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Originally published as Biophys J. BioFAST on June 9, 2006.
doi:10.1529/biophysj.105.078899
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Biophysical Journal 91:1737-1748 (2006)
© 2006 The Biophysical Society

CFTR: Ligand Exchange between a Permeant Anion ([Au(CN)2]–) and an Engineered Cysteine (T338C) Blocks the Pore

José R. Serrano *, Xuehong Liu *, Erik R. Borg *, Christopher S. Alexander *, C. Frank Shaw, 3rd {dagger} and David C. Dawson *

* Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239; and {dagger} Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160

Correspondence: Address reprint requests to David C. Dawson, Dept. of Physiology and Pharmacology, L334 3181 SW Sam Jackson Park Road, Portland, OR 97239. Tel.: 503-494-8262; Fax: 503-494-4352; E-Mail: dawsonda{at}ohsu.edu.

Previous attempts to identify residues that line the pore of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have utilized cysteine-substituted channels in conjunction with impermeant, thiol-reactive reagents like MTSET+ and MTSES–. We report here that the permeant, pseudohalide anion [Au(CN)2]– can also react with a cysteine engineered into the pore of the CFTR channel. Exposure of Xenopus oocytes expressing the T338C CFTR channel to as little as 100 nM [Au(CN)2]– produced a profound reduction in conductance that was not reversed by washing but was reversed by exposing the oocytes to a competing thiol like DTT (dithiothreitol) and 2-ME (2-mercaptoethanol). In detached, inside out patches single-channel currents were abolished by [Au(CN)2]– and activity was not restored by washing [Au(CN)2]– from the bath. Both single-channel and macroscopic currents were restored, however, by exposing [Au(CN)2]–-blocked channels to excess [CN]–. The results are consistent with the hypothesis that [Au(CN)2]– can participate in a ligand exchange reaction with the cysteine thiolate at 338 such that the mixed-ligand complex, with a charge of –1, blocks the anion conduction pathway.




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