Intracellular signaling in platelets

Abstract

Over the past few years, a large portion of platelet research has focused on intracellular signaling events that contribute to stable platelet adhesion and aggregation. Studies of knockout mice have suggested critical roles for several previously unappreciated signaling molecules including phosphatidylinositol 3-kinase, the exchange factor CalDAG-GEFI, and the small GTPase Rap1b. These proteins may function to remodel the platelet cytoskeleton and thereby regulate both adhesion and aggregation. The abundant cytoskeletal protein talin appears to be a key regulator of the platelet integrin alphaIIbbeta3. Recent evidence suggests that talin binding to the cytoplasmic tail of beta3 promotes integrin oligomerization, thereby increasing the binding avidity the alphaIIbbeta3 complex for fibrinogen. The identification of platelet signaling pathways not only has clinical implications for diagnosis, but perhaps more importantly for rationale drug design. Aspirin, dipyridamole (Persantine), and thienopyridines (ticlopidine and clopidogrel) are all examples of agents that specifically target discrete platelet signaling pathways. These drugs have already been proven to be beneficial in the treatment of cardiovascular disease. Novel agents that target newly identified signaling pathways hold promise of greater specificity and efficacy.