© 1997 American Heart Association, Inc.
Articles |
Modulation of Na+ Current Inactivation by Stimulation of Protein Kinase C in Cardiac Cells
From the University of Maryland, Department of Medicine, Baltimore.
Correspondence to Michael R. Gold, University of Maryland, Department of Medicine, Division of Cardiology, 22 South Greene St, Baltimore, MD 21201. E-mail mgold{at}medicine.ab.umd.edu
Abstract Modulation of the inward Na+ current
(INa) by protein kinase C (PKC) was investigated
by intracellular perfusion of a peptide corresponding to the catalytic
subunit of PKC (PKCP). The effects of PKC activation independent of
membrane-receptor pathways were studied in neonatal rat
ventricular myocytes using whole-cell patch-clamp
techniques. Perfusion with 2 nmol/L PKCP caused a depolarizing shift in
steady state half-inactivation relative to control (-83.2±1.3 versus
-74.9±1.6 mV for control versus PKCP, respectively) without a change
in current-voltage relationships or peak INa.
The development of resting inactivation was slowed by PKCP (
,
69.1±7.6 [control] versus 100.4±5.1 ms). Open-channel inactivation,
estimated by measuring INa decay from peak
current at test voltages between -10 and +30 mV was significantly
slowed by PKCP. Recovery from inactivation was more rapid during PKCP
perfusion, with a shortening of both the fast (f) and
slow (s) components of (f, 38.5±7.0
[control] versus 14.2±4.7 ms; s, 163.4±47.9
[control] versus 51.3±9.2 ms). All of the effects of PKCP on
INa were antagonized by the PKC
inhibitors chelerythrine chloride or
staurosporine or by downregulation of PKC using phorbol
ester preincubation. We conclude that the actions of PKC on the
Na+ channel result in slowing the development of
inactivation and accelerating reactivation, resulting in less resting
inactivation.
Key Words: Na+ current • protein kinase C • cardiac myocyte
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