Update of P2Y receptor pharmacology: IUPHAR Review 27

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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: P2Y₁ , P2Y₂ , P2Y₄ , P2Y₆ , and P2Y₁₁ (principally G_q protein-coupled P2Y₁ -like) and P2Y_12-14 (principally G_i protein-coupled P2Y₁₂ -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y₁ , P2Y₂ , P2Y₄ , and P2Y₆ receptors induce vasodilation, while smooth muscle P2Y₂ , P2Y₄ , and P2Y₆ receptor activation leads to vasoconstriction. Pancreatic P2Y₁ and P2Y₆ receptors stimulate while P2Y₁₃ receptors inhibits insulin secretion. Antagonists of P2Y₁₂ receptors, and potentially P2Y₁ receptors, are anti-thrombotic agents, and a P2Y₂ /P2Y₄ 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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