Adenosine A_2B receptor

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.[5]

ADORA2B
Identifiers
Aliases	ADORA2B, ADORA2, adenosine A2b receptor
External IDs	OMIM: 600446 MGI: 99403 HomoloGene: 20167 GeneCards: ADORA2B
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17p12 Start 15,944,917 bp[1] End 15,975,746 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B2 Start 62,248,984 bp[2] End 62,266,453 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • G-protein coupled adenosine receptor activity • G-protein coupled receptor activity • signal transducer activity Cellular component • integral component of membrane • membrane • cell membrane • integral component of plasma membrane • intracellular • synapse • Schaffer collateral - CA1 synapse • glutamatergic synapse Biological process • cellular response to extracellular stimulus • cellular protein metabolic process • positive regulation of chronic inflammatory response to non-antigenic stimulus • G-protein coupled receptor signaling pathway • adenosine receptor signaling pathway • excretion • positive regulation of guanylate cyclase activity • adenylate cyclase-activating G-protein coupled receptor signaling pathway • positive regulation of mast cell degranulation • activation of adenylate cyclase activity • cellular defense response • JNK cascade • activation of MAPK activity • positive regulation of interleukin-6 production • relaxation of vascular smooth muscle • positive regulation of chemokine production • positive regulation of vascular endothelial growth factor production • signal transduction • positive regulation of cGMP-mediated signaling • regulation of synaptic vesicle exocytosis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	136	11541
Ensembl	ENSG00000170425	ENSMUSG00000018500
UniProt	P29275	Q60614
RefSeq (mRNA)	NM_000676	NM_007413
RefSeq (protein)	NP_000667	NP_031439
Location (UCSC)	Chr 17: 15.94 – 15.98 Mb	Chr 11: 62.25 – 62.27 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5]

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,[6][7][8][9][10][11][12][13][14][15] and research into their potential therapeutic applications is ongoing.[16][17][18][19][20][21]

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:[22] antagonist, high affinity and good subtype selectivity
• ATL-801
• CVT-6883
• MRS-1706
• MRS-1754
• OSIP-339,391
• PSB-603
• PSB-0788
• PSB-1115
• PSB-1901:[23] antagonist with picomolar potency

