期刊论文详细信息
FEBS Letters
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker
Fanen, Pascale1  Verkman, A.S2  Zegarra-Moran, Olga3  Taddei, Alessandro3  Folli, Chiara3  Galietta, Luis J.V3 
[1] INSERM U. 468, Hôpital Henri Mondor, 94010 Créteil, France;Departments of Medicine and Physiology, University of California San Francisco, CA 94143, USA;Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, 16148 Genoa, Italy
关键词: Cystic fibrosis transmembrane conductance regulator;    Chloride channel;    Channel blocker;    Cystic fibrosis;    Chloride secretion;   
DOI  :  10.1016/S0014-5793(04)00011-0
学科分类:生物化学/生物物理
来源: John Wiley & Sons Ltd.
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【 摘 要 】

The thiazolidinone CFTRinh-172 was identified recently as a potent and selective blocker of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel. Here, we characterized the CFTRinh-172 inhibition mechanism by patch-clamp and short-circuit analysis using cells stably expressing wild-type and mutant CFTRs. CFTRinh-172 did not alter CFTR unitary conductance (8 pS), but reduced open probability by >90% with K i≈0.6 μM. This effect was due to increased mean channel closed time without changing mean channel open time. Short-circuit current experiments indicated similar CFTRinh-172 inhibitory potency (K i≈0.5 μM) for inhibition of Cl current in wild-type, G551D, and G1349D CFTR; however, K i was significantly reduced to 0.2 μM for ΔF508 CFTR. Our studies provide evidence for CFTR inhibition by CFTRinh-172 by a mechanism involving altered CFTR gating.

【 授权许可】

Unknown   

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