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Gene Review

ADORA3  -  adenosine A3 receptor

Homo sapiens

Synonyms: AD026
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Disease relevance of ADORA3

  • We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells [1].
  • The adenosine A3 receptor-selective antagonist 3-ethyl 5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) caused a biphasic inhibition of the protective effect of the brief ischemia [2].
  • The selective A2aAR agonist, 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680), the A3AR agonist, N6-2-(4-aminophenyl) ethyladenosine (APNEA), and the A1AR antagonist, 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) each inhibited TF activity expression induced by TNF, thrombin, or PMA on HUVECs [3].
  • NECA-stimulated degranulation is not prevented by pertussis toxin and is blocked by enprofylline (Ki = 7 microM), an antiasthmatic xanthine with low affinity (Ki > 100 microM) for A1AR, A2AAR, and A3AR [4].
  • Although canine BR mastocytoma cells contain A1AR, A2BAR, and A3AR, degranulation seems to be mediated primarily by A2BARs stimulated by the nonselective agonist 5'-N-ethylcarboxamidoadenosine (NECA) but not by the A3-selective agonist N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide [4].

High impact information on ADORA3

  • Transfection of atrial cells with cDNA encoding the human adenosine A3 receptor causes a sustained A3 agonist-mediated cardioprotection [2].
  • A cultured chicken ventricular myocyte model was used to investigate the cardioprotective role of a novel adenosine A3 receptor [2].
  • By analyzing the GC-induced expression pattern in human monocytes by microarray technology, we identified for the first time GC-dependent regulation of 133 genes, including anti-inflammatory molecules such as adenosine A3 receptor, CD1d, and IL-1 receptor II [5].
  • Under conditions in which exposure of transfected cells to 5 microM (-)-(R)-N6-(phenylisopropyl)adenosine resulted in the functional desensitization and phosphorylation of the A3AR, neither property was exhibited by the A1AR [6].
  • The A3 adenosine receptor, A3AR, belongs to the family of Gi proteins, which upon induction, suppresses the formation of cAMP and its downstream effectors [7].

Chemical compound and disease context of ADORA3

  • Increases in enzyme activity were attenuated by theophylline (an antagonist of the A3AR) and by pertussis toxin, implicating a role of A3AR/Gi protein in the activation [8].
  • Available evidence indicates that this receptor sub-type is minimally activated by endogenous adenosine during ischemia (A3AR antagonists exerting no effects on ischemic outcome), and is thus amenable to activation with exogenous agonists [9].

Biological context of ADORA3


Anatomical context of ADORA3

  • Regulation of p42/p44 mitogen-activated protein kinase by the human adenosine A3 receptor in transfected CHO cells [13].
  • However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested [1].
  • Northern analysis of various human tissues showed the human A3AR gene to be expressed primarily in lung, liver, kidney and heart, with very little expression in the brain or in skeletal muscle [11].
  • Our results suggest that stimulation of A2aAR and A3AR down-regulates and that of A1AR up-regulates the endothelial cell TF expression induced by TNF, PMA, or thrombin [3].
  • Canine A3AR transcript is found predominantly in spleen, lung, liver, and testes and encodes a 314-amino acid heptahelical receptor [4].

Associations of ADORA3 with chemical compounds


Physical interactions of ADORA3


Other interactions of ADORA3

  • In contrast, inhibition of protein kinase C had no significant effect on adenosine A3 receptor-induced p42/p44 MAPK activation [13].
  • Moreover, increased A3AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals [16].
  • The role of adenosine A3 receptor activation during ischaemia-like conditions produced by oxygen and glucose deprivation (OGD) was evaluated with extracellular recordings from the CA1 region of rat hippocampal slices [17].

Analytical, diagnostic and therapeutic context of ADORA3

  • A3AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis [16].
  • Specifically, in situ ischemic preconditioning conferred cardioprotection in A1 AR-/-, A2A AR-/-, or A3 AR-/- mice but not in A2B AR-/- mice or in wild-type mice after inhibition of the A2B AR [18].
  • The highly selective A3AR agonist, IB-MECA was earlier shown to prevent the clinical and pathological manifestations of arthritis in experimental animal models of collagen and adjuvant induced arthritis (AIA) [19].


