Alpha-2B adrenergic receptor

Adrenoceptor alpha 2B

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
2CVA

Identifiers

Symbols

ADRA2B ; ADRA2L1; ADRA2RL1; ADRARL1; ALPHA2BAR; FAME2; alpha-2BAR

External IDs

OMIM: 104260 MGI: 87935 HomoloGene: 553 IUPHAR: 26 ChEMBL: 1942 GeneCards: ADRA2B Gene

Gene ontology
Molecular function	• alpha2-adrenergic receptor activity • protein binding • epinephrine binding
Cellular component	• plasma membrane • integral component of plasma membrane
Biological process	• regulation of smooth muscle contraction • G-protein coupled receptor signaling pathway • cell-cell signaling • blood coagulation • negative regulation of norepinephrine secretion • regulation of vasoconstriction • platelet activation • activation of protein kinase B activity • negative regulation of epinephrine secretion • epidermal growth factor-activated receptor transactivation by G-protein coupled receptor signaling pathway • positive regulation of neuron differentiation • activation of MAPK activity by adrenergic receptor signaling pathway
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

151

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 2:
96.11 – 96.12 Mb

Chr 2:
127.36 – 127.37 Mb

PubMed search

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.^[1] ADRA2B orthologs^[2] 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.^[1]

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 without 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.^[2] 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

References

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

Lomasney JW, Lorenz W, Allen LF, King K, Regan JW, Yang-Feng TL, Caron MG, Lefkowitz RJ (Jul 1990). "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. doi:10.1073/pnas.87.13.5094. PMC 54268. PMID 2164221.
McClue SJ, Milligan G (Sep 1990). "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. doi:10.1016/0014-5793(90)81209-7. PMID 2169434.
Weinshank RL, Zgombick JM, Macchi M, Adham N, Lichtblau H, Branchek TA, Hartig PR (Nov 1990). "Cloning, expression, and pharmacological characterization of a human alpha 2B-adrenergic receptor". Molecular Pharmacology 38 (5): 681–8. PMID 2172775.
Chang AC, Ho TF, Chang NC (Oct 1990). "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. doi:10.1016/0006-291X(90)90748-C. PMID 2173582.
Regan JW, Kobilka TS, Yang-Feng TL, Caron MG, Lefkowitz RJ, Kobilka BK (Sep 1988). "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. doi:10.1073/pnas.85.17.6301. PMC 281957. PMID 2842764.
Petrash AC, Bylund DB (Jun 1986). "Alpha-2 adrenergic receptor subtypes indicated by [3H]yohimbine binding in human brain". Life Sciences 38 (23): 2129–37. doi:10.1016/0024-3205(86)90212-2. PMID 3012234.
Klein U, Ramirez MT, Kobilka BK, von Zastrow M (Aug 1997). "A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation factor 2B". The Journal of Biological Chemistry 272 (31): 19099–102. doi:10.1074/jbc.272.31.19099. PMID 9235896.
Okusa MD, Huang L, Momose-Hotokezaka A, Huynh LP, Mangrum AJ (Dec 1997). "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. PMID 9435676.
Prezeau L, Richman JG, Edwards SW, Limbird LE (May 1999). "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. doi:10.1074/jbc.274.19.13462. PMID 10224112.
Heinonen P, Koulu M, Pesonen U, Karvonen MK, Rissanen A, Laakso M, Valve R, Uusitupa M, Scheinin M (Jul 1999). "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. doi:10.1210/jc.84.7.2429. PMID 10404816.
Hein L, Altman JD, Kobilka BK (Nov 1999). "Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission". Nature 402 (6758): 181–4. doi:10.1038/46040. PMID 10647009.
Small KM, Brown KM, Forbes SL, Liggett SB (Feb 2001). "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. doi:10.1074/jbc.M008118200. PMID 11056163.
Snapir A, Mikkelsson J, Perola M, Penttilä A, Scheinin M, Karhunen PJ (Jan 2003). "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. doi:10.1016/S0735-1097(02)02702-X. PMID 12535806.
Sykiotis GP, Polyzogopoulou E, Georgopoulos NA, Trakada G, Spyropoulos K, Kalfarentzos F, Papavassiliou AG, Vagenakis AG, Flordellis CS (Jun 2003). "The alpha2B adrenergic receptor deletion/insertion polymorphism in morbid obesity". Clinical Autonomic Research 13 (3): 203–7. doi:10.1007/s10286-003-0087-5. PMID 12822042.
Chotani MA, Mitra S, Su BY, Flavahan S, Eid AH, Clark KR, Montague CR, Paris H, Handy DE, Flavahan NA (Jan 2004). "Regulation of alpha(2)-adrenoceptors in human vascular smooth muscle cells". American Journal of Physiology. Heart and Circulatory Physiology 286 (1): H59–67. doi:10.1152/ajpheart.00268.2003. PMID 12946937.
Von Wowern F, Bengtsson K, Lindblad U, Råstam L, Melander O (Mar 2004). "Functional variant in the (alpha)2B adrenoceptor gene, a positional candidate on chromosome 2, associates with hypertension". Hypertension 43 (3): 592–7. doi:10.1161/01.HYP.0000116224.51189.80. PMID 14744925.
Cayla C, Heinonen P, Viikari L, Schaak S, Snapir A, Bouloumié A, Karvonen MK, Pesonen U, Scheinin M, Paris H (Feb 2004). "Cloning, characterisation and identification of several polymorphisms in the promoter region of the human alpha2B-adrenergic receptor gene". Biochemical Pharmacology 67 (3): 469–78. doi:10.1016/j.bcp.2003.09.029. PMID 15037199.
Phares DA, Halverstadt AA, Shuldiner AR, Ferrell RE, Douglass LW, Ryan AS, Goldberg AP, Hagberg JM (May 2004). "Association between body fat response to exercise training and multilocus ADR genotypes". Obesity Research 12 (5): 807–15. doi:10.1038/oby.2004.97. PMID 15166301.
Siitonen N, Lindström J, Eriksson J, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Tuomilehto J, Laakso M, Uusitupa M (Aug 2004). "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. doi:10.1007/s00125-004-1462-z. PMID 15309292.
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Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)

Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)

Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Adhesion	ADGRG (1 2 3 4 5 6 7)

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	Calcium-sensing receptor GABA B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F: Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

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