Intracellular platelet signalling as a target for drug development

Platelets are endowed with a repertoire of surface receptors that enable them to adhere, activate and aggregate upon vascular injury. Platelet adhesion is governed by the interaction between vascular collagen and GPIb-IX-V and GPVI-FcR gamma complexes. Platelet kinases downstream 14-3-3 zeta-bound GPIb and the FcR gamma ITAM domain enable the activation of PLC-gamma 2 whereas the engagement of soluble agonists (predominantly ADP, TXA(2) and thrombin) with Gq-protein coupled receptor trigger PLC-beta activation. Once activated, PLC-gamma 2/beta induces the generation of second messengers IP3 and DAG. IP3 is involved in Ca2+ cytosolic release from the dense tubular system whereas DAG induces PKC activation. CalDAG-GEFI sensors Ca2+ mobilization and, through activation of the small GTPase Rap1, induces cytoskeleton re-arrangements, extrusion of platelet granules and conversion of integrin alpha II beta 3 into a high-affinity state (inside-out signalling). These events are found to be reinforced by PKC, MAPK, and ROS-dependent GPVI pathways. Finally, ligand-interaction with alpha IIb beta 3 bridges platelets together and triggers outside-in signalling that orchestrates cytoskeletal rearrangements for platelet spreading and clot stabilization through the PI3K/PDK1/Akt/GSK3 axis. Understanding the platelet signalling machinery involved in thrombus formation is necessary to identify potential targets for the development of new antiplatelet agents.