Adenosine A3 receptor

Adenosine A3 receptor
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1OEA​, 1R7N​
Identifiers
Symbols	ADORA3 ; A3AR
External IDs	OMIM: 600445 MGI: 104847 HomoloGene: 550 IUPHAR: 21 ChEMBL: 256 GeneCards: ADORA3 Gene
Gene ontology Molecular function • G-protein coupled adenosine receptor activity Cellular component • plasma membrane • integral component of membrane Biological process • adenosine receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	140	11542
Ensembl	ENSG00000282608	ENSMUSG00000000562
UniProt	P0DMS8	Q3U4C5
RefSeq (mRNA)	NM_000677	NM_009631
RefSeq (protein)	NP_000668	NP_033761
Location (UCSC)	Chr 1: 111.5 – 111.5 Mb	Chr 3: 105.87 – 105.91 Mb
PubMed search

The adenosine A₃ receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it.

Function

Adenosine A₃ receptors are G protein-coupled receptors that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions. It mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death. Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potencial in bronchial asthma (17,18).

Gene

Multiple transcript variants encoding different isoforms have been found for this gene.^[1]

Therapeutic implications

An adenosine A₃ receptor agonist (CF-101) is in clinical trials for the treatment of rheumatoid arthritis.^[2] In a mouse model of infarction the A₃ selective agonist CP-532,903 protected against myocardial ischemia and reperfusion injury.^[3]

Selective Ligands

A number of selective A₃ ligands are available.^{[4][5][6][7][8][9][10][11][12][13][14][15]}

Agonists/Positive Allosteric Modulators

• 2-(1-Hexynyl)-N-methyladenosine
• CF-101 (IB-MECA)
• CF-102
• 2-Cl-IB-MECA
• CP-532,903
• Inosine^[16]
• LUF-6000
• MRS-3558

Antagonists/Negative Allosteric Modulators

• KF-26777
• MRS-545
• MRS-1191
• MRS-1220
• MRS-1334
• MRS-1523
• MRS-3777
• MRE-3005-F20
• MRE-3008-F20
• PSB-11
• OT-7999
• VUF-5574
• SSR161421^[17][18]

Inverse Agonists

• PSB-10

References

1. "Entrez Gene: ADORA3 adenosine A3 receptor".
2. Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P (January 2008). "Clinical evidence for utilization of the A₃ adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial". J. Rheumatol. 35 (1): 41–8. PMID 18050382.
3. Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, Gross GJ, Kwok WM, Auchampach JA (January 2008). "The A3 adenosine receptor agonist CP-532,903 protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP sensitive potassium channel". J. Pharmacol. Exp. Ther. 324 (1): 234–43. doi:10.1124/jpet.107.127480. PMC 2435594. PMID 17906066.
4. Jeong LS, Lee HW, Jacobson KA, Lee SK, Chun MW (2005). "Development of potent and selective human A3 adenosine receptor agonists". Nucleic Acids Symposium Series (2004) 49 (49): 31–2. doi:10.1093/nass/49.1.31. PMID 17150618.
5. 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.
6. Kim SK, Gao ZG, Jeong LS, Jacobson KA (December 2006). "Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor". Journal of Molecular Graphics & Modelling 25 (4): 562–77. doi:10.1016/j.jmgm.2006.05.004. PMID 16793299.
7. Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (December 2006). "Cl-IB-MECA Reduces Ischemia/Reperfusion Injury in Mice by Activating the A3 Adenosine Receptor". The Journal of Pharmacology and Experimental Therapeutics 319 (3): 1200–10. doi:10.1124/jpet.106.111351. PMC 2430759. PMID 16985166.
8. Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V, Sheehan MJ, Reeves J, Wilson DJ (June 2007). "Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A(2A) receptor agonist and adenosine A(3) receptor antagonist activity". European Journal of Pharmacology 564 (1-3): 219–25. doi:10.1016/j.ejphar.2007.01.094. PMID 17382926.
9. Priego EM, Pérez-Pérez MJ, von Frijtag Drabbe Kuenzel JK, de Vries H, Ijzerman AP, Camarasa MJ, Martín-Santamaría S (January 2008). "Selective human adenosine A3 antagonists based on pyrido[2,1-f]purine-2,4-diones: novel features of hA3 antagonist binding". ChemMedChem 3 (1): 111–9. doi:10.1002/cmdc.200700173. PMID 18000937.
10. Jeong LS, Lee HW, Kim HO, Tosh DK, Pal S, Choi WJ, Gao ZG, Patel AR, Williams W, Jacobson KA, Kim HD (March 2008). "Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists". Bioorganic & Medicinal Chemistry Letters 18 (5): 1612–6. doi:10.1016/j.bmcl.2008.01.070. PMID 18255292.
11. Cordeaux Y, Briddon SJ, Alexander SP, Kellam B, Hill SJ (March 2008). "Agonist-occupied A3 adenosine receptors exist within heterogeneous complexes in membrane microdomains of individual living cells". The FASEB Journal 22 (3): 850–60. doi:10.1096/fj.07-8180com. PMID 17959910.
12. Gao ZG, Jacobson KA (April 2008). "Translocation of Arrestin Induced by Human A3 Adenosine Receptor Ligands in an Engineered Cell Line: Comparison with G Protein-dependent Pathways". Pharmacological Research : the Official Journal of the Italian Pharmacological Society 57 (4): 303–11. doi:10.1016/j.phrs.2008.02.008. PMC 2409065. PMID 18424164.
13. Miwatashi S, Arikawa Y, Matsumoto T, Uga K, Kanzaki N, Imai YN, Ohkawa S (August 2008). "Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists". Chemical & Pharmaceutical Bulletin 56 (8): 1126–37. doi:10.1248/cpb.56.1126. PMID 18670113.
14. Gao ZG, Ye K, Göblyös A, Ijzerman AP, Jacobson KA (2008). "Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000". BMC Pharmacology 8: 20. doi:10.1186/1471-2210-8-20. PMC 2625337. PMID 19077268.
15. Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, Perez-Liz G, Del Valle L, Fishman P (August 2008). "The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways". International Journal of Oncology 33 (2): 287–95. PMID 18636149.
16. Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"
17. Mikus EG, Szeredi J, Boer K, Tímári G, Finet M, Aranyi P, Galzin AM (December 2012). "Evaluation of SSR161421, a novel orally active adenosine A(3) receptor antagonist on pharmacology models". Eur. J. Pharmacol. 699 (1-3): 172–179. doi:10.1016/j.ejphar.2012.11.049. PMID 23219796.
18. Mikus EG, Boér K, Timári G, Urbán-Szabó K, Kapui Z, Szeredi J, Gerber K, Szabó T, Bátori S, Finet M, Arányi P, Galzin AM (December 2012). "Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo". Eur. J. Pharmacol. 699 (1-3): 62–66. doi:10.1016/j.ejphar.2012.11.046. PMID 23219789.

