Activation of CFTR Cl(-) channel by tyrphostins via a protein tyrosine kinase-independent pathway in forskolin-stimulated renal epithelial A6 cells.
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.
Niisato
Naomi
N
Department of Cellular and Molecular Physiology, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan.
Nishio
Kyosuke
K
Marunaka
Yoshinori
Y
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D009579:Nitrobenzoates / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D013696:Temperature; D020032:Tyrphostins / Q000494:pharmacology*
D018118:Chloride Channels; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D020032:Tyrphostins; C013407:benzamil; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D000584:Amiloride; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases