Alternative titles; symbols
HGNC Approved Gene Symbol: P2RY1
Cytogenetic location: 3q25.2 Genomic coordinates (GRCh38) : 3:152,835,131-152,841,439 (from NCBI)
P2 purinoceptors have been broadly classified as P2X receptors (e.g., 600843), which are ATP-gated channels; P2Z receptors, which mediate nonselective pores in mast cells; and P2Y receptors, a family of G protein-coupled receptors. Based on the recommendation for nomenclature of P2 purinoceptors, the P2Y purinoceptors were numbered in the order of cloning. Ayyanathan et al. (1996) noted that P2Y1, P2Y2 (PR2Y2; 600041), and P2Y3 have been cloned from a variety of species. P2Y1 responds to both ADP and ATP. The P2Y2 receptor cDNA was cloned in the human and this receptor was known as P2U under previous nomenclature. Ayyanathan et al. (1996) cloned the human P2Y1 receptor (P2RY1) and its 2 alternately polyadenylated forms of mRNA. The P2Y1 purinoceptor was also cloned from a human placenta cDNA library by Leon et al. (1996). They found that the gene encodes a 372-amino acid polypeptide. Northern blot analysis revealed 2 transcripts of 4.6 and 7.5 kb which were expressed in many tissues.
Leon et al. (1997) expressed the cloned P2Y1 gene in Jurkat T lymphocytes, a cell line that is not naturally responsive to nucleotides. They treated the transfected cells with ATP and measured Ca(2+) fluxes and responses to agonists. The pharmacologic properties of the P2Y1 receptor are similar to those of the P2T ADP receptor that is responsible for platelet aggregation. They showed that the P2Y1 receptor is expressed by human platelets and megakaryoblasts. The authors suggested that the P2Y1 receptor may be the P2T receptor.
Adrian et al. (2000) analyzed the expression of several purinergic receptors during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. No change from the moderate basal expression of P2Y1 was detected during granulocytic differentiation. During monocytic differentiation, expression was transiently upregulated about 3-fold and returned to preinduction levels after 36 hours.
Mutafova-Yambolieva et al. (2007) identified P2ry1 as a receptor for beta-nicotinamide adenine dinucleotide (beta-NAD) by measuring receptor-mediated responses in HEK293 cells transfected with guinea pig P2ry1. They found that beta-NAD behaved as an inhibitory neurotransmitter in mouse colonic muscle. Beta-NAD was released by stimulation of enteric nerves of mouse gastrointestinal muscles, and release of beta-NAD depended on the frequency of nerve stimulation. Responses to beta-NAD and inhibitory junction potentials were blocked by a P2Y1-selective antagonist and by nonselective P2 receptor antagonists in mouse colonic muscles.
Masse et al. (2007) determined that ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2; 602012), an ectoenzyme that converts ATP to ADP, acts upstream of the eye field transcription factors Pax6 (607108), Rx1, and Six3 (603714). To test whether ADP, the product of ENTPD2, might act to trigger eye development through P2Y1 receptors, selective in Xenopus for ADP, Masse et al. (2007) simultaneously knocked down expression of the genes encoding ENTPD2 and the P2Y1 receptor. This prevented the expression of Rx1 and Pax6 and eye formation completely.
Ayyanathan et al. (1996) amplified the genomic region encoding the P2RY1 receptor and found that the gene contains no introns.
Crystal Structure
Zhang et al. (2015) reported the crystal structures of human P2RY1 in complex with the nucleotide antagonist MRS2500 at 2.7-angstrom resolution, and with the non-nucleotide antagonist BPTU at 2.2-angstrom resolution. The structures reveal 2 distinct ligand-binding sites, providing atomic details of P2RY1's unique ligand-binding modes. MRS2500 recognizes a binding site within the 7-transmembrane bundle of P2RY1, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2RY12 (600515), representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G protein-coupled receptor ligand located entirely outside of the helical bundle.
Using oligonucleotide primers specific for the human P2Y1 purinergic receptor, Ayyanathan et al. (1996) amplified a region from genomic DNA from a panel of mouse/human somatic cell hybrid cell lines and localized the P2Y1 gene to human chromosome 3.
By sequence tagged site (STS) mapping utilizing the National Center for Biotechnology Information (NCBI) database, Somers et al. (1997) mapped the P2RY1 gene between flanking markers D3S1279 and D3S1280 at a position 173 to 174 cM from the most telomeric markers on the short arm of chromosome 3.
