, great variations are observed in the very long, third intracellular loop, with a polyglutamyl domain displaying pervasive length differences.^[7]

Ligands

Agonists

• (−)-Dibromophakellin^[8]

Antagonists

• Imiloxan
• Yohimbine

See also

• Adrenergic receptor

Further reading

• Lomasney JW, Lorenz W, Allen LF, King K, Regan JW, Yang-Feng TL, Caron MG, Lefkowitz RJ . Expansion of the alpha 2-adrenergic receptor family: cloning and characterization of a human alpha 2-adrenergic receptor subtype, the gene for which is located on chromosome 2 . Proceedings of the National Academy of Sciences of the United States of America . 87 . 13 . 5094–8 . Jul 1990 . 2164221 . 54268 . 10.1073/pnas.87.13.5094 . 1990PNAS...87.5094L . free .
• McClue SJ, Milligan G . The alpha 2B adrenergic receptor of undifferentiated neuroblastoma x glioma hybrid NG108-15 cells, interacts directly with the guanine nucleotide binding protein, Gi2 . FEBS Letters . 269 . 2 . 430–4 . Sep 1990 . 2169434 . 10.1016/0014-5793(90)81209-7 . 24246875 . free .
• Weinshank RL, Zgombick JM, Macchi M, Adham N, Lichtblau H, Branchek TA, Hartig PR . Cloning, expression, and pharmacological characterization of a human alpha 2B-adrenergic receptor . Molecular Pharmacology . 38 . 5 . 681–8 . Nov 1990 . 2172775 .
• Chang AC, Ho TF, Chang NC . In vitro amplification by polymerase chain reaction of a partial gene encoding the third subtype of alpha-2 adrenergic receptor in humans . Biochemical and Biophysical Research Communications . 172 . 2 . 817–23 . Oct 1990 . 2173582 . 10.1016/0006-291X(90)90748-C .
• 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 . Proceedings of the National Academy of Sciences of the United States of America . 85 . 17 . 6301–5 . Sep 1988 . 2842764 . 281957 . 10.1073/pnas.85.17.6301 . 1988PNAS...85.6301R . free .
• Petrash AC, Bylund DB . Alpha-2 adrenergic receptor subtypes indicated by [3H]yohimbine binding in human brain . Life Sciences . 38 . 23 . 2129–37 . Jun 1986 . 3012234 . 10.1016/0024-3205(86)90212-2 .
• Klein U, Ramirez MT, Kobilka BK, von Zastrow M . A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation factor 2B . The Journal of Biological Chemistry . 272 . 31 . 19099–102 . Aug 1997 . 9235896 . 10.1074/jbc.272.31.19099 . free .
• Okusa MD, Huang L, Momose-Hotokezaka A, Huynh LP, Mangrum AJ . Regulation of adenylyl cyclase in polarized renal epithelial cells by G protein-coupled receptors . The American Journal of Physiology . 273 . 6 Pt 2 . F883–91 . Dec 1997 . 9435676 . 10.1152/ajprenal.1997.273.6.F883.
• 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 . The Journal of Biological Chemistry . 274 . 19 . 13462–9 . May 1999 . 10224112 . 10.1074/jbc.274.19.13462 . free .
• Heinonen P, Koulu M, Pesonen U, Karvonen MK, Rissanen A, Laakso M, Valve R, Uusitupa M, Scheinin M . Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects . The Journal of Clinical Endocrinology and Metabolism . 84 . 7 . 2429–33 . Jul 1999 . 10.1210/jcem.84.7.5818 . 10404816 . free .
• Hein L, Altman JD, Kobilka BK . Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission . Nature . 402 . 6758 . 181–4 . Nov 1999 . 10647009 . 10.1038/46040 . 1999Natur.402..181H . 205047992 .
• Small KM, Brown KM, Forbes SL, Liggett SB . Polymorphic deletion of three intracellular acidic residues of the alpha 2B-adrenergic receptor decreases G protein-coupled receptor kinase-mediated phosphorylation and desensitization . The Journal of Biological Chemistry . 276 . 7 . 4917–22 . Feb 2001 . 11056163 . 10.1074/jbc.M008118200 . free .
• Snapir A, Mikkelsson J, Perola M, Penttilä A, Scheinin M, Karhunen PJ . Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death . Journal of the American College of Cardiology . 41 . 2 . 190–4 . Jan 2003 . 12535806 . 10.1016/S0735-1097(02)02702-X . free .
• Sykiotis GP, Polyzogopoulou E, Georgopoulos NA, Trakada G, Spyropoulos K, Kalfarentzos F, Papavassiliou AG, Vagenakis AG, Flordellis CS . The alpha2B adrenergic receptor deletion/insertion polymorphism in morbid obesity . Clinical Autonomic Research . 13 . 3 . 203–7 . Jun 2003 . 12822042 . 10.1007/s10286-003-0087-5 . 10913264 .
• 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 . American Journal of Physiology. Heart and Circulatory Physiology . 286 . 1 . H59–67 . Jan 2004 . 12946937 . 10.1152/ajpheart.00268.2003 .
• Von Wowern F, Bengtsson K, Lindblad U, Råstam L, Melander O . Functional variant in the (alpha)2B adrenoceptor gene, a positional candidate on chromosome 2, associates with hypertension . Hypertension . 43 . 3 . 592–7 . Mar 2004 . 14744925 . 10.1161/01.HYP.0000116224.51189.80 . free .
• Cayla C, Heinonen P, Viikari L, Schaak S, Snapir A, Bouloumié A, Karvonen MK, Pesonen U, Scheinin M, Paris H . Cloning, characterisation and identification of several polymorphisms in the promoter region of the human alpha2B-adrenergic receptor gene . Biochemical Pharmacology . 67 . 3 . 469–78 . Feb 2004 . 15037199 . 10.1016/j.bcp.2003.09.029 .
• Phares DA, Halverstadt AA, Shuldiner AR, Ferrell RE, Douglass LW, Ryan AS, Goldberg AP, Hagberg JM . Association between body fat response to exercise training and multilocus ADR genotypes . Obesity Research . 12 . 5 . 807–15 . May 2004 . 15166301 . 10.1038/oby.2004.97 . free .
• Siitonen N, Lindström J, Eriksson J, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Tuomilehto J, Laakso M, Uusitupa M . Association between a deletion/insertion polymorphism in the alpha2B-adrenergic receptor gene and insulin secretion and Type 2 diabetes. The Finnish Diabetes Prevention Study . Diabetologia . 47 . 8 . 1416–24 . Aug 2004 . 15309292 . 10.1007/s00125-004-1462-z . free .
• 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 . Journal of Human Genetics . 50 . 1 . 12–20 . 2005 . 15592690 . 10.1007/s10038-004-0211-y . free .

