Activation of CFTR Cl(-) channel by tyrphostins via a protein tyrosine kinase-independent pathway in forskolin-stimulated renal epithelial A6 cells

Life Sci. 2002 Jul 26;71(10):1199-207. doi: 10.1016/s0024-3205(02)01824-6.

Abstract

We studied effects of tyrphostin A23 (an inhibitor of protein tyrosine kinase; PTK) and tyrphostin A63 (an inactive analog of tyrphostin A23) on forskolin-activated cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels and Cl(-) secretion in renal epithelial A6 cells. Tyrphostin A23 and A63 had no effects on the basal CFTR Cl(-) channel and Cl(-) secretion. However, under the forskolin-stimulated condition, tyrphostin A23 and A63 stimulated Cl(-) secretion by activating CFTR Cl(-) channels. These observations suggest that: 1) tyrphostin A23 and A63 stimulate the cAMP-activated CFTR Cl(-) channel via a PTK-independent, structure-dependent mechanism, and 2) tyrphostin A23 and A63 do not stimulate the basal CFTR Cl(-) channel. These lead us to an idea that: 1) cAMP might cause a conformational change of CFTR Cl(-) channel which is accessible by tyrphostins, and 2) tyrphostins would stimulate translocation of the cAMP-modified channel to the apical membrane by binding to the channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiloride / analogs & derivatives*
  • Amiloride / pharmacology
  • Animals
  • Cells, Cultured
  • Chloride Channels / drug effects
  • Chloride Channels / metabolism*
  • Colforsin / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kinetics
  • Nitrobenzoates / pharmacology
  • Patch-Clamp Techniques
  • Protein-Tyrosine Kinases / physiology*
  • Temperature
  • Tyrphostins / pharmacology*

Substances

  • Chloride Channels
  • Enzyme Inhibitors
  • Nitrobenzoates
  • Tyrphostins
  • benzamil
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin
  • 5-nitro-2-(3-phenylpropylamino)benzoic acid
  • Amiloride
  • Protein-Tyrosine Kinases
  • Cyclic AMP-Dependent Protein Kinases