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Dual P2Y 12 receptor signaling in thrombin‐stimulated platelets – involvement of phosphoinositide 3‐kinase β but not γ isoform in Ca 2+ mobilization and procoagulant activity
Author(s) -
van der Meijden Paola E. J.,
Schoenwaelder Simone M.,
Feijge Marion A. H.,
Cosemans Judith M. E. M.,
Munnix Imke C. A.,
Wetzker Reinhard,
Heller Regine,
Jackson Shaun P.,
Heemskerk Johan W. M.
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.06207.x
Subject(s) - thrombin , phosphoinositide 3 kinase , platelet , autocrine signalling , phospholipase c , signal transduction , microbiology and biotechnology , p2y receptor , thrombin receptor , receptor , platelet activation , phosphatidylinositol , protein kinase c , inositol , chemistry , kinase , biology , biochemistry , protein kinase b , immunology , purinergic receptor
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 p110γ deficient platelets demonstrated that the phosphoinositide 3‐kinase β and not the phosphoinositide 3‐kinase γ 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.