Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker

FEBS Letters

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.

【 摘 要 】

The thiazolidinone CFTR_inh-172 was identified recently as a potent and selective blocker of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel. Here, we characterized the CFTR_inh-172 inhibition mechanism by patch-clamp and short-circuit analysis using cells stably expressing wild-type and mutant CFTRs. CFTR_inh-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 CFTR_inh-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 CFTR_inh-172 by a mechanism involving altered CFTR gating.

【 授权许可】

Unknown