Letter | Published:

Multi-ion pore behaviour in the CFTR chloride channel

Naturevolume 366pages7982 (1993) | Download Citation

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Abstract

CYSTIC fibrosis transmembrane conductance regulator (CFTR) is a non-rectifying, low-conductance channel1,2 regulated by ATP3 and phosphorylation4, which mediates apical chloride conductance in secretory epithelia5,6 and malfunctions in cystic fibrosis (CF)7,8. Mutations at Lys 335 and Arg 347 in the sixth predicted transmembrane helix of CFTR alter its halide selectivity in whole-cell studies9 and its single channel conductance10, but the physical basis of these alterations is unknown and permeation in CFTR is poorly understood. Here we present evidence that wild-type CFTR can contain more than one anion simultaneously. The conductance of CFTR passes through a minimum when channels are bathed in mixtures of two permeant anions. This anomalous mole fraction effect can be abolished by replacing Arg 347 with an aspartate and can be toggled on or off by varying the pH after the same residue is replaced with a histidine. Thus the CFTR channel should provide a convenient model in which to study multi-ion pore behaviour and conduction. The loss of multiple occupancy may explain how naturally occurring CF mutations at this site cause disease.

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Author notes

  1. John W. Hanrahan: To whom correspondence should be addressed.

Affiliations

  1. Department of Physiology, McGill University, 3655 Drummond Street, Montréal, Québec, H3G 1Y6, Canada

    • Joseph A. Tabcharani
    •  & John W. Hanrahan
  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada

    • Johanna M. Rommens
    •  & Lap-Chee Tsui
  3. Department of Biochemistry and Clinical Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A1, Canada

    • John R. Riordan
  4. Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada

    • Johanna M. Rommens
    • , Yue-Xian Hou
    • , Xiu-Bao Chang
    • , Lap-Chee Tsui
    •  & John R. Riordan

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https://doi.org/10.1038/366079a0

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