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PKC isozyme in the
regulation of cardiac Na+ channels
1 Molecular and Cellular Cardiology Program, Veterans Affairs New York Harbor Healthcare System, and State University of New York Health Science Center, Brooklyn, New York 11209; and 2 Department of Molecular Pharmacology, Stanford University, Stanford, California 94305
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 (
V1-7) of PKC 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 (INa) was recorded using
two-electrode voltage clamp. V1-7 (100 nM) and PMA (100 nM)
inhibited INa by 31 ± 5% and 44 ± 8% (at 
20 mV), respectively. These effects were not seen with the
scrambled peptide for V1-7 (100 nM) or the PMA analog
4
-phorbol 12,13-didecanoate (100 nM). However, V1-7-
and PMA-induced INa inhibition was abolished by
V1-2, a peptide-specific antagonist of PKC. Furthermore,
PMA-induced INa inhibition was not altered by
100 nM peptide-specific inhibitors for -, 
-, 
-, or 
PKC. PMA
and V1-7 induced translocation of PKC from soluble to
particulate fraction in Xenopus oocytes. This translocation
was antagonized by V1-2. In native rat ventricular myocytes,
PMA and V1-7 also inhibited INa; this
inhibition was antagonized by V1-2. In conclusion, the results
provide evidence for selective regulation of cardiac Na+
channels by PKC isozyme.
protein kinase C; two-electrode voltage clamp; peptides; Xenopus oocyte; electrophysiology
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