Ayyanathan et al. (1996) localized the P2RY1 gene to chromosome 3q25 by PCR of a subchromosomal hybrid panel.
Leon et al. (1999) generated P2Y1-null mice to define the physiologic role of the P2Y1 receptor. These mice were viable with no apparent abnormalities affecting their development, survival, reproduction, or morphology of platelets, and the platelet count in these animals was identical to that of wildtype mice. However, platelets from P2Y1-deficient mice were unable to aggregate in response to usual concentrations of ADP and displayed impaired aggregation to other agonists, while high concentrations of ADP induced platelet aggregation without shape change. In addition, ADP-induced inhibition of adenylyl cyclase still occurred, demonstrating the existence of an ADP receptor distinct from P2Y1. P2Y1-null mice had no spontaneous bleeding tendency but were resistant to thromboembolism induced by intravenous injection of ADP or collagen and adrenaline. Hence, the P2Y1 receptor plays an essential role in thrombotic states and represents a potential target for antithrombotic drugs.
Adrian, K., Bernhard, M. K., Breitinger, H.-G., Ogilvie, A. Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochim. Biophys. Acta 1492: 127-138, 2000. [PubMed: 11004484] [Full Text: https://doi.org/10.1016/s0167-4781(00)00094-4]
Ayyanathan, K., Naylor, S. L., Kunapuli, S. P. Structural characterization and fine chromosomal mapping of the human P2Y(1) purinergic receptor gene (P2RY1). Somat. Cell Molec. Genet. 22: 419-424, 1996. [PubMed: 9039850] [Full Text: https://doi.org/10.1007/BF02369897]
Ayyanathan, K., Webbs, T. E., Sandhu, A. K., Athwal, R. S., Barnard, E. A., Kunapuli, S. P. Cloning and chromosomal localization of the human P2Y1 purinoceptor. Biochem. Biophys. Res. Commun. 218: 783-788, 1996. [PubMed: 8579591] [Full Text: https://doi.org/10.1006/bbrc.1996.0139]
Leon, C., Hechler, B., Freund, M., Eckly, A., Vial, C., Ohlmann, P., Dierich, A., LeMeur, M., Cazenave, J.-P., Gachet, C. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor-null mice. J. Clin. Invest. 104: 1731-1737, 1999. [PubMed: 10606627] [Full Text: https://doi.org/10.1172/JCI8399]
Leon, C., Hechler, B., Vial, C., Leray, C., Cazenave, J.-P., Gachet, C. The P2Y(1) receptor is an ADP receptor antagonized by ATP and expressed in platelets and megakaryoblastic cells. FEBS Lett. 403: 26-30, 1997. [PubMed: 9038354] [Full Text: https://doi.org/10.1016/s0014-5793(97)00022-7]
Leon, C., Vial, C., Cazenave, J.-P., Gachet, C. Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor. Gene 171: 295-297, 1996. [PubMed: 8666290] [Full Text: https://doi.org/10.1016/0378-1119(96)00027-3]
Masse, K., Bhamra, S., Eason, R., Dale, N., Jones, E. A. Purine-mediated signalling triggers eye development. Nature 449: 1058-1062, 2007. [PubMed: 17960245] [Full Text: https://doi.org/10.1038/nature06189]
Mutafova-Yambolieva, V. N., Hwang, S. J., Hao, X., Chen, H., Zhu, M. X., Wood, J. D., Ward, S. M., Sanders, K. M. Beta-nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc. Nat. Acad. Sci. 104: 16359-16364, 2007. [PubMed: 17913880] [Full Text: https://doi.org/10.1073/pnas.0705510104]
Somers, G. R., Hammet, F., Woollatt, E., Richards, R. I., Southey, M. C., Venter, D. J. Chromosomal localization of the human P2Y(6) purinoceptor gene and phylogenetic analysis of the P2y purinoceptor family. Genomics 44: 127-130, 1997. [PubMed: 9286708] [Full Text: https://doi.org/10.1006/geno.1997.4841]
Zhang, D., Gao, Z.-G., Zhang, K., Kiselev, E., Crane, S., Wang, J., Paoletta, S., Yi, C., Ma, L., Zhang, W., Han, G. W., Liu, H., Cherezov, V., Katritch, V., Jiang, H., Stevens, R. C., Jacobson K. A., Zhao, Q., Wu, B. Two disparate ligand-binding sites in the human P2Y(1) receptor. Nature 520: 317-321, 2015. [PubMed: 25822790] [Full Text: https://doi.org/10.1038/nature14287]