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  • Title: Dual P2Y 12 receptor signaling in thrombin-stimulated platelets--involvement of phosphoinositide 3-kinase beta but not gamma isoform in Ca2+ mobilization and procoagulant activity.
    Author: van der Meijden PE, Schoenwaelder SM, Feijge MA, Cosemans JM, Munnix IC, Wetzker R, Heller R, Jackson SP, Heemskerk JW.
    Journal: FEBS J; 2008 Jan; 275(2):371-85. PubMed ID: 18081863.
    Abstract:
    During thrombus formation, thrombin, which is abundantly present at sites of vascular injury, activates platelets in part via autocrine-produced ADP. We investigated the signaling pathways by which thrombin and ADP in synergy induced platelet Ca(2+) elevation and procoagulant activity, and we monitored the consequences for the coagulation process. Even at high thrombin concentration, autocrine and added ADP enhanced and prolonged Ca(2+) depletion from internal stores via stimulation of the P2Y(12) receptors. This P2Y(12)-dependent effect was mediated via two distinct signaling pathways. The first is enhanced Ca(2+) mobilization by the inositol 1,4,5-trisphosphate receptors due to inhibition of protein kinase A. The second pathway concerns prolonged activation of phosphoinositide 3-kinase (PI3-K) and phospholipase C. Experiments with phosphoinositide 3-kinase isoform-selective inhibitors and p110gamma deficient platelets demonstrated that the phosphoinositide 3-kinase beta and not the phosphoinositide 3-kinase gamma isoform is responsible for the prolonged Ca(2+) response and for the subsequent increases in procoagulant activity and coagulation. Taken together, these results demonstrate a dual P2Y(12)-dependent signaling mechanism, which increases the platelet-activating effect of thrombin by prolongation of Ca(2+) elevation, thereby facilitating the coagulation process.
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