ABCMdb

PMID: 14759515

Taddei A, Folli C, Zegarra-Moran O, Fanen P, Verkman AS, Galietta LJ
Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker.
FEBS Lett. 2004 Jan 30;558(1-3):52-6., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp Short-circuit current experiments indicated similar CFTRinh-172 inhibitory potency (KiW W0.5 W WM) for inhibition of Cl3 current in wild-type, G551D, and G1349D CFTR; however, Ki was signi'cantly reduced to 0.2 W WM for v vF508 CFTR. Login to comment 93 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp To test whether CFTRinh-172 interacts with one of the NBDs, we compared the inhibitory potency of CFTRinh-172 on wild-type CFTR and the mutants G551D and G1349D that produce defective CFTR gating NBD-1 and NBD-2, respectively. Login to comment 96 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp The &#a3;avone genistein (at 200 WM) together with cpt-cAMP was used to maximally activate the CFTR mutants G551D and G1349D. Login to comment 97 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Gly1349Asp CFTRinh-172 blocked G551D and G1349D Cl3 currents with potency not signi'cantly di&#a1;erent from that for inhibition of wild-type CFTR, with Ki of 0.53 WM (nH = 0.90) and 0.51 (nH = 1.17), respectively, for G551D and G1349D (Fig. 4B,C). Login to comment 114 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp A: Representative short-circuit current experiments on permeabilized FRT cells expressing wild-type CFTR, or G551D, G1349D, and vF508 mutants. Login to comment 115 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp cpt-cAMP concentration was 100 WM and genistein concentrations were 50 WM (wild-type and vF508) or 200 WM (G551D and G1349D). Login to comment 121 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp After genistein activation, the CFTRinh-172 inhibitory potency did not di&#a1;er signi'cantly (Ki = 0.48; nH = 0.96) from that measured for G551D and G1349D. Login to comment 124 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp Interestingly, vF508-CFTR Cl3 currents were inhibited by CFTRinh-172 with a signi'cant about twofold greater e/cacy than found for wild-type CFTR and the G551D and G1349D mutants (Fig. 4B,C). Login to comment 143 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp We also tested the e&#a1;ect of CFTR mutations that impair NBD function and thus reduce CFTR opening, including G551D and G1349D. Login to comment 145 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp CFTRinh-172 had comparable inhibitory potency for reducing Cl3 currents for wild-type CFTR, G551D, and G1349D. Login to comment