Human platelets are rapidly activated at sites of vascular injury by agonists such as collagen, thrombin and AP. With the notable exception of collagen, most agonists activate platelets via cell surface receptors coupled to heterotrimeric G proteins. Collectively, G proteins and G protein coupled receptors provide a sensitive mechanism that allows rapid platelet activation. However, this sensitivity also increases the risk that inappropriate platelet activation will, if unchecked, cause tissue ischemia and infarction. This is particularly true when progressive diseases such as atherosclerosis narrow the vascular lumen. Since passage through the circulatory system will predictably expose platelets to conditions that could cause unwanted activation, it is reasonable to propose that mechanisms exist to place limits on signaling through G proteins. It is our hypothesis that in platelets such regulatory mechanisms are directed towards both receptors and G proteins, but those working at the level of the G proteins are particularly important and work in concert with endothelial but those working at the level of the G proteins Are particularly important and work in concert with endothelial PGI2, NO and CD39 to prevent inappropriate platelet activation. The goal of the proposed studies is to test this hypothesis and to extend current information about the regulation of G protein-dependent signaling in platelets. Three related issues will be addressed using human platelets and platelets from genetically-engineered mice. First, there are at least 1o different G proteins in platelets. To what extend does each make a unique contribution to signaling and to what extent are they redundant? Second, will persistent activation of G proteins in platelet hyperactivity ex vivo and will it contribute to the development of thrombosis and the progression of atherosclerosis in vivo. Third, what are the roles of RGS proteins in limiting G protein signaling in platelets and do they provide a means of preventing unwarranted platelet activation? We will address these questions primarily using transgenic engineered for both a gain and loss of function of platelet G protein signaling. The results of these studies should new information about normal platelet biology, identify potential targets for therapeutic intervention, and create model systems in which the consequences of dysregulated platelet activation can be studied and understood.
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