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P2Y Receptor

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Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases

Abstract

Purinergic receptors (P2Ys) are rhodopsin-like GPCR (metabotropic receptors) that are activated by extracellular nucleotides (ATP, ADP, UTP and UDP). They stimulate a wide range of signaling pathways through activation of a variety of G proteins. P2Y family contains 8 members and they are grouped as P2Y1-like receptors (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) and P2Y12-like receptors (P2Y12, P2Y13, P2Y14) based on their amino acid sequence homology and preference for ligands. These receptors are ubiquitously expressed in the biological system and they have unavoidable role in many physiological functions including neurotransmission, hormone secretion, blood vessel contraction, homeostasis and metabolism. As P2Y receptors can interact and/or heterodimerize with various GPCRs and other family receptors, they are now gaining much attention as a potential therapeutic target for various disorders including stroke, epilepsy and cancer. This chapter illustrates the classification, characteristic features and distribution of members of P2Y receptor family. In addition, the current knowledge of physiological and pathological functions of P2Y receptors are described.

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References

  • Abbracchio, M. P., Boeynaems, J. M., Barnard, E. A., Boyer, J. L., Kennedy, C., Miras-Portugal, M. T., King, B. F., Gachet, C., Jacobson, K. A., Weisman, G. A., & Burnstock, G. (2003). Characterization of the UDP-glucose receptor (re-named here the P2Y14 receptor) adds diversity to the P2Y receptor family. Trends in Pharmacological Science, 24, 52–55.

    Article  CAS  Google Scholar 

  • Andre, P., Delaney, S. M., LaRocca, T., Vincent, D., DeGuzman, F., Jurek, M., Koller, B., Phillips, D. R., & Conley, P. B. (2003). P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. Journal of Clinical Investigation, 112, 398–406.

    Article  CAS  Google Scholar 

  • Arase, T., Uchida, H., Kajitani, T., Ono, M., Tamaki, K., Oda, H., Nishikawa, S., Kagami, M., Nagashima, T., Masuda, H., Asada, H., Yoshimura, Y., & Maruyama, T. (2009). The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8. Journal of Immunology, 182, 7074–7084.

    Article  CAS  Google Scholar 

  • Arthur, D. B., Akassoglou, K., & Insel, P. A. (2005). P2Y2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation. Proceedings of the National Academy of Sciences, USA, 102, 19138–19143.

    Article  CAS  Google Scholar 

  • Ayata, C. K., Ganal, S. C., Hockenjos, B., Willim, K., Vieira, R. P., Grimm, M., Robaye, B., Boeynaems, J. M., Di Virgilio, F., Pellegatti, P., Diefenbach, A., Idzko, M., & Hasselblatt, P. (2012). Purinergic P2Y(2) receptors promote neutrophil infiltration and hepatocyte death in mice with acute liver injury. Gastroenterology, 143(1620–1629), e1624.

    Google Scholar 

  • Azroyan, A., Cortez-Retamozo, V., Bouley, R., Liberman, R., Ruan, Y. C., Kiselev, E., Jacobson, K. A., Pittet, M. J., Brown, D., & Breton, S. (2015). Renal intercalated cells sense and mediate inflammation via the P2Y14 receptor. PLoS One, 10, e0121419.

    Article  Google Scholar 

  • Burnstock, G. (2006). Purinergic signalling. British Journal of Pharmacology, 147(Suppl 1), S172–S181.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Burnstock, G. (2012). Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. BioEssays, 34, 218–225.

    Article  CAS  Google Scholar 

  • Burnstock, G., Vaughn, B., & Robson, S. C. (2014). Purinergic signalling in the liver in health and disease. Purinergic Signalling, 10, 51–70.

    Article  CAS  Google Scholar 

  • Cohen, R., Shainberg, A., Hochhauser, E., Cheporko, Y., Tobar, A., Birk, E., Pinhas, L., Leipziger, J., Don, J., & Porat, E. (2011). UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor. Biochemical Pharmacology, 82, 1126–1133.

    Article  CAS  Google Scholar 

  • Costanzi, S., Mamedova, L., Gao, Z. G., & Jacobson, K. A. (2004). Architecture of P2Y nucleotide receptors: structural comparison based on sequence analysis, mutagenesis, and homology modeling. Journal of Medicnal Chemistry, 47, 5393–5404.

    Article  CAS  Google Scholar 

  • Eckly, A., Gendrault, J. L., Hechler, B., Cazenave, J. P., & Gachet, C. (2001). Differential involvement of the P2Y1 and P2YT receptors in the morphological changes of platelet aggregation. Thrombosis and Haemostasis, 85, 694–701.

    Article  CAS  Google Scholar 

  • Erb, L., & Weisman, G. A. (2012). Coupling of P2Y receptors to G proteins and other signaling pathways. Wiley Interdisciplinary Reviews-Developmental Biology, 1, 789–803.

