Pharmacology and structure of P2Y receptors

• Published in: Neuropharmacology 2016-05, Vol.104, p.50-61
• Main Authors: von Kügelgen, Ivar, Hoffmann, Kristina
• Format: Article
• Language: English
• Subjects: Adenine nucleotides; Adenosine Diphosphate - metabolism; Adenosine Triphosphate - metabolism; Animals; Brain - metabolism; Cardiovascular Diseases - metabolism; Crystal structure; Humans; Inflammation; Microglia - metabolism; Neurodegenerative Diseases - metabolism; Neuromodulation; Neurons - metabolism; P2Y receptors; Platelet Aggregation; Purinergic P2Y Receptor Agonists - pharmacology; Purinergic P2Y Receptor Antagonists - pharmacology; Receptor ligands; Receptors, Purinergic P2Y - chemistry; Receptors, Purinergic P2Y - metabolism; Receptors, Purinergic P2Y - physiology; Uracil nucleotides; Uridine Triphosphate - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.10.030

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). P2Y receptors are widely expressed and play important roles in physiology and pathophysiology. One important example is the ADP-induced platelet aggregation mediated by P2Y1 and P2Y12 receptors. Active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel as well as the nucleoside analogue ticagrelor block P2Y12 receptors and thereby platelet aggregation. These drugs are used for the prevention and therapy of cardiovascular events. Moreover, P2Y receptors play important roles in the nervous system. Adenine nucleotides modulate neuronal activity and neuronal fibre outgrowth by activation of P2Y1 receptors and control migration of microglia by P2Y12 receptors. UDP stimulates microglial phagocytosis through activation of P2Y6 receptors. There is evidence for a role for P2Y2 receptors in Alzheimer's disease pathology. The P2Y receptor subtypes are highly diverse in both their amino acid sequences and their pharmacological profiles. Selective receptor ligands have been developed for the pharmacological characterization of the receptor subtypes. The recently published three-dimensional crystal structures of the human P2Y1 and P2Y12 receptors will facilitate the development of therapeutic agents that selectively target P2Y receptors. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’. •P2Y receptors are activated by extracellular nucleotides as such ADP, ATP and UTP.•The crystal structures of P2Y1 and P2Y12 receptors have recently been identified.•Blockade of platelet P2Y12 receptors reduces cardiovascular events.•P2Y6 and P2Y12 receptors control microglial function.•P2Y receptors play a role in neuroprotection and neurodegeneration.