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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)52-56
Number of pages5
JournalFEBS Letters
Volume558
Issue number1-3
DOIs
Publication statusPublished - 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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