Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC

J Physiol. 1998 May 1;508 ( Pt 3)(Pt 3):825-36. doi: 10.1111/j.1469-7793.1998.825bp.x.

Abstract

1. Epithelial Na+ channels (ENaCs) are inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is activated by protein kinase A. Since cAMP-dependent activation of CFTR Cl- conductance is defective in cystic fibrosis (CF), ENaC currents are not inhibited by CFTR. This could explain the enhanced Na+ conductance found in CF. In the present study, we examined possible mechanisms of interaction between CFTR and ENaC co-expressed in Xenopus oocytes. 2. The magnitude of CFTR Cl- currents activated by 3-isobutyl-1-methylxanthine (IBMX) in oocytes co-expressing either wild-type or mutant CFTR and ENaC determined the degree of downregulation of ENaC currents. 3. The ability of CFTR to inhibit ENaC currents was significantly reduced either when extracellular Cl- was replaced by poorly conductive anions, e.g. SCN- or gluconate, or when CFTR was inhibited by diphenylamine-carboxylate (DPC, 1 mmol l-1). 4. Downregulation of ENaC was more pronounced at positive when compared with negative clamp voltages. This suggests that outward currents, i.e. influx of Cl- through activated CFTR most effectively downregulated ENaC. 5. Activation of endogenous Ca2+-activated Cl- currents by 1 micromol l-1 ionomycin did not inhibit ENaC current. This suggests that inhibition of ENaC mediated by Cl- currents may be specific to CFTR. 6. The present findings indicate that downregulation of ENaC by CFTR is correlated to the ability of CFTR to conduct Cl-. The data have implications for how epithelia switch from NaCl absorption to NaCl secretion when CFTR is activated by secretagogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Amiloride / pharmacology
  • Animals
  • Calcium / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Chlorides / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Cytosol / chemistry
  • Diuretics / pharmacology
  • Down-Regulation / physiology
  • Electrophysiology
  • Epithelial Cells / chemistry
  • Epithelial Cells / metabolism
  • Epithelial Sodium Channels
  • Female
  • Gene Expression / physiology
  • Humans
  • Mutation / physiology
  • Oocytes / physiology
  • Phosphodiesterase Inhibitors / pharmacology
  • Rats
  • Sodium Channel Blockers
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*
  • Sodium Chloride / metabolism
  • Transfection
  • Xenopus laevis
  • ortho-Aminobenzoates / pharmacology

Substances

  • CFTR protein, human
  • Calcium Channel Blockers
  • Chlorides
  • Diuretics
  • Epithelial Sodium Channels
  • Phosphodiesterase Inhibitors
  • Sodium Channel Blockers
  • Sodium Channels
  • ortho-Aminobenzoates
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Sodium Chloride
  • Amiloride
  • fenamic acid
  • Calcium
  • 1-Methyl-3-isobutylxanthine