Am J Physiol Cell Physiol 2001 Nov 01;2815:C1477-86. doi: 10.1152/ajpcell.2001.281.5.C1477.

Evidence for functional role of epsilonPKC isozyme in the regulation of cardiac Na(+) channels.

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Investigation of the role of individual protein kinase C (PKC) isozymes in the regulation of Na(+) channels has been largely limited by the lack of isozyme-selective modulators. Here we used a novel peptide-specific activator (epsilonV1-7) of epsilonPKC and other peptide isozyme-specific inhibitors in addition to the general PKC activator phorbol 12-myristate 13-acetate (PMA) to dissect the role of individual PKCs in the regulation of the human cardiac Na(+) channel hH1, heterologously expressed in Xenopus oocytes. Peptides were injected individually or in combination into the oocyte. Whole cell Na(+) current (I(Na)) was recorded using two-electrode voltage clamp. epsilonV1-7 (100 nM) and PMA (100 nM) inhibited I(Na) by 31 +/- 5% and 44 +/- 8% (at -20 mV), respectively. These effects were not seen with the scrambled peptide for epsilonV1-7 (100 nM) or the PMA analog 4alpha-phorbol 12,13-didecanoate (100 nM). However, epsilonV1-7- and PMA-induced I(Na) inhibition was abolished by epsilonV1-2, a peptide-specific antagonist of epsilonPKC. Furthermore, PMA-induced I(Na) inhibition was not altered by 100 nM peptide-specific inhibitors for alpha-, beta-, delta-, or etaPKC. PMA and epsilonV1-7 induced translocation of epsilonPKC from soluble to particulate fraction in Xenopus oocytes. This translocation was antagonized by epsilonV1-2. In native rat ventricular myocytes, PMA and epsilonV1-7 also inhibited I(Na); this inhibition was antagonized by epsilonV1-2. In conclusion, the results provide evidence for selective regulation of cardiac Na(+) channels by epsilonPKC isozyme.

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