A DUAL THROMBIN RECEPTOR SYSTEM FOR PLATELET ACTIVATION

Plalelet-dependent arterial thrombosis triggers most heart attacks and strokes. Because the coagulation protease thrombin is the most potent activator of platelets', identification of the platelet receptors for thrombin is critical for understanding thrombosis and haemostasis. Pr otease-activated receptor-1 (PAR1) is important for activation of huma n platelets by thrombin(2-6), but plays no apparent role in mouse plat elet activation(7-9) PAR3 is a thrombin receptor that is expressed in mouse megakaryocytes(10). Here we report that thrombin responses in pl atelets from PAR3-deficient mice were markedly delayed and diminished but not absent. We have also identified PAR4, a new thrombin-activated receptor. PAR4 messenger RNA was detected in mouse megakaryocytes and a PAR4-activating peptide caused secretion and aggregation of PARS-de ficient mouse platelets. Thus PAR3 is necessary for normal thrombin re sponses in mouse platelets, but a second PAR4-mediated mechanism for t hrombin signalling exists. Studies with PAR-activating peptides sugges t that PAR4 also functions in human platelets, which implies that an a nalogous dual-receptor system also operates isl humans. The identifica tion of a two-receptor system for platelet activation by thrombin has important implications for the development of antithrombotic therapies .