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Novel regulation of cystic fibrosis transmembrane conductance regulator (CFTR) channel gating by external chloride

Lookup NU author(s): Professor Barry Argent, Dr Michael Gray


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The cystic fibrosis transmembrane conductance regulator (CFTR) is vital for Cl- and HCO3- transport in many epithelia. As the HCO3- concentration in epithelial secretions varies and can reach as high as 140 mM, the lumen-facing domains of CFTR are exposed to large reciprocal variations in Cl- and HCO3- levels. We have investigated whether changes in the extracellular anionic environment affects the activity of CFTR using the patch clamp technique. In fast whole cell current recordings, the replacement of 100 mM external Cl - (Cl0-) with HCO3-, Br-, NO3-, or aspartate- inhibited inward CFTR current (Cl- efflux) by ∼50% in a reversible manner. Lowering Cl0- alone by iso-osmotic replacement with mannitol also reduced Cl- efflux to a similar extent. The maximal inhibition of CFTR current was ∼70%. Raising cytosolic calcium shifted the Cl- dose-inhibition curve to the left but did not alter the maximal current inhibition observed. In contrast, a reduction in the internal [Cl -] neither inhibited CFTR nor altered the block caused by reduced Cl0-. Single channel recordings from outside-out patches showed that lowering Cl0- markedly reduced channel open probability with little effect on unitary conductance. Together, these results indicate that alterations in Cl0- alone and not the Cl-/HCO3- ratio regulate the gating of CFTR. Physiologically, our data have implications for current models of epithelial HCO3- secretion and for the control of pH at epithelial cell surfaces.

Publication metadata

Author(s): Wright AM, Gong X, Verdon B, Linsdell P, Mehta A, Riordan JR, Argent BE, Gray MA

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2004

Volume: 279

Issue: 40

Pages: 41658-41663

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.


DOI: 10.1074/jbc.M405517200

PubMed id: 15286085


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