    Article  CAS  Google Scholar 

  • Fabre, A. C., Malaval, C., Ben Addi, A., Verdier, C., Pons, V., Serhan, N., Lichtenstein, L., Combes, G., Huby, T., Briand, F., Collet, X., Nijstad, N., Tietge, U. J., Robaye, B., Perret, B., Boeynaems, J. M., & Martinez, L. O. (2010). P2Y13 receptor is critical for reverse cholesterol transport. Hepatology, 52, 1477–1483.

    Article  CAS  Google Scholar 

  • Goffinet, M., Tardy, C., Boubekeur, N., Cholez, G., Bluteau, A., Oniciu, D. C., Lalwani, N. D., Dasseux, J. L., Barbaras, R., & Baron, R. (2014). P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo. PLoS One, 9, e95807.

    Article  Google Scholar 

  • Hochhauser, E., Cohen, R., Waldman, M., Maksin, A., Isak, A., Aravot, D., Jayasekara, P. S., Muller, C. E., Jacobson, K. A., & Shainberg, A. (2013). P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo. Purinergic Signalling, 9, 633–642.

    Article  CAS  Google Scholar 

  • Horckmans, M., Esfahani, H., Beauloye, C., Clouet, S., di Pietrantonio, L., Robaye, B., Balligand, J. L., Boeynaems, J. M., Dessy, C., & Communi, D. (2015). Loss of mouse P2Y4 nucleotide receptor protects against myocardial infarction through endothelin-1 downregulation. Journal of Immunology, 194, 1874–1881.

    Article  CAS  Google Scholar 

  • Ishimaru, M., Yusuke, N., Tsukimoto, M., Harada, H., Takenouchi, T., Kitani, H., & Kojima, S. (2014). Purinergic signaling via P2Y receptors up-mediates IL-6 production by liver macrophages/Kupffer cells. Journal of Toxicological Sciences, 39, 413–423.

    Article  CAS  Google Scholar 

  • Jacobson, K. A., & Muller, C. E. (2016). Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology, 104, 31–49.

    Article  CAS  Google Scholar 

  • Jacobson, K. A., Paoletta, S., Katritch, V., Wu, B., Gao, Z. G., Zhao, Q., Stevens, R. C., & Kiselev, E. (2015). Nucleotides acting at P2Y receptors: Connecting structure and function. Molecular Pharmacology, 88, 220–230.

    Article  CAS  Google Scholar 

  • Kanamarlapudi, V., Owens, S. E., Saha, K., Pope, R. J., & Mundell, S. J. (2012). ARF6-dependent regulation of P2Y receptor traffic and function in human platelets. PLoS One, 7, e43532.

    Article  CAS  Google Scholar 

  • Kauffenstein, G., Tamareille, S., Prunier, F., Roy, C., Ayer, A., Toutain, B., Billaud, M., Isakson, B. E., Grimaud, L., Loufrani, L., Rousseau, P., Abraham, P., Procaccio, V., Monyer, H., de Wit, C., Boeynaems, J. M., Robaye, B., Kwak, B. R., & Henrion, D. (2016). Central role of P2Y6 UDP receptor in arteriolar myogenic tone. Arteriosclerosis, Thrombosis and Vascular Biology, 36, 1598–1606.

    Article  CAS  Google Scholar 

  • Khalid, M., Brisson, L., Tariq, M., Hao, Y., Guibon, R., Fromont, G., Mortadza, S. A. S., Mousawi, F., Manzoor, S., Roger, S., & Jiang, L. H. (2017). Carcinoma-specific expression of P2Y11 receptor and its contribution in ATP-induced purinergic signalling and cell migration in human hepatocellular carcinoma cells. Oncotarget, 8, 37278–37290.

    Article  Google Scholar 

  • Kim, H. J., Ajit, D., Peterson, T. S., Wang, Y., Camden, J. M., Gibson Wood, W., Sun, G. Y., Erb, L., Petris, M., & Weisman, G. A. (2012). Nucleotides released from Abeta(1)(-)(4)(2) -treated microglial cells increase cell migration and Abeta(1)(-)(4)(2) uptake through P2Y(2) receptor activation. Journal of Neurochemistry, 121, 228–238.

    Article  CAS  Google Scholar 

  • Lee, Y. J., & Han, H. J. (2005). Effect of adenosine triphosphate in renal ischemic injury: involvement of NF-kappaB. Journal of Cellular Physiology, 204, 792–799.

    Article  CAS  Google Scholar 

  • Lee, S. H., Hollingsworth, R., Kwon, H. Y., Lee, N., & Chung, C. Y. (2012). beta-arrestin 2-dependent activation of ERK1/2 is required for ADP-induced paxillin phosphorylation at Ser(83) and microglia chemotaxis. Glia, 60, 1366–1377.

