Update of P2Y receptor pharmacology: IUPHAR Review 27
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2020
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Wiley
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Jacobson KA, Delicado EG, Gachet C, Charles K, von Kügelgen I, Li B, Miras-Portugal MT, Novak I, Schöneberg T, Perez‐Sen R, Thor D, Wu B, Yang Z, Müller CE. Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol. 2020; 177: 2413 2433. https://doi.org/10.1111/bph.15005.
Abstract
Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the delta group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y(1), P2Y(2), P2Y(4), P2Y(6), and P2Y(11) (principally G(q) protein-coupled P2Y(1)-like) and P2Y(12-14) (principally G(i) protein-coupled P2Y(12)-like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors induce vasodilation, while smooth muscle P2Y(2), P2Y(4), and P2Y(6) receptor activation leads to vasoconstriction. Pancreatic P2Y(1) and P2Y(6) receptors stimulate while P2Y(13) receptors inhibits insulin secretion. Antagonists of P2Y(12) receptors, and potentially P2Y(1) receptors, are anti-thrombotic agents, and a P2Y(2)/P2Y(4) receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.
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DATES: Received: 12 August 2019; Revised: 12 January 2020; Accepted: 15 January 2020.
1-Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Massachusetts.
2-Dpto. Bioquimica y Biologia Molecular, Universidad Complutense de Madrid, Madrid, Spain.
3-Université de Strasbourg INSERM, EFS Grand Est, BPPS UMR-S 1255, FMTS, Strasbourg, France.
4-Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
5-Biomedical Research Center, Department of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
6-CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
7-Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark.
8-Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
9-IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, Germany.
10-Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany.
ACKNOWLEDGEMENTS: The research of Doreen Thor and Torsten Schöneberg was mainly supported by the German Research Foundation (DFG) in SFB 1052, the Integrated Research and Treatment Center (IFB) AdiposityDiseases (BMBF), and intramural funding of the State of Saxony, Germany. Ivana Novak acknowledges support by the Independent Research Fund Denmark (DFF-4002-00162). We thank the NIDDK Intramural Research Program (K.A.J.) for support. Christa Müller is grateful for support by the DFG (GRK1873 and FOR2372).