ABCMdb

PMID: 21730204

Phuan PW, Yang B, Knapp JM, Wood AB, Lukacs GL, Kurth MJ, Verkman AS
Cyanoquinolines with independent corrector and potentiator activities restore {delta}phe508-cystic fibrosis transmembrane conductance regulator chloride channel function in cystic fibrosis.
Mol Pharmacol. 2011 Oct;80(4):683-93. Epub 2011 Jul 5., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Gly551Asp CoPo-22 also activated wild-type and G551D CFTR chloride conductance within minutes in a forskolin-dependent manner. Login to comment 9 ABCC7 p.Gly551Asp CoPo-22 also activated wild type and G551D CFTR chloride conductance within minutes, in a forskolin-dependent manner. Login to comment 34 ABCC7 p.Gly551Asp Fisher rat thyroid (FRT) epithelial cells were stably transfected with ∆F508, G551D or wild type CFTR as reported (Pedemonte et al., 2005b). Login to comment 36 ABCC7 p.Gly551Asp Materials and Methods Cell Lines Fisher rat thyroid (FRT) epithelial cells were stably transfected with ⌬Phe508, G551D, or wild-type CFTR as reported previously (Pedemonte et al., 2005b). Login to comment 38 ABCC8 p.Ile152Leu Each of the CFTR-expressing cell lines (and the nontransfected parental cells) was also transfected with halide-sensitive green fluorescent protein YFP-H148Q/I152L/F46L. Login to comment 162 ABCC7 p.Gly551Asp Potentiator studies were also done in FRT cells expressing G551D-CFTR, a CF-causing CFTR mutation with defective channel gating but not plasma membrane trafficking. Login to comment 163 ABCC7 p.Gly551Asp Fig. 6A shows that CoPo-22 functioned as a weak potentiator of G551D-CFTR, producing a smaller increase in chloride current than that produced by genistein. Login to comment 164 ABCC7 p.Gly551Asp Fluorescence plate reader assays in Fig. 6B confirmed that CoPo-22 activated G551D-CFTR in the presence of forskolin, albeit with lower maximal efficacy than genistein. Login to comment 177 ABCC7 p.Gly551Asp The rapid normalization of defective ∆F508-CFTR channel gating by CoPo-22 is probably a consequence of direct binding, as is its efficacy in the rapid activation of chloride conductance in wild typeand G551D-CFTR. Login to comment 196 ABCC7 p.Gly551Asp Potentiator studies were also done in FRT cells expressing G551D-CFTR, a CF-causing CFTR mutation with defective channel gating but not plasma membrane trafficking. Login to comment 197 ABCC7 p.Gly551Asp Figure 6A shows that CoPo-22 functioned as a weak potentiator of G551D-CFTR, producing a smaller increase in chloride current than that produced by genistein. Login to comment 198 ABCC7 p.Gly551Asp Fluorescence plate reader assays in Fig. 6B confirmed that CoPo-22 activated G551D-CFTR in the presence of forskolin, albeit with lower maximal efficacy than genistein. Login to comment 201 ABCC7 p.Gly551Asp The mechanism of action of AATs is also unclear, although it was speculated that AATs bind directly to a different site from that of classical potentiators, as evidenced by their similar efficacy for activation of G551D and other CFTR mutants. Login to comment 203 ABCC7 p.Gly551Asp Though their rapid, cell type-independent potentiator action on ∆F508, G551D and wild type CF suggests direct CFTR binding, their corrector mechanism is less clear. Login to comment 217 ABCC7 p.Gly551Asp ⌬Phe508-CFTR channel gating by CoPo-22 is probably a consequence of direct binding, as is its efficacy in the rapid activation of chloride conductance in wild-type and G551D-CFTR. Login to comment 232 ABCC7 p.Gly551Asp CoPo-22 activity in G551D-CFTR expressing FRT cells and ⌬Phe508-CFTR-expressing A459 cells. Login to comment 233 ABCC7 p.Gly551Asp A, top, short-circuit current measured in FRT cells expressing G551D-CFTR, showing responses to indicated forskolin and CoPo-22 concentrations. Login to comment 236 ABCC7 p.Gly551Asp Bottom, plate reader assay of G551D-CFTR chloride conductance showing representative fluorescence quenching curves (inset) and deduced concentration dependence of CoPo-22 and genistein potentiator action (S.E.M., n ϭ 4). Login to comment 252 ABCC7 p.Gly551Asp The mechanism of action of AATs is also unclear, although it was speculated that AATs bind directly to a different site from that of other potentiators, as evidenced by their similar efficacy for activation of G551D and other CFTR mutants. Login to comment 254 ABCC7 p.Gly551Asp Although their rapid, cell type-independent potentiator action on ⌬Phe508, G551D, and wild-type CF suggests direct CFTR binding, their corrector mechanism is less clear. Login to comment