Alternative titles; symbols
HGNC Approved Gene Symbol: ADORA3
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:111,499,429-111,503,633 (from NCBI)
There are 3 types of adenosine receptors, each of which contains 7 transmembrane domains and interacts with G proteins. The A1 receptors inhibit adenylate cyclase while the type A2 receptors stimulate activity. Each adenosine receptor has a specific pattern of ligand binding and a unique tissue distribution (Zhao et al., 1995).
Zhou et al. (1992) cloned the A3 adenosine receptor from rat brain. Using rat A3ar as probe, Sajjadi and Firestein (1993) cloned A3AR from a heart cDNA library. The deduced 319-amino acid protein had a sequence consistent with other G protein-coupled receptors, including 7 putative transmembrane motifs and 3 potential N-glycosylation sites. The mRNA contains 2 putative polyadenylation signals. The rat A3 receptor protein is about 50 to 60% identical to the A1 and A2 receptors and has been shown to be an inhibitor of adenylate cyclase activity. A3AR shares about 71% homology with rat A3ar. Northern blot analysis detected a transcript of about 2 kb expressed primarily in placenta, lung, heart, liver, and kidney. Little expression was detected in skeletal muscle or brain. Salvatore et al. (1993) cloned the A3 adenosine receptor from a striatal cDNA library using the rat sequence as probe. The deduced protein contained 318 amino acids and shared 72% and 85% overall identity with rat and sheep A3 adenosine receptors, respectively. Northern blot analysis detected the 2-kb transcript expressed at highest amounts in lung and liver, at moderate levels in brain and aorta, and at low levels in testis and heart. No expression was detected in spleen or kidney. By Northern blot analysis, Murrison et al. (1996) found expression of a single 2.1-kb transcript expressed primarily in liver, lung, placenta, and in all brain regions tested. No signal was observed in heart, skeletal muscle, kidney, or pancreas.
Murrison et al. (1996) determined that the ADORA3 gene contains 2 exons separated by a single intron of about 2.2 kb. The upstream sequence does not contain a TATA-like motif, but it has a CCAAT sequence and consensus binding sites for SP1 (189906), NFIL6 (CEBPB; 189965), GATA1 (305371), and GATA3 (131320).
Salvatore et al. (1993) characterized the A3 adenosine receptor expressed in Chinese hamster ovary cells and found that agonist binding to membrane preparations inhibited cAMP accumulation. Pharmacologic characterization with several adenosine receptor agonists and xanthine antagonists showed that the human receptor is more similar to the sheep A3 adenosine receptor than to the rat A3 adenosine receptor. Salvatore et al. (1993) also noted that the tissue distribution of the human receptor is more similar to the widespread profile found in sheep than to the restricted profile found in rat.
Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart. The adenosine A3 receptor is expressed on cardiac ventricular cells, and its activation protects the ventricular heart cell against injury during a subsequent exposure to ischemia. Liang and Jacobson (1998) used a cultured chicken ventricular myocyte model to investigate the cardioprotective role of the adenosine A3 receptor. They could show that cardiac adenosine A3 receptor mediates a sustained cardioprotective function and represents a new cardiac therapeutic target. Cardiac atrial cells lack native A3 receptors and exhibited a shorter duration of cardioprotection than did ventricular cells. Transfection of atrial cells with cDNA encoding the human adenosine A3 receptor caused a sustained A3 agonist-mediated cardioprotection.
Adenosine is increasingly released in metabolic stress conditions, such as hypoxia or ischemia, and regulates many physiologic processes, such as aqueous humor secretion and intraocular pressure, via activation of the adenosine receptors. Schlotzer-Schrehardt et al. (2005) found that all 4 adenosine receptor subtypes (ADORA1, 102775; ADORA2A, 102776; ADORA2B, 600446; and ADORA3) were coexpressed in the ciliary body but differently distributed in the ciliary epithelium of control eyes, with the A3 receptor being localized to the basolateral membrane infoldings of the nonpigmented epithelial cells. A selective, approximately 10-fold upregulation of ADORA3 mRNA and protein was consistently found in the nonpigmented ciliary epithelium of all eyes from patients with pseudoexfoliation of the lens (177650), with or without glaucoma.
