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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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Submitted July 18, 2008
Accepted December 14, 2008
Impaired activation of platelets lacking protein kinase C  isoform
Bela Nagy Jr., Kamala Bhavaraju, Todd Getz, Yamini S. Bynagari, Soochong Kim, and Satya P. Kunapuli*
Department of Physiology, Temple University School of Medicine, Philadelphia, PA, United States
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, United States
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, United States
* Corresponding author; email: spk{at}temple.edu.
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 ADP. 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 IIb 3 receptor was also significantly decreased in PKC-/- mice compared to WT littermates. PKC-/- murine platelets showed significantly lower agonist-induced thromboxane A2 (TXA2) release through reduced extracellular-signal regulated kinase (ERK) phosphorylation. Finally, PKC-/- mice displayed unstable thrombus formation and prolonged arterial occlusion in the FeCl3 in vivo thrombosis model compared to WT mice. In conclusion, PKC isoform plays a significant role in platelet functional responses downstream of PAR and GPVI receptors.
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