Notes and References

1. Web site: OrthoMaM phylogenetic marker: ADRA2B coding sequence .
2. Web site: Entrez Gene: ADRA2B adrenergic, alpha-2B-, receptor.
3. de Quervain DJ, Kolassa IT, Ertl V, Onyut PL, Neuner F, Elbert T, Papassotiropoulos A . A deletion variant of the alpha2b-adrenoceptor is related to emotional memory in Europeans and Africans . Nature Neuroscience . 10 . 9 . 1137–9 . Sep 2007 . 17660814 . 10.1038/nn1945 . 899166 .
4. Todd RM, Müller DJ, Lee DH, Robertson A, Eaton T, Freeman N, Palombo DJ, Levine B, Anderson AK . Genes for emotion-enhanced remembering are linked to enhanced perceiving . Psychol Sci . 24 . 11 . 2244–53 . 2013 . 24058067 . 10.1177/0956797613492423 . 9603198.
5. Gibbs AA, Bautista CE, Mowlem FD, Naudts KH, Duka T . Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers . J. Neurosci. . 33 . 43 . 17023–8 . 2013 . 24155306 . 6618435 . 10.1523/JNEUROSCI.2124-13.2013.
6. Madsen O, Scally M, Douady CJ, Kao DJ, DeBry RW, Adkins R, Amrine HM, Stanhope MJ, de Jong WW, Springer MS . Parallel adaptive radiations in two major clades of placental mammals . Nature . 409 . 6820 . 610–4 . Feb 2001 . 11214318 . 10.1038/35054544 . 2001Natur.409..610M . 4398233 .
7. Madsen O, Willemsen D, Ursing BM, Arnason U, de Jong WW . Molecular evolution of the mammalian alpha 2B adrenergic receptor . Molecular Biology and Evolution . 19 . 12 . 2150–60 . Dec 2002 . 12446807 . 10.1093/oxfordjournals.molbev.a004040 . free .
8. Davis RA, Fechner GA, Sykes M, Garavelas A, Pass DM, Carroll AR, Addepalli R, Avery VM, Hooper JN, Quinn RJ . (-)-Dibromophakellin: an alpha2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata . Bioorganic & Medicinal Chemistry . 17 . 6 . 2497–500 . Mar 2009 . 19243956 . 10.1016/j.bmc.2009.01.065 . 10072/28568 . free .