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Am J Physiol Lung Cell Mol Physiol 274: L305-L312, 1998;
1040-0605/98 $5.00
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Vol. 274, Issue 3, L305-L312, March 1998

Fluoride stimulates cystic fibrosis transmembrane conductance regulator Clminus channel activity

Herbert A. Berger, Sue M. Travis, and Michael J. Welsh

Departments of Internal Medicine and Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa 52242

While studying the regulation of the cystic fibrosis transmembrane conductance regulator (CFTR), we found that addition of F- to the cytosolic surface of excised, inside-out membrane patches reversibly increased Cl- current in a dose-dependent manner. Stimulation required prior phosphorylation and the presence of ATP. F- increased current even in the presence of deferoxamine, which chelates Al3+, suggesting that stimulation was not due to AlF<SUP>−</SUP><SUB>4</SUB>. F- also stimulated current in a CFTR variant that lacked a large part of the R domain, suggesting that the effect was not mediated via this domain. Studies of single channels showed that F- increased the open-state probability by slowing channel closure from bursts of activity; the mean closed time between bursts and single-channel conductance was not altered. These results suggested that F- influenced regulation by the cytosolic domains, most likely the nucleotide-binding domains (NBDs). Consistent with this, we found that mutation of a conserved Walker lysine in NBD2 changed the relative stimulatory effect of F- compared with wild-type CFTR, whereas mutation of the Walker lysine in NBD1 had no effect. Based on these and previous data, we speculate that F- interacts with CFTR, possibly via NBD2, and slows the rate of channel closure.

nucleotide-binding domain; adenosine 5'-triphosphate; patch clamp; channel gating


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