Structure, Pharmacology and Roles in Physiology of the P2Y12 Receptor

Abstract

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. The platelet ADP-receptor which has been denominated P2Y receptor is an important target in pharmacotherapy. The receptor couples to G mediating an inhibition of cyclic AMP accumulation and additional downstream events including the activation of phosphatidylinositol-3-kinase and Rap1b proteins. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel block P2Y receptors and, thereby, inhibit ADP-induced platelet aggregation. These drugs are used for the prevention and therapy of cardiovascular events such as acute coronary syndromes or stroke. The recently published three-dimensional crystal structures of the human P2Y receptor in complex with agonists and antagonists will facilitate the development of novel therapeutic agents with reduced adverse effects. P2Y receptors are also expressed on vascular smooth muscle cells and may be involved in the pathophysiology of atherogenesis. P2Y receptors on microglial cells operate as sensors for adenine nucleotides released during brain injury. A recent study indicated the involvement of microglial P2Y receptors in the activity-dependent neuronal plasticity. Interestingly, there is evidence for changes in P2Y receptor expression in CNS pathologies including Alzheimer's diseases and multiple sclerosis. P2Y receptors may also be involved in systemic immune modulating responses and the susceptibility to develop bronchial asthma.

Dual Anticoagulant/Antiplatelet Activity of Polyphenolic Grape Seeds Extract

“…Previous studies with receptor agonists have suggested that activation of both P2Y receptors is required for a full response of platelets to ADP. Generally, the P2Y1 pathway initiates platelet activation and mediates weak responses to ADP, whereas the P2Y12 receptor plays a role in strongly amplifying the platelets activation process and is essential for a full aggregation response to ADP and the stabilization of aggregates [38]. VASP is an intracellular platelet protein that is non-phosphorylated in its basal state.…”

Characterisation of P2Y2 receptors in human vascular endothelial cells using AR‐C118925XX, a competitive and selective P2Y2 antagonist

“…Currently, potent, selective antagonists have only been developed for P2Y 1 (e.g., MRS2179, MRS2279, and MRS2500) and P2Y 12 (e.g., ticagrelor, cangrelor, and clopidogrel) receptors (see Abbracchio et al, ; Kennedy et al, ). These played a major role in identifying physiological roles, such as that of P2Y 1 receptors in peristalsis in the gut (see Kennedy, ) and of P2Y 1 and P2Y 12 receptors in platelet aggregation (Abbracchio et al, ; von Kügelgen, ). Clearly, the development of potent and selective antagonists at the other P2Y subtypes would greatly enhance our ability to determine their functions in health and disease.…”

“…played a major role in identifying physiological roles, such as that of P2Y 1 receptors in peristalsis in the gut (see Kennedy, 2015) and of P2Y 1 and P2Y 12 receptors in platelet aggregation (Abbracchio et al, 2006;von Kügelgen, 2017). Clearly, the development of potent and selective antagonists at the other P2Y subtypes would greatly enhance our ability to determine their functions in health and disease.…”

Prevention of P2 Receptor-Dependent Thrombocyte Activation by Pore-Forming Bacterial Toxins Improves Outcome in A Murine Model of Urosepsis

“…However, P2Y 1 receptors are expressed on various cells in the vascular compartment [49], and, thus, the increased survival could, in principle, result from effects on the endothelial cells or other immune cells. The expression profile for P2Y 12 is (for review, see [50]), however, much more restrictive and is primarily confined to the thrombocytes. Therefore, it is interesting to observe that cangrelor tendentially improve the survival of sepsis even though this is not statistically significant.…”