References

1. GRCh38: Ensembl release 89: ENSG00000170425 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000018500 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: ADORA2B adenosine A2b receptor".
6. Volpini R, Costanzi S, Lambertucci C, Taffi S, Vittori S, Klotz KN, Cristalli G (July 2002). "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): 3271–9. doi:10.1021/jm0109762. PMID 12109910.
7. Volpini R, Costanzi S, Lambertucci C, Vittori S, Cristalli G (2002). "Purine nucleosides bearing 1-alkynyl chains as adenosine receptor agonists". Current Pharmaceutical Design. 8 (26): 2285–98. doi:10.2174/1381612023392856. PMID 12369946. Archived from the original on 2013-04-14.
8. Baraldi PG, Tabrizi MA, Preti D, Bovero A, Romagnoli R, Fruttarolo F, Zaid NA, Moorman AR, Varani K, Gessi S, Merighi S, Borea PA (March 2004). "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): 1434–47. doi:10.1021/jm0309654. PMID 14998332.
9. Cacciari B, Pastorin G, Bolcato C, Spalluto G, Bacilieri M, Moro S (December 2005). "A2B adenosine receptor antagonists: recent developments". Mini Reviews in Medicinal Chemistry. 5 (12): 1053–60. doi:10.2174/138955705774933374. PMID 16375751. Archived from the original on 2013-04-14.
10. Baraldi PG, Romagnoli R, Preti D, Fruttarolo F, Carrion MD, Tabrizi MA (2006). "Ligands for A2B adenosine receptor subtype". Current Medicinal Chemistry. 13 (28): 3467–82. doi:10.2174/092986706779010306. PMID 17168717. Archived from the original on 2013-04-14.
11. Beukers MW, Meurs I, Ijzerman AP (September 2006). "Structure-affinity relationships of adenosine A2B receptor ligands". Medicinal Research Reviews. 26 (5): 667–98. doi:10.1002/med.20069. PMID 16847822. S2CID 24390495.
12. Elzein E, Kalla R, Li X, Perry T, Parkhill E, Palle V, Varkhedkar V, Gimbel A, Zeng D, Lustig D, Leung K, Zablocki J (January 2006). "Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 16 (2): 302–6. doi:10.1016/j.bmcl.2005.10.002. PMID 16275090.
13. Carotti A, Cadavid MI, Centeno NB, Esteve C, Loza MI, Martinez A, Nieto R, Raviña E, Sanz F, Segarra V, Sotelo E, Stefanachi A, Vidal B (January 2006). "Design, synthesis, and structure-activity relationships of 1-,3-,8-, and 9-substituted-9-deazaxanthines at the human A2B adenosine receptor". Journal of Medicinal Chemistry. 49 (1): 282–99. doi:10.1021/jm0506221. PMID 16392813.
14. Tabrizi MA, Baraldi PG, Preti D, Romagnoli R, Saponaro G, Baraldi S, Moorman AR, Zaid AN, Varani K, Borea PA (March 2008). "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): 2419–30. doi:10.1016/j.bmc.2007.11.058. PMID 18077171.
15. 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 (March 2008). "1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor". Bioorganic & Medicinal Chemistry. 16 (6): 2852–69. doi:10.1016/j.bmc.2008.01.002. PMID 18226909.
16. Volpini R, Costanzi S, Vittori S, Cristalli G, Klotz KN (2003). "Medicinal chemistry and pharmacology of A2B adenosine receptors". Current Topics in Medicinal Chemistry. 3 (4): 427–43. doi:10.2174/1568026033392264. PMID 12570760. Archived from the original on 2013-04-14.
17. Gao ZG, Jacobson KA (September 2007). "Emerging adenosine receptor agonists". Expert Opinion on Emerging Drugs. 12 (3): 479–92. doi:10.1517/14728214.12.3.479. PMID 17874974. S2CID 13777846.
18. Kolachala V, Ruble B, Vijay-Kumar M, Wang L, Mwangi S, Figler H, Figler R, Srinivasan S, Gewirtz A, Linden J, Merlin D, Sitaraman S (September 2008). "Blockade of adenosine A2B receptors ameliorates murine colitis". British Journal of Pharmacology. 155 (1): 127–37. doi:10.1038/bjp.2008.227. PMC 2440087. PMID 18536750.
19. Haskó G, Linden J, Cronstein B, Pacher P (September 2008). "Adenosine receptors: therapeutic aspects for inflammatory and immune diseases". Nature Reviews Drug Discovery. 7 (9): 759–70. doi:10.1038/nrd2638. PMC 2568887. PMID 18758473.
20. Ham J, Rees DA (December 2008). "The adenosine a2b receptor: its role in inflammation". Endocrine, Metabolic & Immune Disorders Drug Targets. 8 (4): 244–54. doi:10.2174/187153008786848303. PMID 19075778. Archived from the original on 2013-04-14.
21. Kim MO, Kim MH, Lee SH, Suh HN, Lee YJ, Lee MY, Han HJ (June 2009). "5'-N-ethylcarboxamide induces IL-6 expression via MAPKs and NF-kappaB activation through Akt, Ca(2+)/PKC, cAMP signaling pathways in mouse embryonic stem cells". Journal of Cellular Physiology. 219 (3): 752–9. doi:10.1002/jcp.21721. PMID 19194991. S2CID 11066973.
22. Stefanachi A, Nicolotti O, Leonetti F, et al. (2008). "1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines as potent A(2B) adenosine receptor antagonists: Design, synthesis, structure-affinity and structure-selectivity relationships". Bioorganic & Medicinal Chemistry. 16 (22): 9780–9. doi:10.1016/j.bmc.2008.09.067. PMID 18938084.
23. Jiang J, Seel CJ, Temirak A, Namasivayam V, Arridu A, Schabikowski J, Baqi Y, Hinz S, Hockemeyer J, Müller CE (2019). "A2B Adenosine Receptor Antagonists with Picomolar Potency". Journal of Medicinal Chemistry. 62 (8): 4032–4055. doi:10.1021/acs.jmedchem.9b00071. PMID 30835463.

