Functional effects of protein kinase C activation on the human cardiac Na+ channel

Katherine T. Murray*, Ningning Hu, J. Richard Daw, Hyeon Gyu Shin, Marshall T. Watson, Amy B. Mashburn, Alfred L. George

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

The cardiac Na+ current plays an important role in determining normal and abnormal impulse propagation in the heart. We have investigated the effects of protein kinase C (PKC) activation on the recombinant human cardia Na+ channel (hH1) following heterologous expression in Xenopus laevis oocytes. Phorbol 12-myristate 13-acetate (PMA), which directly activates PKC, reduced current amplitude at all test potentials (43±12% at -10 mV). In contrast to the rat brain IIA (rBIIa) channel, there was no apparent change in either macroscopic Na+ current decay or the voltage dependence of channel gating. Further experiments indicate that the effects of PMA were mediated by PKC activation: (1) an inactive stereoisomer, 4α-PMA, had no effect; (2) preincubation with the protein kinase inhibitor chelerythrine prevented the PMA effects; and (3) a hydrolyzable diacylglycerol analogue, 1-oleoyl-2- acetyl-glycerol, also reduced current (22±5%). In addition, when the α(1H)- adrenergic receptor was coexpressed with hH1, the α-receptor agonist methoxamine reduced hH1 current (45±10%), an effect that could be eliminated by chelerythrine preincubation. When a conserved consensus PKC site (serine 1503) in the III-IV interdomain linker thought to be responsible for the PKC effects on rBIIA was mutated, PMA still reduced Na+ current, but the magnitude of the effect was smaller compared with that for the wild-type channel. Similar findings were obtained with α1-receptor stimulation following receptor coexpression with the mutant channel. We conclude that activation of PKC modulates the human cardiac Na+ channel by at least two mechanisms, one similar to that seen with rat brain channels involving a conserved putative PKC site, and a second more specific to the cardiac isoform.

Original languageEnglish (US)
Pages (from-to)370-376
Number of pages7
JournalCirculation research
Volume80
Issue number3
DOIs
StatePublished - 1997

Keywords

  • heart
  • phosphorylation
  • protein kinase C
  • sodium channels
  • xenopus oocyte

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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