In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant ΔF508 in murine nasal epithelium

In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant ΔF508 in murine nasal epithelium

Departments of ^*Pediatrics and ^‡Genetics and Center for Human Genetics, Case Western Reserve University, 8th Floor BRB, 10900 Euclid Avenue, Cleveland, OH 44106-4948; and ^†Department of Medicine and the Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112

Abstract

The gene causing cystic fibrosis (CF) encodes the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. Mutations in this gene result in reduced transepithelial chloride permeability across tissues affected in CF. Consequently, restoring chloride permeability to these tissues may prove therapeutic. Here we report that a combination of forskolin, an adenylate cyclase activator, and milrinone, an inhibitor of class III phosphodiesterases, increases the magnitude of the potential difference across nasal epithelium of mice homozygous for the most common CF mutation, ΔF508, while neither drug alone has a significant effect on potential difference. Transgenic mice lacking CFTR do not respond to the milrinone/forskolin combination, indicating that the effect in ΔF508 mice requires CFTR. These results suggest that, by pharmacological means, at least partial CFTR-mediated electrolyte transport can be restored in vivo to CF tissues expressing ΔF508.

Footnotes

↵ § To whom reprint requests should be addressed.
Francis Collins, National Institutes of Health, Bethesda, MD
ABBREVIATIONS:

CF,

cystic fibrosis;

CFTR,

cystic fibrosis transmembrane conductance regulator;

PD,

potential difference;

PDE,

phosphodiesterase;

DPC,

diphenylamine-2-carboxylate;

DIDS,

4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid