Modulation of an inactivating human cardiac K+ channel by protein kinase C.

Murray KT, Fahrig SA, Deal KK, Po SS, Hu NN, Snyders DJ, Tamkun MM, Bennett PB
Circ Res. 1994 75 (6): 999-1005

PMID: 7955154 · DOI:10.1161/01.res.75.6.999

The transient outward current (ITO) is an important repolarizing component of the cardiac action potential. In native cardiac myocytes, ITO is modulated after activation of protein kinase C, although the molecular nature of this effect is not well understood. A channel recently cloned from human ventricular myocardium (Kv1.4, HK1) produces a rapidly inactivating K+ current, which has phenotypic similarities to the 4-aminopyridine-sensitive component of ITO. Therefore, we examined whether this recombinant channel was also modulated by protein kinase C activation by investigating the effects of the diacylglycerol analogue phorbol 12-myristate 13-acetate (PMA) on Kv1.4 K+ current expressed in Xenopus oocytes. At a concentration of 10 nmol/L, PMA caused a biphasic response with an initial increase (14 +/- 4%, mean +/- SEM) in current, which peaked in 14 minutes. This was followed by a significant reduction (40 +/- 11%) in the current within 30 minutes. There was no significant change in cell membrane electrical capacitance with 10 nmol/L PMA (1 +/- 1% decline in 30 minutes), demonstrating that loss of cell membrane surface area did not explain the reduction in K+ current, although cell capacitance did decrease when using a higher concentration of PMA (81 nmol/L). The inactive stereoisomer, 4 alpha-PMA, had no effect on Kv1.4 current, whereas preincubation with the protein kinase inhibitor staurosporine or protein kinase C-selective chelerythrine prevented the effects of PMA. When purified from a stably transfected mammalian cell line by using immunoprecipitation, the channel protein was readily phosphorylated in vitro by purified protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)

MeSH Terms (21)

Action Potentials Alkaloids Animals Benzophenanthridines Cell Membrane Cloning, Molecular Enzyme Activation Heart Humans Myocardium Oocytes Phenanthridines Phenotype Phorbol Esters Phosphorylation Potassium Channels Protein Kinase C Staurosporine Time Factors Transfection Xenopus

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