Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the α-glucosidase inhibitor miglustat

• Published in: FEBS letters Vol. 580; no. 8; pp. 2081 - 2086
• Main Authors: Norez, Caroline, Noel, Sabrina, Wilke, Martina, Bijvelds, Marcel, Jorna, Huub, Melin, Patricia, DeJonge, Hugo, Becq, Frederic
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 03.04.2006
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - pharmacology; Animals; Calnexin; Calnexin - metabolism; Castanospermine; Cercopithecus aethiops; CF transmembrane conductance regulator; CFTR; Chloride channels; COS Cells; Cricetinae; Cricetulus; Cst; cystic fibrosis; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Cystic fibrosis transmembrane conductance regulator; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; delF508-mice; endoplasmic reticulum; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Glycoside Hydrolase Inhibitors; Humans; In Vitro Techniques; Intestinal Mucosa - cytology; Intestinal Mucosa - pathology; Isc; Mice; Mice, Inbred CFTR; Mice, Knockout; Miglustat; N-butyldeoxygalactonojirimycin; N-butyldeoxynojirimycin; NB-DGJ; NB-DNJ; Protein Binding - drug effects; Protein Processing, Post-Translational; Protein Transport; short-circuit current; CF; Cst; Castanospermine; Miglustat; Calnexin; ER; NB-DNJ; Isc; Chloride channels; Cystic fibrosis transmembrane conductance regulator; CFTR; delF508-mice; NB-DGJ
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2006.03.010

In the disease cystic fibrosis (CF), the most common mutation delF508 results in endoplasmic reticulum retention of misfolded CF gene proteins (CFTR). We show that the α-1,2-glucosidase inhibitor miglustat ( N-butyldeoxynojirimycin, NB-DNJ) prevents delF508-CFTR/calnexin interaction and restores cAMP-activated chloride current in epithelial CF cells. Moreover, miglustat rescues a mature and functional delF508-CFTR in the intestinal crypts of ileal mucosa from delF508 mice. Since miglustat is an orally active orphan drug (Zavesca ®) prescribed for the treatment of Gaucher disease, our findings provide the basis for future clinical evaluation of miglustat in CF patients.