Impaired activation of platelets lacking protein kinase C- isoform

Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Blood (Impact Factor: 10.45). 02/2009; 113(11):2557-67. DOI: 10.1182/blood-2008-07-169268
Source: PubMed


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-theta is activated by glycoprotein VI (GPVI) and protease-activated receptor (PAR) agonists, but not by adenosine diphosphate. In human platelets, PKC-theta-selective antagonistic (RACK; receptor for activated C kinase) peptide significantly inhibited GPVI and PAR-induced aggregation, dense and alpha-granule secretion at low agonist concentrations. Consistently, in murine platelets lacking PKC-theta, platelet aggregation and secretion were also impaired. PKC-mediated phosphorylation of tSNARE protein syntaxin-4 was strongly reduced in human platelets pretreated with PKC-theta RACK peptide, which may contribute to the lower levels of granule secretion when PKC-theta function is lost. Furthermore, the level of JON/A binding to activated alpha(IIb)beta(3) receptor was also significantly decreased in PKC-theta(-/-) mice compared with wild-type littermates. PKC-theta(-/-) murine platelets showed significantly lower agonist-induced thromboxane A(2) (TXA(2)) release through reduced extracellular signal-regulated kinase phosphorylation. Finally, PKC-theta(-/-) mice displayed unstable thrombus formation and prolonged arterial occlusion in the FeCl(3) in vivo thrombosis model compared with wild-type mice. In conclusion, PKC-theta isoform plays a significant role in platelet functional responses downstream of PAR and GPVI receptors.

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Available from: Yamini Bynagari, Dec 31, 2015
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    • "Similarly, the role for PRKCQ is debatable (Harper & Poole, 2009). Nagy et al (2009) showed that platelet activation and secretion is impaired in Prkcq À/À animals, whereas another study suggested an enhancement of alpha granule secretion, but not dense granule secretion, at low levels of GPVI stimulation (Harper & Poole, 2009). These discrepancies may hint at the complex nature of control of secretion in platelets, with responses varying depending on agonist and degree of stimulation. "
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    • "GPVI fragment with molecular mass matching remnant murine GPVI fragment by Western blot analysis (Fig. 2D)[19]. "
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    • "However, it is important to point out that T cells also express other isoforms of PKC (Bauer et al., 2000). Furthermore, although most studies have so far focused on PKC-θ function in T cells, there is evidence supporting that PKC-θ is also expressed and play a role in other tissues including muscle (Kim et al., 2004; Benoit et al., 2009; Paoletti et al., 2010), platelets (Nagy et al., 2009; Harper and Poole, 2010; Cohen et al., 2011), natural killer (NK) cells (Aguilo et al., 2009), and likely mast cells (Kempuraj et al., 2005). Therefore, inhibition or targeting of PKC-θ for immunotherapeutic treatments may also affect other tissues in addition to T cells. "
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