Adenosine A2B receptor explained

The adenosine A_2B receptor, also known as ADORA2B, is a G-protein coupled adenosine receptor, and also denotes the human adenosine A_2b receptor gene which encodes it.^[1]

Mechanism

This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation.

Gene

The gene is located near the Smith-Magenis syndrome region on chromosome 17.^[1]

Ligands

Research into selective A_2B ligands has lagged somewhat behind the development of ligands for the other three adenosine receptor subtypes, but a number of A_2B-selective compounds have now been developed,^{[2] [3] [4] [5] [6] [7] [8] [9] [10] [11]} and research into their potential therapeutic applications is ongoing.^{[12] [13] [14] [15] [16] [17] [18]}

Agonists

• BAY 60-6583
• NECA (N-ethylcarboxamidoadenosine)
• (S)-PHPNECA - high affinity and efficacy at A_2B, but poor selectivity over other adenosine receptor subtypes
• LUF-5835
• LUF-5845 - partial agonist

Antagonists and inverse agonists

• Compound 38:^[19] antagonist, high affinity and good subtype selectivity
• ISAM-R56A:^[18] non-xanthinic high affinity selective antagonist (K_i: 1.50 nM)
• ISAM-140:^[20] non-xanthinic selective antagonist (K_i = 3.49 nM).
• ISAM-R324A:^[21] Soluble and metabolically stable non-xanthinic selective antagonist (K_i = 6.10 nM).
• ATL-801
• CVT-6883
• MRS-1706
• MRS-1754
• OSIP-339,391
• PSB-603: xanthinic antagonist
• PSB-0788: xanthinic antagonist
• PSB-1115: xanthinic antagonist
• PSB-1901:^[22] xanthinic antagonist with picomolar potency

Further reading

• Stiles GL . Adenosine receptors . The Journal of Biological Chemistry . 267 . 10 . 6451–6454 . April 1992 . 1551861 . 10.1016/S0021-9258(19)50445-8 . free .
• Pierce KD, Furlong TJ, Selbie LA, Shine J . Molecular cloning and expression of an adenosine A2b receptor from human brain . Biochemical and Biophysical Research Communications . 187 . 1 . 86–93 . August 1992 . 1325798 . 10.1016/S0006-291X(05)81462-7 .
• Li Q, Han X, Lan X, Hong X, Li Q, Gao Y, Luo T, Yang Q, Koehler RC, Zhai Y, Zhou J, Wang J . 6 . Inhibition of tPA-induced hemorrhagic transformation involves adenosine A2b receptor activation after cerebral ischemia . Neurobiology of Disease . 108 . 173–182 . December 2017 . 28830843 . 5675803 . 10.1016/j.nbd.2017.08.011 .
• Jacobson MA, Johnson RG, Luneau CJ, Salvatore CA . Cloning and chromosomal localization of the human A2b adenosine receptor gene (ADORA2B) and its pseudogene . Genomics . 27 . 2 . 374–376 . May 1995 . 7558011 . 10.1006/geno.1995.1061 .
• Townsend-Nicholson A, Baker E, Sutherland GR, Schofield PR . Localization of the adenosine A2b receptor subtype gene (ADORA2B) to chromosome 17p11.2-p12 by FISH and PCR screening of somatic cell hybrids . Genomics . 25 . 2 . 605–607 . January 1995 . 7790006 . 10.1016/0888-7543(95)80074-V . Grant Robert Sutherland .
• Strohmeier GR, Reppert SM, Lencer WI, Madara JL . The A2b adenosine receptor mediates cAMP responses to adenosine receptor agonists in human intestinal epithelia . The Journal of Biological Chemistry . 270 . 5 . 2387–2394 . February 1995 . 7836474 . 10.1074/jbc.270.5.2387 . free .
• Feoktistov I, Murray JJ, Biaggioni I . Positive modulation of intracellular Ca2+ levels by adenosine A2b receptors, prostacyclin, and prostaglandin E1 via a cholera toxin-sensitive mechanism in human erythroleukemia cells . Molecular Pharmacology . 45 . 6 . 1160–1167 . June 1994 . 8022409 .
• Mirabet M, Herrera C, Cordero OJ, Mallol J, Lluis C, Franco R . Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation . Journal of Cell Science . 112 (Pt 4) . 4 . 491–502 . February 1999 . 9914161 . 10.1242/jcs.112.4.491 .
• Feoktistov I, Goldstein AE, Biaggioni I . Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells . Molecular Pharmacology . 55 . 4 . 726–734 . April 1999 . 10101031 .
• Corset V, Nguyen-Ba-Charvet KT, Forcet C, Moyse E, Chédotal A, Mehlen P . Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor . Nature . 407 . 6805 . 747–750 . October 2000 . 11048721 . 10.1038/35037600 . 4423128 . 2000Natur.407..747C .
• Herrera C, Casadó V, Ciruela F, Schofield P, Mallol J, Lluis C, Franco R . Adenosine A2B receptors behave as an alternative anchoring protein for cell surface adenosine deaminase in lymphocytes and cultured cells . Molecular Pharmacology . 59 . 1 . 127–134 . January 2001 . 11125033 . 10.1124/mol.59.1.127 .
• Christofi FL, Zhang H, Yu JG, Guzman J, Xue J, Kim M, Wang YZ, Cooke HJ . 6 . Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system . The Journal of Comparative Neurology . 439 . 1 . 46–64 . October 2001 . 11579381 . 10.1002/cne.1334 . 46222306 .
• Hayallah AM, Sandoval-Ramírez J, Reith U, Schobert U, Preiss B, Schumacher B, Daly JW, Müller CE . 6 . 1,8-disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists . Journal of Medicinal Chemistry . 45 . 7 . 1500–1510 . March 2002 . 11906291 . 10.1021/jm011049y .
• Sitaraman SV, Wang L, Wong M, Bruewer M, Hobert M, Yun CH, Merlin D, Madara JL . 6 . The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation . The Journal of Biological Chemistry . 277 . 36 . 33188–33195 . September 2002 . 12080047 . 10.1074/jbc.M202522200 . free .
• Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I . Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors . Circulation Research . 92 . 5 . 485–492 . March 2003 . 12600879 . 10.1161/01.RES.0000061572.10929.2D . 10346424 .
• Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K, Robson SC, Colgan SP . 6 . Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors . The Journal of Experimental Medicine . 198 . 5 . 783–796 . September 2003 . 12939345 . 2194189 . 10.1084/jem.20030891 .
• Ryzhov S, Goldstein AE, Matafonov A, Zeng D, Biaggioni I, Feoktistov I . Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma . Journal of Immunology . 172 . 12 . 7726–7733 . June 2004 . 15187156 . 10.4049/jimmunol.172.12.7726 . free .
• Kolachala V, Asamoah V, Wang L, Srinivasan S, Merlin D, Sitaraman SV . Interferon-gamma down-regulates adenosine 2b receptor-mediated signaling and short circuit current in the intestinal epithelia by inhibiting the expression of adenylate cyclase . The Journal of Biological Chemistry . 280 . 6 . 4048–4057 . February 2005 . 15550390 . 10.1074/jbc.M409577200 . free .

