PKC regulation of cardiac CFTR Cl- channel function in guinea pig ventricular myocytes

Lisa M. Middleton, Robert D. Harvey

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The role of protein kinase C (PKC) in regulating the protein kinase A (PKA)-activated C1- current conducted by the cardiac isoform of the cystic fibrosis transmembrane conductance regulator (cCFTR) was studied in guinea pig ventricular myocytes using the whole cell patch-clamp technique. Although stimulation of endogenous PKC with phorbol 12,13-dibutyrate (PDBu) alone did not activate this Cl- current, even when intracellular dialysis was limited with the perforated patch-clamp technique, activation of PKC did elicit a significant response in the presence of PKA-dependent activation of the current by the β-adrenergic receptor agonist isoproterenol. PDBu increased the magnitude of the Cl- conductance activated by a supramaximally stimulating concentration of isoproterenol by 21 ± 3.3% (n = 9) when added after isoproterenol and by 36 ± 16% (n = 14) when introduced before isoproterenol. 4α-Phorbol 12,13-didecanoate, a phorbol ester that does not activate PKC, did not mimic these effects. Preexposure to chelerythrine or bisindolylmaleimide, two highly selective inhibitors of PKC, significantly reduced the magnitude of the isoproterenol-activated Cl- current by 79 ± 7.7% (n = 11) and 52 ± 10% (n = 8), respectively. Our results suggest that although acute activation of endogenous PKC alone does not significantly regulate cCFTR Cl- channel activity in native myocytes, it does potentiate PKA-dependent responses, perhaps most dramatically demonstrated by basal PKC activity, which may play a pivotal role in modulating the function of these channels.

Original languageEnglish (US)
Pages (from-to)C293-C302
JournalAmerican Journal of Physiology - Cell Physiology
Volume275
Issue number1 44-1
DOIs
StatePublished - Jul 1998
Externally publishedYes

Keywords

  • Bisindolylmaleimide
  • Cardiac isoform of cystic fibrosis transmembrane conductance regulator
  • Chelerythrine
  • Cross talk
  • Phorbol 12,13- dibutyrate
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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