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Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker
Author(s) -
Taddei Alessandro,
Folli Chiara,
Zegarra-Moran Olga,
Fanen Pascale,
Verkman A.S,
Galietta Luis J.V
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(04)00011-0
Subject(s) - gating , chemistry , mechanism (biology) , biophysics , pharmacology , channel (broadcasting) , computer science , medicine , biology , physics , computer network , quantum mechanics
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.