ABCMdb

PMID: 21897819

Dannhoffer L, Billet A, Jollivet M, Melin-Heschel P, Faveau C, Becq F
Stimulation of Wild-Type, F508del- and G551D-CFTR Chloride Channels by Non-Toxic Modified pyrrolo[2,3-b]pyrazine Derivatives.
Front Pharmacol. 2011 Aug 23;2:48. doi: 10.3389/fphar.2011.00048. eCollection 2011., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Gly551Asp Moreover, RP193 stimulates CFTR in temperature-rescued CuFi-1 (F508del/F508del) HBEC and in CHO cells stably expressing G551D-CFTR. Login to comment 9 ABCC7 p.Gly551Asp This study shows that it is feasible to reduce cytotoxicity of chemical compounds without affecting their potency to activate CFTR and to rescue the class 2 F508del-CFTR and class 3 G551D-CFTR CF mutant activities. Login to comment 20 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp Patients with a class 3 mutation of CFTR (e.g.,G551D,G1349D) have also a severe form of CF, because they do not have or reduced activation of the CFTR chloride function at the plasma membrane. Login to comment 52 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp CHO cells stably transfected with pNUT vector alone or containing wild-type CFTR (wt-CFTR-CHO) and the mutant G551D-CFTR (Tabcharani et al., 1991; Becq et al., 1994, 1999) were cultured in b1;-minimal essential medium-GlutaMAX containing 7% of fetal bovine serum, 50 IU/ml penicillin and 50 bc;g/ml streptomycin, and methotrexate for cell selection (wt-CFTR-CHO: 100 bc;M; G551D-CHO: 20 bc;M; pNUT-CHO: 20 bc;M). Login to comment 158 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp RP 193 ACTIVATES TWO CFTR MUTANTS G551D- AND F508del-CFTR CAUSING SEVERE CF DISEASE To determine whether RP193 could activate CFTR mutants, we performed iodide efflux experiments with cells expressing two of the most frequent CF mutations, the class 3 CF mutation G551D-CFTR, studied in CHO cells stably expressing G551D-CFTR, and the class 2 CF mutation F508del-CFTR, studied in CuFi-1 cells derived from a human CF bronchial epithelium (F508del/F508del genotype). Login to comment 184 ABCC7 p.Gly551Asp However, RP193 10 bc;M stimulated an efflux in G551D-CFTR-CHO cells in presence of forskolin 10 bc;M (n = 4,Figure 5G) while RP193 alone did not have any effect (not shown). Login to comment 185 ABCC7 p.Gly551Asp Taken together these experiments revealed that RP193 is able not only to activate wt-CFTR but also rescued F508del-CFTR and G551D-CFTR. Login to comment 190 ABCC7 p.Gly551Asp Bar chart showing iodide efflux experiments on NuLi-1 (B), CuFi-1 treated by low temperature (24 h, 27da;C) (E), CuFi-1 treated with miglustat (24 h, 100 bc;M) (F) and G551D-CHO cells (G). Login to comment 205 ABCC7 p.Gly551Asp Our data demonstrated that RP193 was able to stimulate rescued F508del-CFTR and G551D-CFTR. Login to comment 230 ABCC7 p.Gly551Asp Secondly,we performed experiments on G551D-CFTR, a class 3 mutation retrieved in patients with severe disease and which present no or reduced activation of the CFTR chloride function. Login to comment 231 ABCC7 p.Gly551Asp Our studies revealed that in presence of a low forskolin concentration, RP193 potentiates the activity of G551D-CFTR. Login to comment 238 ABCC7 p.Gly551Asp Finally, we identified RP193 as a new compound able to stimulate, through a cAMP-independent pathway, wt-CFTR, rescued F508del-CFTR, and G551D-CFTR activity in HBEC. Login to comment