Adenosine A3 receptor explained

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 potential in bronchial asthma (17,18).

Gene

Multiple transcript variants encoding different isoforms have been found for this gene.

Therapeutic implications

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

Selective Ligands

A number of selective A₃ ligands are available.^[1]

Agonists/Positive Allosteric Modulators

• 2-(1-Hexynyl)-N-methyladenosine
• CF-101 (IB-MECA)
• CF-102
• 2-Cl-IB-MECA
• CP-532,903
• Inosine^[2]
• LUF-6000^[3]
• 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
• ISAM-DM10

Inverse Agonists

• PSB-10

Further reading

• Klotz KN . Adenosine receptors and their ligands . Naunyn-Schmiedeberg's Archives of Pharmacology . 362 . 4–5 . 382–391 . November 2000 . 11111832 . 10.1007/s002100000315 . 12938732 .
• Monitto CL, Levitt RC, DiSilvestre D, Holroyd KJ . Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p . Genomics . 26 . 3 . 637–638 . April 1995 . 7607699 . 10.1016/0888-7543(95)80194-Q . free .
• Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG . 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 . November 1993 . 8234299 . 47775 . 10.1073/pnas.90.21.10365 . free . 1993PNAS...9010365S .
• Sajjadi FG, Firestein GS . cDNA cloning and sequence analysis of the human A3 adenosine receptor . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1179 . 1 . 105–107 . October 1993 . 8399349 . 10.1016/0167-4889(93)90077-3 .
• Murrison EM, Goodson SJ, Edbrooke MR, Harris CA . Cloning and characterisation of the human adenosine A3 receptor gene . FEBS Letters . 384 . 3 . 243–246 . April 1996 . 8617363 . 10.1016/0014-5793(96)00324-9 . 3170758 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Bouma MG, Jeunhomme TM, Boyle DL, Dentener MA, Voitenok NN, van den Wildenberg FA, Buurman WA . Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors . Journal of Immunology . 158 . 11 . 5400–5408 . June 1997 . 10.4049/jimmunol.158.11.5400 . 9164961 . 9984303 . free .
• Atkinson MR, Townsend-Nicholson A, Nicholl JK, Sutherland GR, Schofield PR . Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene . Neuroscience Research . 29 . 1 . 73–79 . September 1997 . 9293494 . 10.1016/S0168-0102(97)00073-4 . 36060683 .
• Palmer TM, Harris CA, Coote J, Stiles GL . Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor . Molecular Pharmacology . 52 . 4 . 632–640 . October 1997 . 9380026 . 10.1124/mol.52.4.632 . 2170191 .
• Liang BT, Jacobson KA . 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 . June 1998 . 9618527 . 22715 . 10.1073/pnas.95.12.6995 . free . 1998PNAS...95.6995L .
• Dougherty C, Barucha J, Schofield PR, Jacobson KA, Liang BT . Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A1 or A3 receptor . FASEB Journal . 12 . 15 . 1785–1792 . December 1998 . 9837869 . 5550893 . 10.1096/fasebj.12.15.1785 . free .
• Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ . Molecular phylogenetics and the origins of placental mammals . Nature . 409 . 6820 . 614–618 . February 2001 . 11214319 . 10.1038/35054550 . 4373847 . 2001Natur.409..614M .
• Gao ZG, Chen A, Barak D, Kim SK, Müller CE, Jacobson KA . 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 . May 2002 . 11891221 . 5602557 . 10.1074/jbc.M110960200 . free .
• Broussas M, Cornillet-Lefèbvre P, Potron G, Nguyên P . Adenosine inhibits tissue factor expression by LPS-stimulated human monocytes: involvement of the A3 adenosine receptor . Thrombosis and Haemostasis . 88 . 1 . 123–130 . July 2002 . 12152652 . 10.1055/s-0037-1613164 . 3118696 .
• Merighi S, Mirandola P, Milani D, Varani K, Gessi S, Klotz KN, Leung E, Baraldi PG, Borea PA . 6 . 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 . October 2002 . 12406340 . 10.1046/j.1523-1747.2002.00111.x . free .
• Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, Abbracchio MP, Jacobson KA, Cattabeni F, Martini C . 6 . A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation . Molecular Pharmacology . 62 . 6 . 1373–1384 . December 2002 . 12435805 . 4806643 . 10.1124/mol.62.6.1373 .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . 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 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . free . 2002PNAS...9916899M .
• 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 . free .
• Gao ZG, Kim SK, Gross AS, Chen A, Blaustein JB, Jacobson KA . Identification of essential residues involved in the allosteric modulation of the human A(3) adenosine receptor . Molecular Pharmacology . 63 . 5 . 1021–1031 . May 2003 . 12695530 . 4367541 . 10.1124/mol.63.5.1021 .

External links

• Web site: Adenosine Receptors: A₃ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-11-25 . 2020-11-30 . https://web.archive.org/web/20201130073403/https://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2172 . dead .

Notes and References

1. Miranda-Pastoriza D, Bernárdez R, Azuaje J, Prieto-Díaz R, Majellaro M, Tamhankar AV, Koenekoop L, González A, Gioé-Gallo C, Mallo-Abreu A, Brea J, Loza MI, García-Rey A, García-Mera X, Gutiérrez-de-Terán H, Sotelo E . 6 . Exploring Non-orthosteric Interactions with a Series of Potent and Selective A₃ Antagonists . ACS Medicinal Chemistry Letters . 13 . 2 . 243–249 . February 2022 . 35178181 . 10.1021/acsmedchemlett.1c00598 . 8842279 .
2. Xiaowei Jin, Rebecca K. Shepherd, Brian R. Duling, and Joel Linden. "Inosine Binds to A3 Adenosine Receptors and Stimulates Mast Cell Degranulation"
3. 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"]