Differential Roles of the PKC Novel Isoforms, PKC[delta] and PKC[epsilon], in Mouse and Human Platelets

Background Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation. Methodology/Principal Findings In this study, we focus on the role of two novel PKC isoforms, PKC[delta] and PKC[epsilon], in both mouse and human platelets. PKC[delta] is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKC[delta] undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKC[epsilon], is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKC[epsilon] in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcR[gamma]-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor. Conclusions These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms [delta] and [epsilon] in human and mouse platelets and a selective role for PKC[epsilon] in signalling through GPVI.