Adenosine A3 receptor

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

ADORA3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OEA, 1R7N
Identifiers
Aliases	ADORA3, A3AR, AD026, bA552M11.5, adenosine A3 receptor
External IDs	OMIM: 600445; MGI: 104847; HomoloGene: 550; GeneCards: ADORA3; OMA:ADORA3 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p13.2 Start 111,499,429 bp[1] End 111,503,633 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 F2.2|3 46.45 cM Start 105,778,174 bp[2] End 105,816,242 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in C1 segment right adrenal cortex left adrenal gland left adrenal cortex inferior ganglion of vagus nerve mucosa of transverse colon substantia nigra Descending thoracic aorta gallbladder internal globus pallidus Top expressed in granulocyte spermatid embryo red pulp morula blastocyst lip dermis dentate gyrus of hippocampal formation granule cell superior frontal gyrus More reference expression data BioGPS 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 plasma membrane membrane integral component of plasma membrane Biological process G protein-coupled adenosine receptor signaling pathway inflammatory response signal transduction activation of adenylate cyclase activity regulation of heart contraction response to wounding negative regulation of cell population proliferation negative regulation of cell migration negative regulation of NF-kappaB transcription factor activity G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 140 11542 Ensembl ENSG00000282608 ENSMUSG00000000562 UniProt P0DMS8 Q61618 Q3U4C5 RefSeq (mRNA) NM_001302679 NM_000677 NM_001302678 NM_009631 RefSeq (protein) NP_000668 NP_001289607 NP_001289608 NP_033761 Location (UCSC) Chr 1: 111.5 – 111.5 Mb Chr 3: 105.78 – 105.82 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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^{[citation needed]}. Recent publications demonstrate that adenosine A3 receptor antagonists (SSR161421) could have therapeutic potential in bronchial asthma (17,18).

Gene

Multiple transcript variants encoding different isoforms have been found for this gene.^[5]

Therapeutic implications

An adenosine A₃ receptor agonist (CF-101) is in clinical trials for the treatment of rheumatoid arthritis.^[6] In a mouse model of infarction the A₃ selective agonist CP-532,903 protected against myocardial ischemia and reperfusion injury.^[7]

Selective Ligands

A number of selective A₃ ligands are available.^{[8][9][10][11][12][13][14][15][16][17][18][19][20]}

Agonists/Positive Allosteric Modulators

• 2-(1-Hexynyl)-N-methyladenosine
• CF-101 (IB-MECA)
• CF-102
• 2-Cl-IB-MECA
• CP-532,903
• Inosine^[21]
• LUF-6000^[22]
• MRS-3558
• AST-004

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^[23][24]
• ISAM-DM10

Inverse Agonists

• PSB-10

References

1. GRCh38: Ensembl release 89: ENSG00000282608 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000000562 – 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: ADORA3 adenosine A3 receptor".
6. Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, et al. (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". The Journal of Rheumatology. 35 (1): 41–48. PMID 18050382.
7. Wan TC, Ge ZD, Tampo A, Mio Y, Bienengraeber MW, Tracey WR, et al. (January 2008). "The A3 adenosine receptor agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel". The Journal of Pharmacology and Experimental Therapeutics. 324 (1): 234–243. doi:10.1124/jpet.107.127480. PMC 2435594. PMID 17906066.
8. 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. 49 (49): 31–32. doi:10.1093/nass/49.1.31. PMID 17150618.
9. Gao ZG, Jacobson KA (September 2007). "Emerging adenosine receptor agonists". Expert Opinion on Emerging Drugs. 12 (3): 479–492. doi:10.1517/14728214.12.3.479. PMID 17874974. S2CID 13777846.
10. 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): 562–577. doi:10.1016/j.jmgm.2006.05.004. PMC 6262875. PMID 16793299.
11. Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (December 2006). "Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor". The Journal of Pharmacology and Experimental Therapeutics. 319 (3): 1200–1210. doi:10.1124/jpet.106.111351. PMC 2430759. PMID 16985166.
12. Bevan N, Butchers PR, Cousins R, Coates J, Edgar EV, Morrison V, et al. (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): 219–225. doi:10.1016/j.ejphar.2007.01.094. PMID 17382926.
13. 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): 111–119. doi:10.1002/cmdc.200700173. hdl:10261/82277. PMID 18000937. S2CID 7128294.
14. Jeong LS, Lee HW, Kim HO, Tosh DK, Pal S, Choi WJ, et al. (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): 1612–1616. doi:10.1016/j.bmcl.2008.01.070. PMC 8611656. PMID 18255292.
15. 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". FASEB Journal. 22 (3): 850–860. doi:10.1096/fj.07-8180com. PMID 17959910. S2CID 10705640.
16. Gao ZG, Jacobson KA (April 2008). "Translocation of arrestin induced by human A(3) adenosine receptor ligands in an engineered cell line: comparison with G protein-dependent pathways". Pharmacological Research. 57 (4): 303–311. doi:10.1016/j.phrs.2008.02.008. PMC 2409065. PMID 18424164.
17. 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): 1126–1137. doi:10.1248/cpb.56.1126. PMID 18670113.
18. Gao ZG, Ye K, Göblyös A, Ijzerman AP, Jacobson KA (December 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.
19. Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, et al. (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): 287–295. doi:10.3892/ijo_00000008. PMID 18636149.
20. Miranda-Pastoriza D, Bernárdez R, Azuaje J, Prieto-Díaz R, Majellaro M, Tamhankar AV, et al. (February 2022). "Exploring Non-orthosteric Interactions with a Series of Potent and Selective A₃ Antagonists". ACS Medicinal Chemistry Letters. 13 (2): 243–249. doi:10.1021/acsmedchemlett.1c00598. PMC 8842279. PMID 35178181.
21. Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"
22. Courtney L. Fisher, Matteo Pavan, Veronica Salmaso, Robert F. Keyes, Tina C. Wan, Balaram Pradhan, Zhan-Guo Gao, Brian C. Smith, Kenneth A. Jacobson and John A. Auchampach. [<https://doi.org/10.1124/molpharm.123.000784> "Extrahelical binding site for a 1H-imidazo[4,5-c]quinolin-4-amine A3 adenosine receptor positive allosteric modulator on helix 8 and distal portions of transmembrane domains 1 and 7"]
23. Mikus EG, Szeredi J, Boer K, Tímári G, Finet M, Aranyi P, Galzin AM (January 2013). "Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models". European Journal of Pharmacology. 699 (1–3): 172–179. doi:10.1016/j.ejphar.2012.11.049. PMID 23219796.
24. Mikus EG, Boér K, Timári G, Urbán-Szabó K, Kapui Z, Szeredi J, et al. (January 2013). "Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo". European Journal of Pharmacology. 699 (1–3): 62–66. doi:10.1016/j.ejphar.2012.11.046. PMID 23219789.

