A thrombin receptor function for platelet glycoprotein Ib-IX unmasked by cleavage of glycoprotein V

Glycoprotein (GP)V is a major substrate cleaved by the protease thrombin du ring thrombin-induced platelet activation. Previous analysis of platelets f rom CP V-null mice suggested a role for GP V as a negative modulator of pla telet activation by thrombin, We now report the mechanism by which thrombin activates GP V -/- platelets. We show that proteolytically inactive forms of thrombin induce robust stimulatory responses in GP V null mouse platelet s, via the platelet GP Ib-IX-V complex. Because proteolytically inactive th rombin can activate wild-type mouse and human platelets after treatment wit h thrombin to cleave GP V, this mechanism is involved in thrombin-induced p latelet aggregation. Platelet activation through GP Ib-IX depends on ADP se cretion, and specific inhibitors demonstrate that the recently cloned P2Y(1 2) ADP receptor (G(i)-coupled ADP receptor) is involved in this pathway, an d that the P2Y(1) receptor (G(q)-coupled ADP receptor) may play a less sign ificant role. Thrombosis was generated in GP V null mice only in response t o catalytically inactive thrombin, whereas thrombosis occurred in both geno types (wild type and CP V null) in response to active thrombin, These data support a thrombin receptor function for the platelet membrane GP Ib-IX-V c omplex, and describe a novel thrombin signaling mechanism involving an init iating proteolytic event followed by stimulation of the GP Ib-IX via thromb in acting as a ligand, resulting in platelet activation.