Platelet hyperreactivity and a prothrombotic phenotype in mice with a gain-of-function mutation in phospholipase C gamma 2

Margitta Elvers, R. Pozgaj, I. Pleines, Frauke May, M. J. E. Kuijpers, J. M. W. Heemskerk, Patrick Yu-Wai-Man, B. Nieswandt*

*Corresponding author for this work

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Abstract

Agonist-induced platelet activation involves different signaling pathways leading to the activation of phospholipase C (PLC) beta or PLCgamma2. Activated PLC produces inositol 1,4,5-trisphosphate and diacylglycerol, which trigger Ca(2+) mobilization and the activation of protein kinase C, respectively. PLCbeta is activated downstream of Gq-coupled receptors for soluble agonists with only short interaction times in flowing blood. In contrast, PLCgamma2 becomes activated downstream of receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI or activated integrins.We speculated that PLCgamma2 activity might be optimized for sustained but submaximal signaling to control relatively slow platelet responses. To test this hypothesis, we analyzed platelets from mice heterozygous for a gain-of-function mutation in the Plcg2 gene (Plcg2(Ali5/+)).Plcg2(Ali5/+) platelets showed enhanced Ca(2+) mobilization, integrin activation, granule secretion and phosphatidylserine exposure upon GPVI or C-type lectin-like receptor-2 stimulation. Furthermore, integrin alpha(IIb)beta(3) outside-in signaling was markedly enhanced in the mutant platelets, as shown by accelerated spreading on different matrices and faster clot retraction. These defects translated into virtually unlimited thrombus formation on collagen under flow in vitro and a prothrombotic phenotype in vivo.These results demonstrate that the enzymatic activity of PLCgamma2 is tightly regulated to ensure efficient but limited platelet activation at sites of vascular injury.
Original languageEnglish
Pages (from-to)1353-1363
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number6
DOIs
Publication statusPublished - Jun 2010

Keywords

  • integrin
  • platelet
  • PLC gamma 2
  • signaling
  • thrombosis

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