Antihypertensive 1,4-dihydropyridines as correctors of the cystic fibrosis transmembrane conductance regulator channel gating defect caused by cystic fibrosis mutations.
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.
Pedemonte
Nicoletta
N
Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini, 5, 16147 Genova, Italy.
Diena
Tullia
T
Caci
Emanuela
E
Nieddu
Erika
E
Mazzei
Mauro
M
Ravazzolo
Roberto
R
Zegarra-Moran
Olga
O
Galietta
Luis J V
LJ
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
D000959:Antihypertensive Agents; D004095:Dihydropyridines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C038806:1,4-dihydropyridine