Further reading

• Stiles GL (1992). "Adenosine receptors". J. Biol. Chem. 267 (10): 6451–4. PMID 1551861.
• Pierce KD, Furlong TJ, Selbie LA, Shine J (1992). "Molecular cloning and expression of an adenosine A2b receptor from human brain". Biochem. Biophys. Res. Commun. 187 (1): 86–93. doi:10.1016/S0006-291X(05)81462-7. PMID 1325798.
• Li Q, Han X, Lan X, Hong X, Li Q, Gao Y, Luo T, Yang Q, Koehler RC, Zhai Y, Zhou J, Wang J (2017). "Inhibition of tPA-induced hemorrhagic transformation involves adenosine A2b receptor activation after cerebral ischemia". Neurobiology of Disease. 108: 173–182. doi:10.1016/j.nbd.2017.08.011. PMC 5675803. PMID 28830843.
• Jacobson MA, Johnson RG, Luneau CJ, Salvatore CA (1995). "Cloning and chromosomal localization of the human A2b adenosine receptor gene (ADORA2B) and its pseudogene". Genomics. 27 (2): 374–6. doi:10.1006/geno.1995.1061. PMID 7558011.
• Townsend-Nicholson A, Baker E, Sutherland GR, Schofield PR (1995). "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): 605–7. doi:10.1016/0888-7543(95)80074-V. PMID 7790006.
• Strohmeier GR, Reppert SM, Lencer WI, Madara JL (1995). "The A2b adenosine receptor mediates cAMP responses to adenosine receptor agonists in human intestinal epithelia". J. Biol. Chem. 270 (5): 2387–94. doi:10.1074/jbc.270.5.2387. PMID 7836474.
• Feoktistov I, Murray JJ, Biaggioni I (1994). "Positive modulation of intracellular Ca2+ levels by adenosine A2b receptors, prostacyclin, and prostaglandin E1 via a cholera toxin-sensitive mechanism in human erythroleukemia cells". Mol. Pharmacol. 45 (6): 1160–7. PMID 8022409.
• Mirabet M, Herrera C, Cordero OJ, et al. (1999). "Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation". J. Cell Sci. 112 (4): 491–502. PMID 9914161.
• Feoktistov I, Goldstein AE, Biaggioni I (1999). "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". Mol. Pharmacol. 55 (4): 726–34. PMID 10101031.
• Corset V, Nguyen-Ba-Charvet KT, Forcet C, et al. (2000). "Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor". Nature. 407 (6805): 747–50. doi:10.1038/35037600. PMID 11048721. S2CID 4423128.
• Herrera C, Casadó V, Ciruela F, et al. (2001). "Adenosine A2B receptors behave as an alternative anchoring protein for cell surface adenosine deaminase in lymphocytes and cultured cells". Mol. Pharmacol. 59 (1): 127–34. doi:10.1124/mol.59.1.127. PMID 11125033.
• Christofi FL, Zhang H, Yu JG, et al. (2001). "Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system". J. Comp. Neurol. 439 (1): 46–64. doi:10.1002/cne.1334. PMID 11579381. S2CID 46222306.
• Hayallah AM, Sandoval-Ramírez J, Reith U, et al. (2002). "1,8-disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists". J. Med. Chem. 45 (7): 1500–10. doi:10.1021/jm011049y. PMID 11906291.
• Sitaraman SV, Wang L, Wong M, et al. (2002). "The adenosine 2b receptor is recruited to the plasma membrane and associates with E3KARP and Ezrin upon agonist stimulation". J. Biol. Chem. 277 (36): 33188–95. doi:10.1074/jbc.M202522200. PMID 12080047.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I (2003). "Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors". Circ. Res. 92 (5): 485–92. doi:10.1161/01.RES.0000061572.10929.2D. PMID 12600879.
• Eltzschig HK, Ibla JC, Furuta GT, et al. (2003). "Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors". J. Exp. Med. 198 (5): 783–96. doi:10.1084/jem.20030891. PMC 2194189. PMID 12939345.
• Ryzhov S, Goldstein AE, Matafonov A, et al. (2004). "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". J. Immunol. 172 (12): 7726–33. doi:10.4049/jimmunol.172.12.7726. PMID 15187156.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Kolachala V, Asamoah V, Wang L, et al. (2005). "Interferon-gamma down-regulates adenosine 2b receptor-mediated signaling and short circuit current in the intestinal epithelia by inhibiting the expression of adenylate cyclase". J. Biol. Chem. 280 (6): 4048–57. doi:10.1074/jbc.M409577200. PMID 15550390.

External links

• "Adenosine Receptors: A_2B". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Human ADORA2B genome location and ADORA2B gene details page in the UCSC Genome Browser.