Phloxine B interacts with the cystic fibrosis transmembrane conductance regulator at multiple sites to modulate channel activity.

Abstract	The fluorescein derivative phloxine B is a potent modulator of the cystic fibrosis transmembrane conductance regulator (CFTR). Low micromolar concentrations of phloxine B stimulate CFTR Cl(-) currents, whereas higher concentrations of the drug inhibit CFTR. In this study, we investigated the mechanism of action of phloxine B. Phloxine B (1 microm) stimulated wild-type CFTR and the most common cystic fibrosis mutation, DeltaF508, by increasing the open probability of phosphorylated CFTR Cl(-) channels. At each concentration of ATP tested, the drug slowed the rate of channel closure without altering the opening rate. Based on the effects of fluorescein derivatives on transport ATPases, these data suggest that phloxine B might stimulate CFTR by binding to the ATP-binding site of the second nucleotide-binding domain (NBD2) to slow the dissociation of ATP from NBD1. Channel block by phloxine B (40 microm) was voltage-dependent, enhanced when external Cl(-) concentration was reduced and unaffected by ATP (5 mm), suggesting that phloxine B inhibits CFTR by occluding the pore. We conclude that phloxine B interacts directly with CFTR at multiple sites to modulate channel activity. It or related agents might be of value in the development of new treatments for diseases caused by the malfunction of CFTR.
Authors	Zhiwei Cai, David N Sheppard
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 22 Pg. 19546-53 (May 31 2002) ISSN: 0021-9258 [Print] United States
PMID	11904291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	CFTR protein, human Fluorescent Dyes Potassium Channels Cystic Fibrosis Transmembrane Conductance Regulator Adenosine Triphosphate Eosine I Bluish
Topics	Adenosine Triphosphate (pharmacology) Animals Binding Sites Cells, Cultured Cystic Fibrosis Transmembrane Conductance Regulator (chemistry, metabolism) Dose-Response Relationship, Drug Electrophysiology Eosine I Bluish (chemistry, pharmacology) Fluorescent Dyes (pharmacology) Humans Kinetics Mice Models, Chemical Mutation Potassium Channels (metabolism) Protein Binding Time Factors

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