Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 4, Pages 1823-1828Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.98.4.1823
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Glycoprotein (GP)V is a major substrate cleaved by the protease thrombin during thrombin-induced platelet activation. Previous analysis of platelets from CP V-null mice suggested a role for GP V as a negative modulator of platelet 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 platelets, via the platelet GP Ib-IX-V complex. Because proteolytically inactive thrombin can activate wild-type mouse and human platelets after treatment with thrombin to cleave GP V, this mechanism is involved in thrombin-induced platelet aggregation. Platelet activation through GP Ib-IX depends on ADP secretion, and specific inhibitors demonstrate that the recently cloned P2Y(12) ADP receptor (G(i)-coupled ADP receptor) is involved in this pathway, and that the P2Y(1) receptor (G(q)-coupled ADP receptor) may play a less significant role. Thrombosis was generated in GP V null mice only in response to catalytically inactive thrombin, whereas thrombosis occurred in both genotypes (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 complex, and describe a novel thrombin signaling mechanism involving an initiating proteolytic event followed by stimulation of the GP Ib-IX via thrombin acting as a ligand, resulting in platelet activation.
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