P2Y12 receptors: structure and function

Abstract

To cite this article: Cattaneo M. P2Y 12 receptors: structure and function. J Thromb Haemost 2015; 13 (Suppl. 1): S10-S6.Summary. The platelet P2Y 12 receptor (P2Y 12 R) for adenosine 5 0 diphosphate (ADP) plays a central role in platelet function, hemostasis, and thrombosis. Patients with inherited P2Y 12 R defects display mild-to-moderate bleeding diatheses. Defects of P2Y 12 R should be suspected when ADP, even at high concentrations (≥ 10 lM), is unable to induce full, irreversible platelet aggregation. P2Y 12 R also plays a role in inflammation: its role in the pathogenesis of allergic asthma has been well characterized. In addition, inhibition or genetic deficiency of P2Y 12 R has antitumor effects. Drugs inhibiting P2Y 12 R are potent antithrombotic drugs. Clopidogrel is the P2Y 12 R antagonist that is most widely used in the clinical setting. Its most important drawback is its inability to inhibit adequately P2Y 12 R-dependent platelet function in about onethird of patients. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y 12 R in the vast majority of patients, have proved to be more efficacious than clopdidogrel in preventing major adverse cardiovascular events.

Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade

“…Loss of microglial expression of P2RY12 in knockout mice resulted in impaired polarization, migration and extension of microglial processes towards extracellular nucleotides released from damaged cells, indicating that P2RY12 is required to guide microglial chemotaxis [12]. Further studies revealed that a raise of local extracellular ATP/ADP levels at the site of CNS injury activates Gi/o-coupled P2RY12, followed by PI3K and PLC signaling-mediated migration of microglial cells towards the chemotactic source [7]. Exogenous stimuli like lipopolysaccharides (LPS) can cause a dramatic reduction of the P2RY12 expression in microglia cells in vitro accompanied by the retraction of microglial processes and metamorphosis into an amoeboid shape [12].…”

“…P2RY12 was claimed as a specific marker for microglial cells in human brains [1, 6, 34]. P2RY12 belongs to the family of P2 purinergic receptors, consisting of seven transmembrane G protein coupled receptors (GPCRs) that contribute to ATP-and ADP-mediated cell migration in vitro [7]. P2RY12 is expressed in activated platelets and notoriously, in microglial cells [20].…”

Breast Carcinoma: From Initial Tumor Cell Detachment to Settlement at Secondary Sites

“…For instance, in vitro studies showed that MCF7 breast cancer cells cotransfected with MMP14/ β 3-integrin caused platelet aggregation via introduced MT1-MMP/MMP14 and via activation of MMP2. Additionally, ADP contributed to TCIPA via stimulation of the corresponding platelet receptor P2Y 12 [107, 108]. Thus, it is feasible that tumor cell-induced platelet aggregation promotes survival of cancer cells in vascular circulation since platelets may shield CTCs from immune cell assaults and from fluid shear stress and may facilitate extravasation at distant organs resulting in enhanced metastatic potential [109–111].…”

RAP1-GTPase signaling and platelet function

“…The formation of a stable hemostatic plug or a pathological thrombus requires sustained integrin inside-out activation, provided by co-stimulatory signaling via the autocrine/paracrine agonists thromboxane (Tx)A 2 and ADP[4, 5]. ADP is released from platelet dense granules and supports sustained integrin activation by binding to the Gi-coupled receptor, P2Y12, the target of currently used anti-platelet drugs[6]. Studies by us and others identified a critical role for the small GTPase RAP1B in platelet activation and integrin-mediated cellular adhesion.…”