P2Y receptors in GtoPdb v.2023.1

Abstract

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 189]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y₁, P2Y₁₁, P2Y₁₂ and P2Y₁₃ are activated by adenosine-nucleotides; P2Y₂, P2Y₄ can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y₆ is mainly activated by UDP; P2Y₁₄ is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [380]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y₁, P2Y₂, P2Y₄, P2Y₆ and P2Y₁₁ receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca²⁺ from intracellular stores. P2Y₁₁ receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y₁₂, P2Y₁₃, and P2Y₁₄ receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [380]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y₂ receptor subtype, approved in Japan and South Korea for the management of dry eye disease [238], and the P2Y₁₂ receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 320].