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Am J Physiol Lung Cell Mol Physiol 281: L852-L867, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 4, L852-L867, October 2001

Identification of a region of strong discrimination in the pore of CFTR

Nael A. McCarty and Zhi-Ren Zhang

Departments of Physiology and Pediatrics, Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322

The variety of methods used to identify the structural determinants of anion selectivity in the cystic fibrosis transmembrane conductance regulator Cl- channel has made it difficult to assemble the data into a coherent framework that describes the three-dimensional structure of the pore. Here, we compare the relative importance of sites previously studied and identify new sites that contribute strongly to anion selectivity. We studied Cl- and substitute anions in oocytes expressing wild-type cystic fibrosis transmembrane conductance regulator or 12-pore-domain mutants to determine relative permeability and relative conductance for 9 monovalent anions and 1 divalent anion. The data indicate that the region of strong discrimination resides between T338 and S341 in transmembrane 6, where mutations affected selectivity between Cl- and both large and small anions. Mutations further toward the extracellular end of the pore only strongly affected selectivity between Cl- and larger anions. Only mutations at S341 affected selectivity between monovalent and divalent anions. The data are consistent with a narrowing of the pore between the extracellular end and a constriction near the middle of the pore.

cystic fibrosis transmembrane conductance regulator; chloride channel; selectivity; anion permeation


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