title: Antihypertensive 1,4-dihydropyridines as correctors of the cystic fibrosis transmembrane conductance regulator channel gating defect caused by cystic fibrosis mutations.
abstract: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel gene. CF mutations like deltaF508 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 deltaF508-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 deltaF508-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.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini, 5, 16147 Genova, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
authors.forename: Tullia
authors.initials: T
authors.lastname: Diena
authors.forename: Emanuela
authors.initials: E
authors.lastname: Caci
authors.forename: Erika
authors.initials: E
authors.lastname: Nieddu
authors.forename: Mauro
authors.initials: M
authors.lastname: Mazzei
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Olga
authors.initials: O
authors.lastname: Zegarra-Moran
authors.forename: Luis J V
authors.initials: LJ
authors.lastname: Galietta
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004095:Dihydropyridines / Q000494:pharmacology*; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000166:cytology; D014162:Transfection
chemical_list: D000959:Antihypertensive Agents; D004095:Dihydropyridines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C038806:1,4-dihydropyridine