By interspecific backcross analysis, Wilkie et al. (1993) localized the adenosine A3 receptor to chromosome 3 in the mouse, suggesting a human chromosomal localization of 1p13 from known mouse/human linkage homologies. Zhao et al. (1995) also mapped the A3 receptor by interspecific backcross analysis to mouse chromosome 3. This prediction was confirmed by Monitto et al. (1995), who mapped the ADORA3 gene to human 1p at a distance between 8 and 17 cM from the centromere. PCR amplification of DNAs from a human/rodent somatic cell hybrid mapping panel was followed by PCR analysis of pooled YAC DNA. From the marker content of the YAC, the gene was thought to map to 1p21-p13.
By in situ hybridization, Zhao et al. (2000) found A3AR expressed at high levels in the vascular smooth muscle layer of normal mouse aortas. They developed A3ar knockout mice and found that the mutant mice showed blood pressure comparable to wildtype mice, but aorta and heart cAMP levels were elevated. When challenged with adenosine, the knockout mice showed further increased cAMP levels in the heart and vascular smooth muscle, and a significant decrease in blood pressure. The affect of adenosine on ADP-induced platelet aggregation was similar in both knockout and wildtype mice, suggesting that mouse platelets do not express A3AR.
Liang, B. T., Jacobson, K. A. A physiological role of the adenosine A3 receptor: sustained cardioprotection. Proc. Nat. Acad. Sci. 95: 6995-6999, 1998. [PubMed: 9618527] [Full Text: https://doi.org/10.1073/pnas.95.12.6995]
Monitto, C. L., Levitt, R. C., DiSilvestre, D., Holroyd, K. J. Localization of the A(3) adenosine receptor gene (ADORA3) to human chromosome 1p. Genomics 26: 637-638, 1995. [PubMed: 7607699] [Full Text: https://doi.org/10.1016/0888-7543(95)80194-q]
Murrison, E. M., Goodson, S. J., Edbrooke, M. R., Harris, C. A. Cloning and characterisation of the human adenosine A3 receptor gene. FEBS Lett. 384: 243-246, 1996. [PubMed: 8617363] [Full Text: https://doi.org/10.1016/0014-5793(96)00324-9]
Sajjadi, F. G., Firestein, G. S. cDNA cloning and sequence analysis of the human A3 adenosine receptor. Biochim. Biophys. Acta 1179: 105-107, 1993. [PubMed: 8399349] [Full Text: https://doi.org/10.1016/0167-4889(93)90077-3]
Salvatore, C. A., Jacobson, M. A., Taylor, H. E., Linden, J., Johnson, R. G. Molecular cloning and characterization of the human A(3) adenosine receptor. Proc. Nat. Acad. Sci. 90: 10365-10369, 1993. [PubMed: 8234299] [Full Text: https://doi.org/10.1073/pnas.90.21.10365]
Schlotzer-Schrehardt, U., Zenkel, M., Decking, U., Haubs, D., Kruse, F. E., Junemann, A., Coca-Prados, M., Naumann, G. O. H. Selective upregulation of the A3 adenosine receptor in eyes with pseudoexfoliation syndrome and glaucoma. Invest. Ophthal. Vis. Sci. 46: 2023-2034, 2005. [PubMed: 15914619] [Full Text: https://doi.org/10.1167/iovs.04-0915]
Wilkie, T. M., Chen, Y., Gilbert, D. J., Moore, K. J., Yu, L., Simon, M. I., Copeland, N. G., Jenkins, N. A. Identification, chromosomal location, and genome organization of mammalian G-protein-coupled receptors. Genomics 18: 175-184, 1993. [PubMed: 8288218] [Full Text: https://doi.org/10.1006/geno.1993.1452]
Zhao, Z., Makaritsis, K., Francis, C. E., Gavras, H., Ravid, K. A role for the A3 adenosine receptor in determining tissue levels of cAMP and blood pressure: studies in knock-out mice. Biochim. Biophys. Acta 1500: 280-290, 2000. [PubMed: 10699369] [Full Text: https://doi.org/10.1016/s0925-4439(99)00111-8]
Zhao, Z., Ravid, S., Ravid, K. Chromosomal mapping of the mouse A3 adenosine receptor gene, Adora3. Genomics 30: 118-119, 1995. [PubMed: 8595892] [Full Text: https://doi.org/10.1006/geno.1995.0023]
Zhou, Q.-Y., Li, C., Olah, M. E., Johnson, R. A., Stiles, G. L., Civelli, O. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc. Nat. Acad. Sci. 89: 7432-7436, 1992. [PubMed: 1323836] [Full Text: https://doi.org/10.1073/pnas.89.16.7432]