Mechanism of direct bicarbonate transport by the CFTR anion channel

被引:74
|
作者
Tang, Lin [1 ]
Fatehi, Mohammad [1 ]
Linsdell, Paul [1 ]
机构
[1] Dalhousie Univ, Dept Phys & Biophys, Halifax, NS B3H 1X5, Canada
基金
加拿大健康研究院;
关键词
Bicarbonate; CFTR; CF mutation; Permeation; Site directed mutagenesis; Electrophysiology; DEPENDENT HCO3-TRANSPORT; CYSTIC-FIBROSIS; CHLORIDE CHANNEL; MATHEMATICAL-MODEL; BINDING-SITE; CONDUCTANCE; SECRETION; PERMEABILITY; PERMEATION; SLC26A6;
D O I
10.1016/j.jcf.2008.10.004
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
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 similar to 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. (C) 2008 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:115 / 121
页数:7
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