ABCMdb

PMID: 26245207

Phuan PW, Veit G, Tan JA, Finkbeiner WE, Lukacs GL, Verkman AS
Potentiators of Defective DeltaF508-CFTR Gating that Do Not Interfere with Corrector Action.
Mol Pharmacol. 2015 Oct;88(4):791-9. doi: 10.1124/mol.115.099689. Epub 2015 Aug 5., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Gly551Asp The DF508-CFTR potentiators also activated wild-type and G551D CFTR, albeit weakly. Login to comment 12 ABCC7 p.Gly551Asp N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1, 4-dihydroquinoline-3-carboxamide (VX-770; Ivacaftor) is approved for therapy of CF caused by mutations that affect CFTR gating but not cellular processing, including G551D and nine other point mutations (Ramsey et al., 2011; Davis et al., 2012; O`Reilly and Elphick, 2013). Login to comment 30 ABCC7 p.Gly551Asp ABCC8 p.Ile152Leu Fisher rat thyroid (FRT) epithelial cells stably expressing ƊF508, wild-type, or G551D CFTR, together with halide-sensitive green fluorescent protein yellow fluorescence protein (YFP)-H148Q/I152L/F46L (Galietta et al., 2001) were as reported (Ma et al., 2002; Pedemonte et al., 2005). Login to comment 60 ABCC7 p.Gly551Asp FRT cells expressing DF508, wild-type, or G551D CFTR were cultured on inserts (Snapwell, Corning) for 5-7 days and used when the transepithelial resistance was .2000 mV/cm2 . Login to comment 159 ABCC7 p.Gly551Asp A04 and P12 were also tested in FRT cells expressing G551D-CFTR (Fig. 5C). Login to comment 160 ABCC7 p.Gly551Asp G551D-CFTR produced little chloride current with maximal forskolin. Login to comment 161 ABCC7 p.Gly551Asp A04 partially activated G551D-CFTR but only at a high concentration (10 mM), whereas P12 showed minimal activation even at a high concentration. Login to comment 188 ABCC7 p.Gly551Asp VX-770 has been approved to treat CF patients with defective CFTR gating but not cellular processing, including G551D-CFTR. Login to comment 197 ABCC7 p.Gly551Asp Interestingly, P12 and A04 only minimally activated G551D-CFTR at high concentrations. Login to comment 198 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Computational modeling has suggested that increased stability of G551D-CFTR compared with wild-type CFTR renders the G551D-CFTR protein too rigid and inflexible for channel gating (Serohijos et al., 2008). Login to comment 199 ABCC7 p.Gly551Asp VX-770- mediated destabilization of G551D-CFTR might increase Fig. 5. Login to comment 200 ABCC7 p.Gly551Asp Functional assays in FRT cells expressing DF508, wild-type, and G551D CFTR. Login to comment 201 ABCC7 p.Gly551Asp Representative short-circuit current measured in FRT cells expressing DF508-CFTR (A), wild-type CFTR (B), and G551D-CFTR (C) showing responses to indicated concentrations of forskolin (fsk), A04, P12, and VX-770. Login to comment 203 ABCC7 p.Gly551Asp G551D-CFTR flexibility and result in restored channel gating function (Cholon et al., 2014). Login to comment