Mechanism of direct bicarbonate transport by the CFTR anion channel.
BACKGROUND
CFTR contributes to HCO(3)(-) transport in epithelial cells both directly (by HCO(3)(-) permeation through the channel) and indirectly (by regulating Cl(-)/HCO(3)(-) exchange proteins). While loss of HCO(3)(-) transport is highly relevant to cystic fibrosis, the relative importance of direct and indirect HCO(3)(-) transport it is currently unknown.


METHODS
Patch clamp recordings from membrane patches excised from cells heterologously expressing wild type and mutant forms of human CFTR were used to isolate directly CFTR-mediated HCO(3)(-) transport and characterize its functional properties.


RESULTS
The permeability of HCO(3)(-) was approximately 25% that of Cl(-) and was invariable under all ionic conditions studied. CFTR-mediated HCO(3)(-) currents were inhibited by open channel blockers DNDS, glibenclamide and suramin, and these inhibitions were affected by mutations within the channel pore. Cystic fibrosis mutations previously associated with disrupted cellular HCO(3)(-) transport did not affect direct HCO(3)(-) permeability.


CONCLUSIONS
Cl(-) and HCO(3)(-) share a common transport pathway in CFTR, and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions. The mechanism of transport is therefore effectively identical for both ions. We suggest that mutations in CFTR that cause cystic fibrosis by selectively disrupting HCO(3)(-) transport do not impair direct CFTR-mediated HCO(3)(-) transport, but may predominantly alter CFTR regulation of other HCO(3)(-) transport pathways.
Tang
Lin
L
Department of Physiology & Biophysics, Dalhousie University, Nova Scotia, Canada.
Fatehi
Mohammad
M
Linsdell
Paul
P
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017136:Ion Transport; D009154:Mutation; D018408:Patch-Clamp Techniques; D010539:Permeability
D001639:Bicarbonates; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator