Adenosine A2B receptor

Adenosine A2b receptor

Identifiers

ADORA2B ; ADORA2

External IDs

OMIM: 600446 MGI: 99403 HomoloGene: 20167 IUPHAR: 20 ChEMBL: 255 GeneCards: ADORA2B Gene

Gene ontology
Molecular function	• G-protein coupled adenosine receptor activity
Cellular component	• intracellular • plasma membrane • integral component of plasma membrane
Biological process	• activation of MAPK activity • adenosine receptor signaling pathway • positive regulation of chronic inflammatory response to non-antigenic stimulus • cellular defense response • G-protein coupled receptor signaling pathway • adenylate cyclase-activating G-protein coupled receptor signaling pathway • activation of adenylate cyclase activity • JNK cascade • excretion • positive regulation of vascular endothelial growth factor production • positive regulation of guanylate cyclase activity • cellular response to extracellular stimulus • positive regulation of chemokine production • positive regulation of interleukin-6 production • positive regulation of mast cell degranulation • relaxation of vascular smooth muscle
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

136

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 17:
15.94 – 15.98 Mb

Chr 11:
62.25 – 62.27 Mb

PubMed search

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]

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:^[18] antagonist, high affinity and good subtype selectivity
ATL-801
CVT-6883
MRS-1706
MRS-1754
OSIP-339,391
PSB-603
PSB-0788
PSB-1115

References

1 2 "Entrez Gene: ADORA2B adenosine A2b receptor".
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

External links

"Adenosine Receptors: A_2B". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

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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.
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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.
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. 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.
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.
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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.
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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

Purinergics

Receptor
(ligands)

P0
(adenine)

Agonists: 8-Aminoadenine
Adenine

P1
(adenosine)

Agonists: 2-(1-Hexynyl)-N-methyladenosine
2-Cl-IB-MECA
2'-MeCCPA
4'-O-β-D-Glucosyl-9-O-(6''-deoxysaccharosyl)olivil
5'-N-ethylcarboxamidoadenosine
Adenosine
ADP
AMP
Apadenoson
ATL-146e
ATP
BAY 60–6583
Binodenoson
Capadenoson
CCPA
CGS-21680
CP-532,903
Evodenoson
GR 79236
LUF-5835
LUF-5845
N⁶-Cyclopentyladenosine
Neladenoson dalanate
Piclidenoson
Regadenoson
SDZ WAG 994
Selodenoson
Sonedenoson
Tecadenoson
UK-432,097

P2
(nucleotide)

P2X (ATP)	Agonists: 2-Me-SATP α,β-Me-ATP Adenosine ADP AMP Ap4A Ap5A ATP ATPγS BzATP Cibacron blue CTP D-β,γ-Me-ATP GTP HT-AMP Ivermectin L-β,γ-Me-ATP MRS-2219 PAPET-ATP UTP Zinc Antagonists: 5-BDBD A-317491 A-438079 A-740003 A-804598 A-839977 AF-353 AZ-10606120 AZ-11645373 BBG Calcium Calmidazolium Chelerythrine Copper Emodin (Rheum officinale) Evans Blue GW-791343 HMA Ip5I isoPPADS JNJ-47965567 KN-04 KN-62 Magnesium MRS-2159 NF-023 NF-110 NF-157 NF-279 NF-449 Oxidized-ATP Phenol Red Phenolphthalein PPADS PPNDS PSB-12062 Puerarin (Radix puerariae) Purotoxin 1 RB-2 Ro 0437626 Ro 51 RO-3 Sodium ferulate (Angelica sinensis, Ligusticum wallichii) Suramin TC-P 262 Tetramethylpyrazine (ligustrazine) (Ligusticum wallichii) TNP-ATP Zinc

P2Y	Agonists: 2-Me-SADP 2-Me-SATP 2-Thio-UTP 5-Br-UDP 5-OMe-UDP α,β-Me-ATP Adenosine ADP ADPβS Ap3A AR-C 67085MX ATP ATPγS CTP dATP Denufosol Diquafosol IDP ITP INS-365 INS-37217 MRS-2365 MRS-2690 MRS-2693 MRS-2768 MRS-2957 MRS-4062 NF-546 PAPET-ATP PSB-0474 PSB-1114 UDP UDPβS UDP-galactose UDP-glucose UDP-N-acetylglucosamine Up3U UTP UTPγS Antagonists: 2-Me-SAMP A3P5PS AMPαS Ap4A AR-C 66096 AR-C 67085MX AR-C 69931MX AR-C 118925XX ATP BzATP C1330-7 Cangrelor Clopidrogel Elinogrel Ip5I MRS-2179 MRS-2211 MRS-2279 MRS-2395 MRS-2500 MRS-2578 NF-157 NF-340 PIT PPADS Prasugrel PSB-0739 RB-2 Regrelor Suramin Ticagrelor Ticlopidine UDP

Transporter
(blockers)

CNTs	6-Hydroxy-7-methoxyflavone Adenosine dMeThPmR Estradiol KGO-2142 KGO-2173 MeThPmR Phloridzin Progesterone

ENTs	Barbiturates Benzodiazepines Cilostazol Dilazep Dipyridamole Estradiol Ethanol Hexobendine NBMPR Pentoxifylline Progesterone Propentofylline

PMAT	Decynium-22

Enzyme
(inhibitors)

XO	Allopurinol Amflutizole Benzbromarone Caffeic acid Cinnamaldehyde Cinnamomum osmophloeum Febuxostat Myo-inositol Kaempferol Myricetin Niraxostat Oxypurinol Phytic acid Pistacia integerrima Propolis Quercetin Tisopurine Topiroxostat

Others	Aminopterin Azathioprine Methotrexate Mycophenolic acid Pemetrexed Pralatrexate Many others

Others

Others: Chrysophanol (rhubarb)

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