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

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Bibliographische Detailangaben
Zeitschriftentitel: FEBS Letters
Personen und Körperschaften: Taddei, Alessandro, Folli, Chiara, Zegarra-Moran, Olga, Fanen, Pascale, Verkman, A.S, Galietta, Luis J.V
In: FEBS Letters, 558, 2004, 1-3, S. 52-56
Format: E-Article
Sprache: Englisch
veröffentlicht:
Wiley
Schlagwörter:
Cell Biology
Genetics
Molecular Biology
Biochemistry
Structural Biology
Biophysics
Details
Zusammenfassung: <jats:p>The thiazolidinone CFTR<jats:sub>inh</jats:sub>‐172 was identified recently as a potent and selective blocker of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl<jats:sup>−</jats:sup> channel. Here, we characterized the CFTR<jats:sub>inh</jats:sub>‐172 inhibition mechanism by patch‐clamp and short‐circuit analysis using cells stably expressing wild‐type and mutant CFTRs. CFTR<jats:sub>inh</jats:sub>‐172 did not alter CFTR unitary conductance (8 pS), but reduced open probability by &gt;90% with <jats:italic>K</jats:italic> <jats:sub>i</jats:sub>≈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<jats:sub>inh</jats:sub>‐172 inhibitory potency (<jats:italic>K</jats:italic> <jats:sub>i</jats:sub>≈0.5 μM) for inhibition of Cl<jats:sup>−</jats:sup> current in wild‐type, G551D, and G1349D CFTR; however, <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> was significantly reduced to 0.2 μM for ΔF508 CFTR. Our studies provide evidence for CFTR inhibition by CFTR<jats:sub>inh</jats:sub>‐172 by a mechanism involving altered CFTR gating.</jats:p>
Umfang: 52-56
ISSN: 0014-5793
1873-3468
DOI: 10.1016/s0014-5793(04)00011-0