ABCMdb

PMID: 16443646

Van Goor F, Straley KS, Cao D, Gonzalez J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, Neuberger T, Olson E, Panchenko V, Rader J, Singh A, Stack JH, Tung R, Grootenhuis PD, Negulescu P
Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules.
Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1117-30. Epub 2006 Jan 27., [PubMed]

Sentences

No. Mutations Sentence Comment

87 ABCC7 p.Gly551Asp Fischer rat thyroid (FRT) epithelia expressing ⌬F508-CFTR or G551D-CFTR were grown on Costar Snapwell cell culture inserts for 4 days. Login to comment 263 ABCC7 p.Gly551Asp This includes the missense mutation G551D, which results in defective gating but does not impair trafficking to the apical membrane (9). Login to comment 264 ABCC7 p.Gly551Asp In FRT epithelial monolayers expressing G551D-CFTR, VRT-532 potentiated forskolin-stimulated Cl-secretion with an EC50 of 20 Ϯ 3 ␮M (n ϭ 3), which was about fivefold less potent than the EC50 observed for ⌬F508-CFTR in temperature-corrected FRT monolayers (EC50 ϭ 3.8 Ϯ 0.5 ␮M; n ϭ 46). Login to comment 358 ABCC7 p.Gly551Asp Although several potent CFTR potentiators have been reported in the literature, CFTR potentiator VRT-532 appears to be distinguished by its ability to potentiate the gating of several forms of CFTR, including ⌬F508-, G551D-, and wt-CFTR. Login to comment 359 ABCC7 p.Gly551Asp Like genistein (38), VRT-532 had an approximately fivefold lower affinity for G551D-CFTR than ⌬F508-CFTR. Login to comment 361 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp G551D (ϳ70 nM and ϳ1,100 nM against ⌬F508- and G551D-CFTR, respectively) or are inactive against G551D-CFTR (benzothiophenes and sulfonamides) (38, 62). Login to comment 387 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Genotype/phenotype correlations of Cl-channel function with disease severity show that mutations resulting in a only modest recovery toward wild-type levels (e.g., 5-30%) increase in CFTR expression or activity (e.g., A455E, 2,789 ϩ 5G3A, 5T, R334W, R347P, and R117H) and are typically associated with pancreatic sufficiency, a slower rate of pulmonary function decline, and a better severity index than that shown in patients with severe disease genotypes (5, 6, 10, 36, 49). Login to comment