期刊
VASCULAR PHARMACOLOGY
卷 111, 期 -, 页码 22-25出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2018.08.007
关键词
Platelet adhesion; Platelet signalling; Inside-out signalling; Outside in signalling; Novel antiplatelet targets
资金
- Spanish Ministry of Science and Innovation [PNS2015-71653-R, PNSSAF2016-76819-R]
- Instituto de Salud Carlos III CIBERCV [CN16/11/00411]
- FEDER funds
- Generalitat of Catalunya (Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat) [2014SGR1303]
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.
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