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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2557-2567.
Prepublished online as a Blood First Edition Paper on January 22, 2009; DOI 10.1182/blood-2008-07-169268.
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PLATELETS AND THROMBOPOIESIS
Impaired activation of platelets lacking protein kinase C- isoform
Bela Nagy, Jr1,
Kamala Bhavaraju1,
Todd Getz1,
Yamini S. Bynagari1,
Soochong Kim1,2, and
Satya P. Kunapuli13
1 Department of Physiology,
2 Sol Sherry Thrombosis Research Center, and
3 Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA
Protein kinase C (PKC) isoforms have been implicated in several platelet functional responses, but the contribution of individual isoforms has not been thoroughly evaluated. Novel PKC isoform PKC- is activated by glycoprotein VI (GPVI) and protease-activated receptor (PAR) agonists, but not by adenosine diphosphate. In human platelets, PKC-–selective antagonistic (RACK; receptor for activated C kinase) peptide significantly inhibited GPVI and PAR-induced aggregation, dense and  -granule secretion at low agonist concentrations. Consistently, in murine platelets lacking PKC-, platelet aggregation and secretion were also impaired. PKC-mediated phosphorylation of tSNARE protein syntaxin-4 was strongly reduced in human platelets pretreated with PKC- RACK peptide, which may contribute to the lower levels of granule secretion when PKC- function is lost. Furthermore, the level of JON/A binding to activated IIbβ3 receptor was also significantly decreased in PKC-–/– mice compared with wild-type littermates. PKC-–/– murine platelets showed significantly lower agonist-induced thromboxane A2 (TXA2) release through reduced extracellular signal–regulated kinase phosphorylation. Finally, PKC-–/– mice displayed unstable thrombus formation and prolonged arterial occlusion in the FeCl3 in vivo thrombosis model compared with wild-type mice. In conclusion, PKC- isoform plays a significant role in platelet functional responses downstream of PAR and GPVI receptors.
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