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Biophys J, March 2002, p. 1278-1292, Vol. 82, No. 3
*Department of Biology, Delaware State University, Dover, Delaware
19901; and Department of Biological Sciences, Stanford
University, Stanford, California 94305-5020 USA
Gating of cystic fibrosis transmembrane conductance
regulator (CFTR) channels requires intermolecular or interdomain
interactions, but the exact nature and physiological significance of
those interactions remains uncertain. Subconductance states of the
channel may result from alterations in interactions among domains, and
studying mutant channels enriched for a single conductance type may
elucidate those interactions. Analysis of CFTR channels in inside-out
patches revealed that mutation of cysteine residues in NBD1 and NBD2
affects the frequency of channel opening to the full-size versus a 3-pS subconductance. Mutating cysteines in NBD1 resulted in channels that
open almost exclusively to the 3-pS subconductance, while mutations of
cysteines in NBD2 decreased the frequency of subconductance openings.
Wild-type channels open to both size conductances and make fast
transitions between them within a single open burst. Full-size and
subconductance openings of both mutant and wild-type channels are
similarly activated by ATP and phosphorylation. However, the different
size conductances open very differently in the presence of a
nonhydrolyzable ATP analog, with subconductance openings significantly
shortened by ATP
S, while full-size channels are locked open. In
wild-type channels, reducing conditions increase the frequency and
decrease the open time of subconductance channels, while oxidizing
conditions decrease the frequency of subconductance openings. In
contrast, in the cysteine mutants studied, altering redox potential has
little effect on gating of the subconductance.
Biophys J, March 2002, p. 1278-1292, Vol. 82, No. 3
© 2002 by the Biophysical Society 0006-3495/02/03/1278/15 $2.00
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