  1. The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers. Chung, H., Jung, J.Y., Cho, S.D., Hong, K.A., Kim, H.J., Shin, D.H., Kim, H., Kim, H.O., Shin, D.H., Lee, H.W., Jeong, L.S., Kong, G. Mol. Cancer Ther. (2006) [Pubmed]
  2. A physiological role of the adenosine A3 receptor: sustained cardioprotection. Liang, B.T., Jacobson, K.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  3. Adenosine regulates tissue factor expression on endothelial cells. Deguchi, H., Takeya, H., Urano, H., Gabazza, E.C., Zhou, H., Suzuki, K. Thromb. Res. (1998) [Pubmed]
  4. Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Auchampach, J.A., Jin, X., Wan, T.C., Caughey, G.H., Linden, J. Mol. Pharmacol. (1997) [Pubmed]
  5. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Ehrchen, J., Steinmüller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkötter, C., Roth, J. Blood (2007) [Pubmed]
  6. Molecular basis for subtype-specific desensitization of inhibitory adenosine receptors. Analysis of a chimeric A1-A3 adenosine receptor. Palmer, T.M., Benovic, J.L., Stiles, G.L. J. Biol. Chem. (1996) [Pubmed]
  7. Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Fishman, P., Madi, L., Bar-Yehuda, S., Barer, F., Del Valle, L., Khalili, K. Oncogene (2002) [Pubmed]
  8. Adenosine acts as an endogenous activator of the cellular antioxidant defense system. Maggirwar, S.B., Dhanraj, D.N., Somani, S.M., Ramkumar, V. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  9. A3 adenosine receptor-mediated protection of the ischemic heart. Headrick, J.P., Peart, J. Vascul. Pharmacol. (2005) [Pubmed]
  10. Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p. Monitto, C.L., Levitt, R.C., DiSilvestre, D., Holroyd, K.J. Genomics (1995) [Pubmed]
  11. cDNA cloning and sequence analysis of the human A3 adenosine receptor. Sajjadi, F.G., Firestein, G.S. Biochim. Biophys. Acta (1993) [Pubmed]
  12. Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene. Atkinson, M.R., Townsend-Nicholson, A., Nicholl, J.K., Sutherland, G.R., Schofield, P.R. Neurosci. Res. (1997) [Pubmed]
  13. Regulation of p42/p44 mitogen-activated protein kinase by the human adenosine A3 receptor in transfected CHO cells. Graham, S., Combes, P., Crumiere, M., Klotz, K.N., Dickenson, J.M. Eur. J. Pharmacol. (2001) [Pubmed]
  14. Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor. Palmer, T.M., Harris, C.A., Coote, J., Stiles, G.L. Mol. Pharmacol. (1997) [Pubmed]
  15. Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-alpha release by reducing calcium-dependent activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2. Martin, L., Pingle, S.C., Hallam, D.M., Rybak, L.P., Ramkumar, V. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  16. Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression. Ochaion, A., Bar-Yehuda, S., Cohn, S., Del Valle, L., Perez-Liz, G., Madi, L., Barer, F., Farbstein, M., Fishman-Furman, S., Reitblat, T., Reitblat, A., Amital, H., Levi, Y., Molad, Y., Mader, R., Tishler, M., Langevitz, P., Zabutti, A., Fishman, P. Arthritis Res. Ther. (2006) [Pubmed]
  17. A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro. Pugliese, A.M., Coppi, E., Spalluto, G., Corradetti, R., Pedata, F. Br. J. Pharmacol. (2006) [Pubmed]
  18. Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors. Eckle, T., Krahn, T., Grenz, A., Köhler, D., Mittelbronn, M., Ledent, C., Jacobson, M.A., Osswald, H., Thompson, L.F., Unertl, K., Eltzschig, H.K. Circulation (2007) [Pubmed]
  19. IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis. Rath-Wolfson, L., Bar-Yehuda, S., Madi, L., Ochaion, A., Cohen, S., Zabutti, A., Fishman, P. Clin. Exp. Rheumatol. (2006) [Pubmed]
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