Further reading

• Klotz KN (November 2000). "Adenosine receptors and their ligands". Naunyn-Schmiedeberg's Archives of Pharmacology. 362 (4–5): 382–391. doi:10.1007/s002100000315. PMID 11111832. S2CID 12938732.
• Monitto CL, Levitt RC, DiSilvestre D, Holroyd KJ (April 1995). "Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p". Genomics. 26 (3): 637–638. doi:10.1016/0888-7543(95)80194-Q. PMID 7607699.
• Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG (November 1993). "Molecular cloning and characterization of the human A3 adenosine receptor". Proceedings of the National Academy of Sciences of the United States of America. 90 (21): 10365–10369. Bibcode:1993PNAS...9010365S. doi:10.1073/pnas.90.21.10365. PMC 47775. PMID 8234299.
• Sajjadi FG, Firestein GS (October 1993). "cDNA cloning and sequence analysis of the human A3 adenosine receptor". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1179 (1): 105–107. doi:10.1016/0167-4889(93)90077-3. PMID 8399349.
• Murrison EM, Goodson SJ, Edbrooke MR, Harris CA (April 1996). "Cloning and characterisation of the human adenosine A3 receptor gene". FEBS Letters. 384 (3): 243–246. doi:10.1016/0014-5793(96)00324-9. PMID 8617363. S2CID 3170758.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Bouma MG, Jeunhomme TM, Boyle DL, Dentener MA, Voitenok NN, van den Wildenberg FA, Buurman WA (June 1997). "Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors". Journal of Immunology. 158 (11): 5400–5408. doi:10.4049/jimmunol.158.11.5400. PMID 9164961. S2CID 9984303.
• Atkinson MR, Townsend-Nicholson A, Nicholl JK, Sutherland GR, Schofield PR (September 1997). "Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene". Neuroscience Research. 29 (1): 73–79. doi:10.1016/S0168-0102(97)00073-4. PMID 9293494. S2CID 36060683.
• Palmer TM, Harris CA, Coote J, Stiles GL (October 1997). "Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor". Molecular Pharmacology. 52 (4): 632–640. doi:10.1124/mol.52.4.632. PMID 9380026. S2CID 2170191.
• Liang BT, Jacobson KA (June 1998). "A physiological role of the adenosine A3 receptor: sustained cardioprotection". Proceedings of the National Academy of Sciences of the United States of America. 95 (12): 6995–6999. Bibcode:1998PNAS...95.6995L. doi:10.1073/pnas.95.12.6995. PMC 22715. PMID 9618527.
• Dougherty C, Barucha J, Schofield PR, Jacobson KA, Liang BT (December 1998). "Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor". FASEB Journal. 12 (15): 1785–1792. doi:10.1096/fasebj.12.15.1785. PMC 5550893. PMID 9837869.
• Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ (February 2001). "Molecular phylogenetics and the origins of placental mammals". Nature. 409 (6820): 614–618. Bibcode:2001Natur.409..614M. doi:10.1038/35054550. PMID 11214319. S2CID 4373847.
• Gao ZG, Chen A, Barak D, Kim SK, Müller CE, Jacobson KA (May 2002). "Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor". The Journal of Biological Chemistry. 277 (21): 19056–19063. doi:10.1074/jbc.M110960200. PMC 5602557. PMID 11891221.
• Broussas M, Cornillet-Lefèbvre P, Potron G, Nguyên P (July 2002). "Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor". Thrombosis and Haemostasis. 88 (1): 123–130. doi:10.1055/s-0037-1613164. PMID 12152652. S2CID 3118696.
• Merighi S, Mirandola P, Milani D, Varani K, Gessi S, Klotz KN, et al. (October 2002). "Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells". The Journal of Investigative Dermatology. 119 (4): 923–933. doi:10.1046/j.1523-1747.2002.00111.x. PMID 12406340.
• Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, et al. (December 2002). "A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation". Molecular Pharmacology. 62 (6): 1373–1384. doi:10.1124/mol.62.6.1373. PMC 4806643. PMID 12435805.
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "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): 16899–16903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I (March 2003). "Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors". Circulation Research. 92 (5): 485–492. doi:10.1161/01.RES.0000061572.10929.2D. PMID 12600879.
• Gao ZG, Kim SK, Gross AS, Chen A, Blaustein JB, Jacobson KA (May 2003). "Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor". Molecular Pharmacology. 63 (5): 1021–1031. doi:10.1124/mol.63.5.1021. PMC 4367541. PMID 12695530.

External links

• "Adenosine Receptors: A₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2020-11-30. Retrieved 2008-11-25.
• Human ADORA3 genome location and ADORA3 gene details page in the UCSC Genome Browser.