Antihypertensive 1,4-Dihydropyridines as Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator Channel Gating Defect Caused by Cystic Fibrosis Mutations

• Published in: Molecular pharmacology 2005-12, Vol.68 (6), p.1736-1746
• Main Authors: Nicoletta Pedemonte, Tullia Diena, Emanuela Caci, Erika Nieddu, Mauro Mazzei, Roberto Ravazzolo, Olga Zegarra-Moran, Luis J. V. Galietta
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Dihydropyridines - pharmacology; Electrophysiology; Ion Channel Gating - drug effects; Ion Channel Gating - genetics; Mice; Mutation; Rats; Rats, Inbred F344; Thyroid Gland - cytology; Transfection
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.105.015149

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 Ca 2+ 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.