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Permeability of Wild-Type and Mutant Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels to Polyatomic Anions

Paul LinsdellFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259Joseph A. TabcharaniFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259Johanna M. RommensFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259Yue-xian HouFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259Xiu-Bao ChangFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259Lap-Chee TsuiFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259John R. RiordanFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259John W. HanrahanFrom the *Department of Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada; ‡Department of Genetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8; and §S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259

1997en

ABI

Annotatsiya

Permeability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel to polyatomic anions of known dimensions was studied in stably transfected Chinese hamster ovary cells by using the patch clamp technique. Biionic reversal potentials measured with external polyatomic anions gave the permeability ratio (P/P) sequence NO > Cl > HCO > formate > acetate. The same selectivity sequence but somewhat higher permeability ratios were obtained when anions were tested from the cytoplasmic side. Pyruvate, propanoate, methane sulfonate, ethane sulfonate, and gluconate were not measurably permeant (P/P < 0.06) from either side of the membrane. The relationship between permeability ratios from the outside and ionic diameters suggests a minimum functional pore diameter of approximately 5.3 A. Permeability ratios also followed a lyotropic sequence, suggesting that permeability is dependent on ionic hydration energies. Site-directed mutagenesis of two adjacent threonines in TM6 to smaller, less polar alanines led to a significant (24%) increase in single channel conductance and elevated permeability to several large anions, suggesting that these residues do not strongly bind permeating anions, but may contribute to the narrowest part of the pore.

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Identifikatorlar

DOI: 10.1085/jgp.110.4.355

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