GRK2 Regulates ADP Signaling in Platelets Via P2Y 1 and P2Y 12

Abstract Venous thromboembolism (VTE), heart attack, and stroke are all diseases in which platelets play a role, through inappropriate platelet activation subsequent thrombus formation. Most agonists activate via G protein-coupled receptors (GPCRs), targeted by many antiplatelet drugs. Along with thrombin TxA 2, ADP has long been recognized for its important role hemostasis thrombosis. It activates GPCRs, P2Y 1 12. However, little is known about the negative feedback mechanisms governing receptor-mediated Here, we provide first evidence that GPCR kinase 2 (GRK2) serves this regulatory during formation using platelet-specific GRK2 deletion mouse model GRK2-specific inhibitor human platelets. Deletion of causes increased accumulation following laser-induced injury cremaster muscle arterioles, particularly shell region thrombi. In addition, increases ADP-induced pulmonary thromboembolism. -/- also have aggregation response to ADP, but not PAR4 receptor agonist, or convulxin. Underlying these changes an increase Ca 2+ mobilization, Akt phosphorylation, Rap1 attenuated rise cAMP levels presence prostaglandin I 2. Furthermore, can be restored re-stimulation, indicating contributes desensitization. To further assess 12 signaling pathway vivo, examine WT mice treated antagonist, cangrelor. Cangrelor treatment eliminates phenotypic difference between injury. Using specific inhibitor, pharmacologic inhibition activity results ADP. Finally, our biochemical studies show binds endogenous Gβγ subunits activation. Taken together, demonstrated time 1) plays attenuating ADP-dependent signaling, 2) it does limiting 12-mediated 3) interacts functions as hub fine-tuning 4) although potential beneficial diseases, maintaining could prevention thrombotic diseases. Disclosures No relevant conflicts interest declare.