Jacobson Kenneth A, Delicado Esmerilda G, Gachet Christian, Kennedy Charles, von Kügelgen Ivar, Li Beibei, Miras-Portugal M Teresa, Novak Ivana, Schöneberg Torsten, Perez-Sen Raquel, Thor Doreen, Wu Beili, Yang Zhenlin, Müller Christa E
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Massachusetts.
Dpto. Bioquimica y Biologia Molecular, Universidad Complutense de Madrid, Madrid, Spain.
Br J Pharmacol. 2020 Jun;177(11):2413-2433. doi: 10.1111/bph.15005. Epub 2020 Apr 6.
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 , P2Y , P2Y , P2Y , and P2Y (principally G protein-coupled P2Y -like) and P2Y (principally G protein-coupled P2Y -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y , P2Y , P2Y , and P2Y receptors induce vasodilation, while smooth muscle P2Y , P2Y , and P2Y receptor activation leads to vasoconstriction. Pancreatic P2Y and P2Y receptors stimulate while P2Y receptors inhibits insulin secretion. Antagonists of P2Y receptors, and potentially P2Y receptors, are anti-thrombotic agents, and a P2Y /P2Y 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.
八种G蛋白偶联P2Y受体亚型可对细胞外腺嘌呤、尿嘧啶单核苷酸和二核苷酸作出反应。P2Y受体属于视紫红质样GPCR的δ组，包含两个结构上不同的亚家族：P2Y₁、P2Y₂、P2Y₄、P2Y₆和P2Y₁₁（主要是G蛋白偶联的P2Y₁样）以及P2Y₁₂（主要是G蛋白偶联的P2Y₁₂样）受体。脑P2Y受体存在于神经元、神经胶质细胞和脉管系统中。内皮细胞的P2Y₁、P2Y₂、P2Y₄和P2Y₆受体可诱导血管舒张，而平滑肌的P2Y₁、P2Y₁₂和P2Y₆受体激活则导致血管收缩。胰腺的P2Y₁和P2Y₆受体刺激胰岛素分泌，而P2Y₁₂受体则抑制胰岛素分泌。P2Y₁₂受体拮抗剂以及潜在的P2Y₁受体拮抗剂是抗血栓形成药物，一种P2Y₁/P2Y₆受体激动剂在亚洲用于治疗干眼症。P2Y受体激动剂通常具有促炎作用，拮抗剂可能最终用于治疗炎症性疾病。本文综述了P2Y受体药理学（使用合成激动剂和拮抗剂）、结构和生物物理特性（使用X射线晶体学、诱变和建模）、生理和病理生理作用以及当前和潜在的未来治疗靶点方面的最新进展。
