Correction of CFTR malfunction and stimulation of Ca-activated Cl channels restore HCO3- secretion in cystic fibrosis bile ductular cells

Hepatology. 2002 Jan;35(1):95-104. doi: 10.1053/jhep.2002.30423.


In view of the occurrence of hepatobiliary disorders in cystic fibrosis (CF) this study addresses the role of the cystic fibrosis transmembrane conductance regulator (CFTR) and of Ca(2+)-activated Cl(-) channels in promoting HCO3- secretion in bile ductular cells. Human cholangiocytes were isolated from control livers and from 1 patient with CF (DeltaF508/G542X mutations). Single channel and whole cell currents were analyzed by patch clamp techniques, and HCO3- secretion was determined by fluorometric analysis of the rate of recovery of intracellular pH following alkaline loading. In control cholangiocytes, both cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) catalytic subunit, activated CFTR Cl(-) channels that exhibited a nonrectifying conductance of 8 pS and appeared in clusters. Activation of Cl(-) current by cAMP was associated with an increase in the rate of HCO3- secretion. The basal rate of HCO3- secretion was lower in CF than in control cholangiocytes. In both control and CF cholangiocytes, raising intracellular Ca(2+) concentrations with ionomycin led to a parallel activation of Cl(-) current and HCO3- secretion. Consistent with reports that premature stop codon mutations (class I; e.g., G542X) can be read over by treatment with aminoglycoside antibiotics, exposure of CF cholangiocytes to gentamicin restored activation by cAMP of Cl(-) current and HCO3- secretion. The observation that activation of Ca(2+)-dependent Cl(-) channels can substitute for cystic fibrosis transmembrane conductance regulator (CFTR) in supporting HCO3- secretion and the efficacy of gentamicin in restoring CFTR function and HCO3- secretion in class I mutations are of potential clinical interest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Bicarbonates / metabolism*
  • Bile Ducts, Intrahepatic / drug effects
  • Bile Ducts, Intrahepatic / physiopathology*
  • Calcium / pharmacology*
  • Cells, Cultured
  • Chloride Channels / drug effects
  • Chloride Channels / physiology*
  • Codon
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / pharmacology
  • Cystic Fibrosis / physiopathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology*
  • Electric Conductivity
  • Gentamicins / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • Ionomycin / pharmacology
  • Mutation
  • Patch-Clamp Techniques


  • Anti-Bacterial Agents
  • Bicarbonates
  • CFTR protein, human
  • Chloride Channels
  • Codon
  • Gentamicins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Ionomycin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium

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