Molecular Pharmacology, Physiology, and Structure of the P2Y Receptors

• Published in: Advances in Pharmacology Vol. 61; pp. 373 - 415
• Main Authors: von Kügelgen, Ivar, Harden, T. Kendall
• Format: Book Chapter Journal Article
• Language: English
• Published: United States Elsevier Inc 2011; Elsevier Science & Technology
• Subjects: Amino Acid Sequence; Animals; G protein; Heterotrimeric GTP-Binding Proteins - metabolism; Humans; Ligands; Molecular biology; Molecular Sequence Data; nucleotide; P2Y receptor; Pharmacology; Receptors, Purinergic P2Y - chemistry; Receptors, Purinergic P2Y - physiology; Signal Transduction; P2Y receptor; nucleotide; G protein
• ISBN: 9780123855268; 0123855268
• ISSN: 1054-3589; 1557-8925
• DOI: 10.1016/B978-0-12-385526-8.00012-6

The P2Y receptors are a widely expressed group of eight nucleotide-activated G protein-coupled receptors (GPCRs). The P2Y 1(ADP), P2Y 2(ATP/UTP), P2Y 4(UTP), P2Y 6(UDP), and P2Y 11(ATP) receptors activate G q and therefore robustly promote inositol lipid signaling responses. The P2Y 12(ADP), P2Y 13(ADP), and P2Y 14(UDP/UDP-glucose) receptors activate G i leading to inhibition of adenylyl cyclase and to Gβγ-mediated activation of a range of effector proteins including phosphoinositide 3-kinase-γ, inward rectifying K + (GIRK) channels, phospholipase C-β2 and -β3, and G protein-receptor kinases 2 and 3. A broad range of physiological responses occur downstream of activation of these receptors ranging from Cl − secretion by epithelia to aggregation of platelets to neurotransmission. Useful structural models of the P2Y receptors have evolved from extensive genetic analyses coupled with molecular modeling based on three-dimensional structures obtained for rhodopsin and several other GPCRs. Selective ligands have been synthesized for most of the P2Y receptors with the most prominent successes attained with highly selective agonist and antagonist molecules for the ADP-activated P2Y 1 and P2Y 12 receptors. The widely prescribed drug, clopidogrel, which results in irreversible blockade of the platelet P2Y 12 receptor, is the most important therapeutic agent that targets a P2Y receptor.