Mechanism of direct bicarbonate transport by the CFTR anion channel

BackgroundCFTR contributes to HCO3− transport in epithelial cells both directly (by HCO3− permeation through the channel) and indirectly (by regulating Cl−/HCO3− exchange proteins). While loss of HCO3− transport is highly relevant to cystic fibrosis, the relative importance of direct and indirect HCO3− transport it is currently unknown.MethodsPatch 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 HCO3− transport and characterize its functional properties.ResultsThe permeability of HCO3− was ~ 25% that of Cl− and was invariable under all ionic conditions studied. CFTR-mediated HCO3− 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 HCO3− transport did not affect direct HCO3− permeability.ConclusionsCl− and HCO3− share a common transport pathway in CFTR, and selectivity between Cl− and HCO3− 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 HCO3− transport do not impair direct CFTR-mediated HCO3− transport, but may predominantly alter CFTR regulation of other HCO3− transport pathways.