RT Journal Article
SR Electronic
T1 Antihypertensive 1,4-Dihydropyridines as Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator Channel Gating Defect Caused by Cystic Fibrosis Mutations
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1736
OP 1746
DO 10.1124/mol.105.015149
VO 68
IS 6
A1 Nicoletta Pedemonte
A1 Tullia Diena
A1 Emanuela Caci
A1 Erika Nieddu
A1 Mauro Mazzei
A1 Roberto Ravazzolo
A1 Olga Zegarra-Moran
A1 Luis J. V. Galietta
YR 2005
UL http://molpharm.aspetjournals.org/content/68/6/1736.abstract
AB Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel gene. CF mutations like ΔF508 cause both a mistrafficking of the protein and a gating defect. Other mutations, like G551D, cause only a gating defect. Our aim was to find chemical compounds able to stimulate the activity of CFTR mutant proteins by screening a library containing approved drugs. Two thousand compounds were tested on Fischer rat thyroid cells coexpressing ΔF508-CFTR and a halide-sensitive yellow fluorescent protein (YFP) after correction of the trafficking defect by low-temperature incubation. The YFP-based screening allowed the identification of the antihypertensive 1,4-dihydropyridines (DHPs) nifedipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine, and niguldipine as compounds able to activate ΔF508-CFTR. This effect was not derived from the inhibition of voltage-dependent Ca2+ channels, the pharmacological target of antihypertensive DHPs. Indeed, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-2(trifluoromethylphenyl)pyridine-5-carboxylate (BayK-8644), a DHP that is effective as an activator of such channels, also stimulated CFTR activity. DHPs were also effective on the G551D-CFTR mutant by inducing a 16- to 45-fold increase of the CFTR Cl- currents. DHP activity was confirmed in airway epithelial cells from patients with CF. DHPs may represent a novel class of therapeutic agents able to correct the defect caused by a set of CF mutations.