Update of P2Y receptor pharmacology: IUPHAR Review 27

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.