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Overview of the pharmacology and physiological roles of P2Y receptors

par Boeynaems, Jean-Marie ;Communi, Didier ;Robaye, Bernard
Référence Wiley Interdisciplinary Reviews: Membrane Transport and Signaling, 1, 5, page (581-588)
Publication Publié, 2012-09

Article révisé par les pairs

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Résumé :

The release of nucleotides in extracellular fluids can result from cell necrosis, exocytosis of secretory granules (such as platelet-dense granules), vesicular trafficking, or efflux through membrane channels. Once in the extracellular fluids, nucleotides are rapidly degraded by ectonucleotidases, such as CD39 and CD73, that transform ATP sequentially into ADP, AMP and finally adenosine. Extracellular nucleotides act on two families of receptors: the ionotropic P2X receptors and the G-protein-coupled P2Y receptors. There are eight genuine P2Y receptor subtypes encoded by distinct genes that can be subdivided in two structurally distinct subfamilies: P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 on one hand and P2Y12, P2Y13, and P2Y14 on the other hand. Whereas P2X receptors are receptors of ATP, the different P2Y receptors are activated by distinct nucleotides, diphosphates or triphosphates, purines or pyrimidines, some of them being conjugated to sugars. The most striking action of nucleotides mediated by P2Y receptors is the aggregation of platelets by ADP that involves a cooperation between P2Y1 and P2Y12. The only drugs targeting a P2Y receptor currently on the market are P2Y12 antagonists used as antiplatelet agents: ticlopidine, clopidogrel, prasugrel, and ticagrelor. However, gene silencing techniques have been instrumental in establishing new unexpected functions of P2Y receptors, such as the role of P2Y2 receptors in leukocyte chemotaxis and tissue infiltration, the attraction of microglia by P2Y12 and the stimulation of their phagocytic activity by P2Y6, and the activation of reverse cholesterol transport by P2Y13 expressed on hepatocytes. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.