Mechanism of direct bicarbonate transport by the CFTR anion channel

Background: CFTR 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. 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 HCO₃^- transport and characterize its functional properties. Results: The 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. Conclusions: Cl^- 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.