Impaired activation of platelets lacking protein kinase C-θ isoform

Bela Nagy, Kamala Bhavaraju, Todd Getz, Yamini S. Bynagari, Soochong Kim, Satya P. Kunapuli

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Abstract

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 iso- form PKC-θ is activated by glycoprotein VI (GPVI) and protease-activated receptor (PAR) agonists, but not by adeno- sine diphosphate. In human platelets, PKC-θ-selective antagonistic (RACK; receptor for activated C kinase) peptide significantly inhibited GPVI and PAR- induced aggregation, dense and αgranule secretion at low agonist concentrations. Consistently, in murine platelets lacking PKC-θ, platelet aggregation and secretion were also impaired. PKC- mediated phosphorylation of tSNARE protein syntaxin-4 was strongly reduced in human platelets pretreated with PKC-θ RACK peptide, which may contribute to the lower levels of granule secretion when PKC-θ function is lost. Furthermore, the level of JON/A binding to activated αIIbβ receptor was also significantly decreased in PKC-θ -/-mice compared with wild-type littermates. PKC-θ -/- murine platelets showed significantly lower agonist-induced thromboxane A 2 (TXA 2) release through reduced extracellular signal-regulated kinase phosphoryla- tion. Finally, PKC-θ -/- mice displayed unstable thrombus formation and prolonged arterial occlusion in the FeCl3 in vivo thrombosis model compared with wild-type mice. In conclusion, PKC-0 isoform plays asignifi- cant role in platelet functional responses downstream of PAR and GPVI receptors.

Original languageEnglish
Pages (from-to)2557-2567
Number of pages11
JournalBlood
Volume113
Issue number11
DOIs
Publication statusPublished - Mar 12 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Nagy, B., Bhavaraju, K., Getz, T., Bynagari, Y. S., Kim, S., & Kunapuli, S. P. (2009). Impaired activation of platelets lacking protein kinase C-θ isoform. Blood, 113(11), 2557-2567. https://doi.org/10.1182/blood-2008-07-169268