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

Alessandro Taddei; Chiara Folli; Olga Zegarra-Moran; Pascale Fanen; A. S. Verkman; Luis J V Galietta

doi:10.1016/S0014-5793(04)00011-0

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

Alessandro Taddei, Chiara Folli, Olga Zegarra-Moran, Pascale Fanen, A. S. Verkman, Luis J V Galietta

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	52-56
Number of pages	5
Journal	FEBS Letters
Volume	558
Issue number	1-3
DOIs	https://doi.org/10.1016/S0014-5793(04)00011-0
Publication status	Published - Jan 30 2004

Keywords

Channel blocker
Chloride channel
Chloride secretion
Cystic fibrosis
Cystic fibrosis transmembrane conductance regulator

ASJC Scopus subject areas

Biochemistry
Biophysics
Molecular Biology

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10.1016/S0014-5793(04)00011-0

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title = "Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker",

abstract = "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 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 Ki≈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 (Ki≈0.5 μM) for inhibition of Cl- current in wild-type, G551D, and G1349D CFTR; however, Ki 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.",

keywords = "Channel blocker, Chloride channel, Chloride secretion, Cystic fibrosis, Cystic fibrosis transmembrane conductance regulator",

author = "Alessandro Taddei and Chiara Folli and Olga Zegarra-Moran and Pascale Fanen and Verkman, {A. S.} and Galietta, {Luis J V}",

year = "2004",

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doi = "10.1016/S0014-5793(04)00011-0",

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AU - Taddei, Alessandro

AU - Folli, Chiara

AU - Zegarra-Moran, Olga

AU - Fanen, Pascale

AU - Verkman, A. S.

AU - Galietta, Luis J V

PY - 2004/1/30

Y1 - 2004/1/30

N2 - 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 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 Ki≈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 (Ki≈0.5 μM) for inhibition of Cl- current in wild-type, G551D, and G1349D CFTR; however, Ki 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.

AB - 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 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 Ki≈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 (Ki≈0.5 μM) for inhibition of Cl- current in wild-type, G551D, and G1349D CFTR; however, Ki 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.

KW - Channel blocker

KW - Chloride channel

KW - Chloride secretion

KW - Cystic fibrosis

KW - Cystic fibrosis transmembrane conductance regulator

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

Abstract

Keywords

ASJC Scopus subject areas

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