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J. Biol. Chem., Vol. 276, Issue 9, 6473-6478, March 2, 2001

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Cystic Fibrosis Transmembrane Conductance Regulator Gating Requires Cytosolic Electrolytes^*

Jin V. Wu, Nam Soo Joo, Mauri E. Krouse, and Jeffrey J. Wine

From the Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California 94305-2130

Cystic fibrosis transmembrane conductance regulator (CFTR), which causes cystic fibrosis when nonfunctional, is an anion channel and a member of the ATP binding cassette superfamily. After phosphorylation, CFTR gates by binding and hydrolyzing ATP. We show that CFTR open probability (P_o) also depends on the electrolyte concentration of the cytosol. Inside-out patches from Calu-3 cells were transiently exposed to solutions of 160 mM salt or solutions in which up to 90% of the salt was replaced by nonionic osmolytes such as sucrose. In lowered salt solutions, CFTR P_o declined within 1 s to a stable lower value that depended on the electrolyte concentration, (K_1/2  80 mM NaCl). P_o was rapidly restored in normal salt concentrations without regard to the electrolyte species. Reducing external electrolytes did not affect CFTR P_o. The same results were obtained when CFTR was stably phosphorylated with adenosine 5'-O-(thiotriphosphate). The decrease in P_o resulted entirely from an increase in mean closed time. Increasing ATP levels up to 20-fold did not counteract the effect of low electrolytes. The same effect was observed for CFTR expressed in C127 cells but not for a different species of anion channel. Cytosolic electrolytes are an unsuspected, essential cofactor for CFTR gating.

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