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Characterization of a functional thrombin receptor. Issues and opportunities.

Introduction How does the protease thrombin activate platelets and other cells? This question presents intriguing issues from both basic scientific and clinical perspectives. From a basic view, the fact that thrombin is a protease raises the possibility of a novel proteolytic mechanism of receptor activation. From a clinical view, thrombin regulates hemostasis and thrombosis. Moreover, a host of thrombin actions on cells have been defined in vitro; in vivo these actions may be critical for both normal responses to wounding and for pathological vascular events. An understanding of the mechanism of thrombin-induced cell activation promises reagents for identifying thrombin's role in cellular responses in vivo and possibly new therapeutics. In this Perspectives, we review the recent cloning and characterization of a platelet thrombin receptor in our laboratory (1). Identification of the thrombin receptor did reveal a unique proteolytic mechanism of receptor activation, and led to the development of a novel agonist peptide which activates the thrombin receptor independent of thrombin and thrombin's protease activity. This agonist peptide is a useful new tool for addressing the role of thrombin receptor activation in cellular responses. It is our hope that having the cloned receptor in hand will also allow the development of thrombin receptor antagonists. Such reagents will define the role of thrombin receptor activation in normal and disease processes in vivo, and may provide the basis for a new class of antithrombotic or antiproliferative pharmaceuticals.