Further reading

• Klotz KN (2001). "Adenosine receptors and their ligands". Naunyn Schmiedebergs Arch. Pharmacol. 362 (4–5): 382–91. doi:10.1007/s002100000315. PMID 11111832.
• Monitto CL, Levitt RC, DiSilvestre D, Holroyd KJ (1995). "Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p". Genomics 26 (3): 637–8. doi:10.1016/0888-7543(95)80194-Q. PMID 7607699.
• Salvatore CA, Jacobson MA, Taylor HE; et al. (1993). "Molecular cloning and characterization of the human A3 adenosine receptor". Proc. Natl. Acad. Sci. U.S.A. 90 (21): 10365–9. doi:10.1073/pnas.90.21.10365. PMC 47775. PMID 8234299.
• Sajjadi FG, Firestein GS (1993). "cDNA cloning and sequence analysis of the human A3 adenosine receptor". Biochim. Biophys. Acta 1179 (1): 105–7. doi:10.1016/0167-4889(93)90077-3. PMID 8399349.
• Murrison EM, Goodson SJ, Edbrooke MR, Harris CA (1996). "Cloning and characterisation of the human adenosine A3 receptor gene". FEBS Lett. 384 (3): 243–6. doi:10.1016/0014-5793(96)00324-9. PMID 8617363.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Bouma MG, Jeunhomme TM, Boyle DL; et al. (1997). "Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors". J. Immunol. 158 (11): 5400–8. PMID 9164961.
• Atkinson MR, Townsend-Nicholson A, Nicholl JK; et al. (1998). "Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene". Neurosci. Res. 29 (1): 73–9. doi:10.1016/S0168-0102(97)00073-4. PMID 9293494.
• Palmer TM, Harris CA, Coote J, Stiles GL (1997). "Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor". Mol. Pharmacol. 52 (4): 632–40. PMID 9380026.
• Liang BT, Jacobson KA (1998). "A physiological role of the adenosine A3 receptor: Sustained cardioprotection". Proc. Natl. Acad. Sci. U.S.A. 95 (12): 6995–9. doi:10.1073/pnas.95.12.6995. PMC 22715. PMID 9618527.
• Dougherty C, Barucha J, Schofield PR; et al. (1999). "Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor". FASEB J. 12 (15): 1785–92. PMID 9837869.
• Murphy WJ, Eizirik E, Johnson WE; et al. (2001). "Molecular phylogenetics and the origins of placental mammals". Nature 409 (6820): 614–8. doi:10.1038/35054550. PMID 11214319.
• Gao ZG, Chen A, Barak D; et al. (2002). "Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor". J. Biol. Chem. 277 (21): 19056–63. doi:10.1074/jbc.M110960200. PMID 11891221.
• Broussas M, Cornillet-Lefèbvre P, Potron G, Nguyên P (2003). "Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor". Thromb. Haemost. 88 (1): 123–30. PMID 12152652.
• Merighi S, Mirandola P, Milani D; et al. (2002). "Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells". J. Invest. Dermatol. 119 (4): 923–33. doi:10.1046/j.1523-1747.2002.00111.x. PMID 12406340.
• Trincavelli ML, Tuscano D, Marroni M; et al. (2002). "A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation". Mol. Pharmacol. 62 (6): 1373–84. doi:10.1124/mol.62.6.1373. PMID 12435805.
• 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". Proc. Natl. Acad. Sci. U.S.A. 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.
• Gao ZG, Kim SK, Gross AS; et al. (2003). "Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor". Mol. Pharmacol. 63 (5): 1021–31. doi:10.1124/mol.63.5.1021. PMID 12695530.

External links

• "Adenosine Receptors: A₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.