    Article  Google Scholar 

  • Lichtenstein, L., Serhan, N., Espinosa-Delgado, S., Fabre, A., Annema, W., Tietge, U. J., Robaye, B., Boeynaems, J. M., Laffargue, M., Perret, B., & Martinez, L. O. (2015). Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport. Cardiovascular Research, 106, 314–323.

    Article  CAS  Google Scholar 

  • Meister, J., Le Duc, D., Ricken, A., Burkhardt, R., Thiery, J., Pfannkuche, H., Polte, T., Grosse, J., Schoneberg, T., & Schulz, A. (2014). The G protein-coupled receptor P2Y14 influences insulin release and smooth muscle function in mice. Journal of Biological Chemistry, 289, 23353–23366.

    Article  CAS  Google Scholar 

  • Mitchell, C., Syed, N. I., Tengah, A., Gurney, A. M., & Kennedy, C. (2012). Identification of contractile P2Y1, P2Y6, and P2Y12 receptors in rat intrapulmonary artery using selective ligands. Journal of Pharmacology and Experimental Therapeutics, 343, 755–762.

    Article  CAS  Google Scholar 

  • Nishida, M., Sato, Y., Uemura, A., Narita, Y., Tozaki-Saitoh, H., Nakaya, M., Ide, T., Suzuki, K., Inoue, K., Nagao, T., & Kurose, H. (2008). P2Y6 receptor-Galpha12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis. EMBO Journal, 27, 3104–3115.

    Article  CAS  Google Scholar 

  • Nishida, M., Ogushi, M., Suda, R., Toyotaka, M., Saiki, S., Kitajima, N., Nakaya, M., Kim, K. M., Ide, T., Sato, Y., Inoue, K., & Kurose, H. (2011). Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kappaB. Proceedings of the Natational Academy of Sciences, USA, 108, 6662–6667.

    Article  CAS  Google Scholar 

  • Nishimura, A., Sunggip, C., Tozaki-Saitoh, H., Shimauchi, T., Numaga-Tomita, T., Hirano, K., Ide, T., Boeynaems, J. M., Kurose, H., Tsuda, M., Robaye, B., Inoue, K., & Nishida, M. (2016). Purinergic P2Y6 receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension. Science Signaling, 9, ra7.

    Article  Google Scholar 

  • Nishimura, A., Sunggip, C., Oda, S., Numaga-Tomita, T., Tsuda, M., & Nishida, M. (2017). Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases. Pharmacology and Therapeutics, 180, 113–128.

    Article  CAS  Google Scholar 

  • Novitskaya, T., Chepurko, E., Covarrubias, R., Novitskiy, S., Ryzhov, S. V., Feoktistov, I., & Gumina, R. J. (2016). Extracellular nucleotide regulation and signaling in cardiac fibrosis. Journal of Molecular and Cellular Cardiology, 93, 47–56.

    Article  CAS  Google Scholar 

  • Osmond, D. A., Zhang, S., Pollock, J. S., Yamamoto, T., De Miguel, C., & Inscho, E. W. (2014). Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. American Journal of Physiology Renal Physiology, 306, F619–F628.

    Article  CAS  Google Scholar 

  • Peter Illes, P., Messemer, N., & Rubini, P. (2013). P2Y receptors in neurogenesis. WIREs Membrane Transport and Signaling, 2, 43–48.

    Article  Google Scholar 

  • Potthoff, S. A., Stegbauer, J., Becker, J., Wagenhaeuser, P. J., Duvnjak, B., Rump, L. C., & Vonend, O. (2013). P2Y2 receptor deficiency aggravates chronic kidney disease progression. Frontiers in Physiology, 4, 234.

    Article  Google Scholar 

  • Robson, S. C., Sevigny, J., & Zimmermann, H. (2006). The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance. Purinergic Signalling, 2, 409–430.

    Article  CAS  Google Scholar 

  • Schafer, R., Sedehizade, F., Welte, T., & Reiser, G. (2003). ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. American Journal of Physiology Lung Cellular and Molecular Physiology, 285, L376–L385.

    Article  Google Scholar 

  • Suzuki, T., Namba, K., Tsuga, H., & Nakata, H. (2006). Regulation of pharmacology by hetero-oligomerization between A1 adenosine receptor and P2Y2 receptor. Biochemistry and Biophysics Research Communication, 351, 559–565.

    Article  CAS  Google Scholar 

  • Tackett, B. C., Sun, H., Mei, Y., Maynard, J. P., Cheruvu, S., Mani, A., Hernandez-Garcia, A., Vigneswaran, N., Karpen, S. J., & Thevananther, S. (2014). P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy. American Journal of Physiology Gastrointestinal and Liver Physiology, 307, G1073–G1087.

