Update of P2Y receptor pharmacology : IUPHAR Review 27

Jacobson, Kenneth A. and Delicado, Esmerilda G. and Gachet, Christian and Kennedy, Charles and von Kügelgen, Ivar and Li, Beibei and Miras-Portugal, M. Teresa and Novak, Ivana and Schöneberg, Torsten and Perez-Sen, Raquel and Thor, Doreen and Wu, Beili and Yang, Zhenlin and Müller, Christa E. (2020) Update of P2Y receptor pharmacology : IUPHAR Review 27. British Journal of Pharmacology, 177 (11). 2413–2433. ISSN 1476-5381

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    Abstract

    Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ 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.