External links

• Web site: Adenosine Receptors: A_2B . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-11-25 . 2016-03-03 . https://web.archive.org/web/20160303165806/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2170 . dead .

Notes and References

1. Web site: Entrez Gene: ADORA2B adenosine A2b receptor.
2. Volpini R, Costanzi S, Lambertucci C, Taffi S, Vittori S, Klotz KN, Cristalli G . N(6)-alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A(3) receptor and a starting point for searching A(2B) ligands . Journal of Medicinal Chemistry . 45 . 15 . 3271–3279 . July 2002 . 12109910 . 10.1021/jm0109762 .
3. Volpini R, Costanzi S, Lambertucci C, Vittori S, Cristalli G . Purine nucleosides bearing 1-alkynyl chains as adenosine receptor agonists . Current Pharmaceutical Design . 8 . 26 . 2285–2298 . 2002 . 12369946 . 10.2174/1381612023392856 . dead . https://archive.today/20130414131152/http://www.bentham-direct.org/pages/content.php?CPD/2002/00000008/00000026/0002B.SGM . 2013-04-14 .
4. Baraldi PG, Tabrizi MA, Preti D, Bovero A, Romagnoli R, Fruttarolo F, Zaid NA, Moorman AR, Varani K, Gessi S, Merighi S, Borea PA . 6 . Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists . Journal of Medicinal Chemistry . 47 . 6 . 1434–1447 . March 2004 . 14998332 . 10.1021/jm0309654 .
5. Cacciari B, Pastorin G, Bolcato C, Spalluto G, Bacilieri M, Moro S . A2B adenosine receptor antagonists: recent developments . Mini Reviews in Medicinal Chemistry . 5 . 12 . 1053–1060 . December 2005 . 16375751 . 10.2174/138955705774933374 . dead . https://archive.today/20130414141112/http://www.bentham-direct.org/pages/content.php?MRMC/2005/00000005/00000012/0001N.SGM . 2013-04-14 .
6. Baraldi PG, Romagnoli R, Preti D, Fruttarolo F, Carrion MD, Tabrizi MA . Ligands for A2B adenosine receptor subtype . Current Medicinal Chemistry . 13 . 28 . 3467–3482 . 2006 . 17168717 . 10.2174/092986706779010306 . dead . https://archive.today/20130414075418/http://www.bentham-direct.org/pages/content.php?CMC/2006/00000013/00000028/0008C.SGM . 2013-04-14 .
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10. Tabrizi MA, Baraldi PG, Preti D, Romagnoli R, Saponaro G, Baraldi S, Moorman AR, Zaid AN, Varani K, Borea PA . 6 . 1,3-Dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives as highly potent and selective human A(2B) adenosine receptor antagonists . Bioorganic & Medicinal Chemistry . 16 . 5 . 2419–2430 . March 2008 . 18077171 . 10.1016/j.bmc.2007.11.058 .
11. Stefanachi A, Brea JM, Cadavid MI, Centeno NB, Esteve C, Loza MI, Martinez A, Nieto R, Raviña E, Sanz F, Segarra V, Sotelo E, Vidal B, Carotti A . 6 . 1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor . Bioorganic & Medicinal Chemistry . 16 . 6 . 2852–2869 . March 2008 . 18226909 . 10.1016/j.bmc.2008.01.002 .
12. Volpini R, Costanzi S, Vittori S, Cristalli G, Klotz KN . Medicinal chemistry and pharmacology of A2B adenosine receptors . Current Topics in Medicinal Chemistry . 3 . 4 . 427–443 . 2003 . 12570760 . 10.2174/1568026033392264 . dead . https://archive.today/20130414065741/http://www.bentham-direct.org/pages/content.php?CTMC/2003/00000003/00000004/0007R.SGM . 2013-04-14 .
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