    Article  CAS  Google Scholar 

  • Thevananther, S., Sun, H., Li, D., Arjunan, V., Awad, S. S., Wyllie, S., Zimmerman, T. L., Goss, J. A., & Karpen, S. J. (2004). Extracellular ATP activates c-jun N-terminal kinase signaling and cell cycle progression in hepatocytes. Hepatology, 39, 393–402.

    Article  CAS  Google Scholar 

  • Tsuchiya, A., & Nishizaki, T. (2015). Anticancer effect of adenosine on gastric cancer via diverse signaling pathways. World Journal of Gastroenterology, 21, 10931–10935.

    Article  CAS  Google Scholar 

  • Vieira, R. P., Muller, T., Grimm, M., von Gernler, V., Vetter, B., Durk, T., Cicko, S., Ayata, C. K., Sorichter, S., Robaye, B., Zeiser, R., Ferrari, D., Kirschbaum, A., Zissel, G., Virchow, J. C., Boeynaems, J. M., & Idzko, M. (2011). Purinergic receptor type 6 contributes to airway inflammation and remodeling in experimental allergic airway inflammation. American Journal of Respiratory and Critical Care Medicine, 184, 215–223.

    Article  CAS  Google Scholar 

  • Wang, X., Li, L., Guan, R., Zhu, D., Song, N., & Shen, L. (2017). Emodin inhibits ATP-induced proliferation and migration by suppressing P2Y receptors in human lung adenocarcinoma cells. Cellular Physiology and Biochemistry, 44, 1337–1351.

    Article  CAS  Google Scholar 

  • Weisman, G. A., Woods, L. T., Erb, L., & Seye, C. I. (2012). P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential. CNS and Neurological Disorders Drug Targets, 11, 722–738.

    Article  CAS  Google Scholar 

  • West, L. E., Steiner, T., Judge, H. M., Francis, S. E., & Storey, R. F. (2014). Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovascular Research, 102, 429–435.

    Article  CAS  Google Scholar 

  • Wihlborg, A. K., Malmsjo, M., Eyjolfsson, A., Gustafsson, R., Jacobson, K., & Erlinge, D. (2003). Extracellular nucleotides induce vasodilatation in human arteries via prostaglandins, nitric oxide and endothelium-derived hyperpolarising factor. British Journal of Pharmacology, 138, 1451–1458.

    Article  CAS  Google Scholar 

  • Wihlborg, A. K., Wang, L., Braun, O. O., Eyjolfsson, A., Gustafsson, R., Gudbjartsson, T., & Erlinge, D. (2004). ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arteriosclerosis, Thrombosis and Vascular Biology, 24, 1810–1815.

    Article  CAS  Google Scholar 

  • Wihlborg, A. K., Balogh, J., Wang, L., Borna, C., Dou, Y., Joshi, B. V., Lazarowski, E., Jacobson, K. A., Arner, A., & Erlinge, D. (2006). Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y2 and P2Y6 receptors on cardiomyocytes and release of UTP in man during myocardial infarction. Circulation Research, 98, 970–976.

    Article  CAS  Google Scholar 

  • Wurm, A., Erdmann, I., Bringmann, A., Reichenbach, A., & Pannicke, T. (2009). Expression and function of P2Y receptors on muller cells of the postnatal rat retina. Glia, 57, 1680–1690.

    Article  Google Scholar 

  • Xie, R., Xu, J., Wen, G., Jin, H., Liu, X., Yang, Y., Ji, B., Jiang, Y., Song, P., Dong, H., & Tuo, B. (2014). The P2Y2 nucleotide receptor mediates the proliferation and migration of human hepatocellular carcinoma cells induced by ATP. Journal of Biological Chemistry, 289, 19137–19149.

    Article  CAS  Google Scholar 

  • Yoshioka, K., Saitoh, O., & Nakata, H. (2001). Heteromeric association creates a P2Y-like adenosine receptor. Proceedings of the National Academy of Sciences, USA, 98, 7617–7622.

    Article  CAS  Google Scholar 

  • Zerr, M., Hechler, B., Freund, M., Magnenat, S., Lanois, I., Cazenave, J. P., Leon, C., & Gachet, C. (2011). Major contribution of the P2Y(1)receptor in purinergic regulation of TNFalpha-induced vascular inflammation. Circulation, 123, 2404–2413.

    Article  CAS  Google Scholar 

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    Authors and Affiliations

    1. Department of Biochemistry, Rayalaseema University, Kurnool, Andhra Pradesh, India

      Senthilkumar Rajagopal

    2. Center for Developmental Cardiology, Institute for Translational Medicine, Qingdao University, Qingdao, China

      Murugavel Ponnusamy

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    1. Senthilkumar Rajagopal
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    Rajagopal, S., Ponnusamy, M. (2018). P2Y Receptor. In: Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases . Springer, Singapore. https://doi.org/10.1007/978-981-13-1571-8_3

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