Update of P2Y receptor pharmacology: IUPHAR Review 27

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.