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Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker
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| Zeitschriftentitel: | FEBS Letters |
|---|---|
| Personen und Körperschaften: | , , , , , |
| In: | FEBS Letters, 558, 2004, 1-3, S. 52-56 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Taddei, Alessandro Folli, Chiara Zegarra-Moran, Olga Fanen, Pascale Verkman, A.S Galietta, Luis J.V Taddei, Alessandro Folli, Chiara Zegarra-Moran, Olga Fanen, Pascale Verkman, A.S Galietta, Luis J.V |
|---|---|
| author |
Taddei, Alessandro Folli, Chiara Zegarra-Moran, Olga Fanen, Pascale Verkman, A.S Galietta, Luis J.V |
| spellingShingle |
Taddei, Alessandro Folli, Chiara Zegarra-Moran, Olga Fanen, Pascale Verkman, A.S Galietta, Luis J.V FEBS Letters Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker Cell Biology Genetics Molecular Biology Biochemistry Structural Biology Biophysics |
| author_sort |
taddei, alessandro |
| spelling |
Taddei, Alessandro Folli, Chiara Zegarra-Moran, Olga Fanen, Pascale Verkman, A.S Galietta, Luis J.V 0014-5793 1873-3468 Wiley Cell Biology Genetics Molecular Biology Biochemistry Structural Biology Biophysics http://dx.doi.org/10.1016/s0014-5793(04)00011-0 <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 >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> Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker FEBS Letters |
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10.1016/s0014-5793(04)00011-0 |
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Online Free |
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Biologie Chemie und Pharmazie Physik |
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Wiley, 2004 |
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Wiley, 2004 |
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0014-5793 1873-3468 |
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0014-5793 1873-3468 |
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2004 |
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FEBS Letters |
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49 |
| title |
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_unstemmed |
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_full |
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_fullStr |
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_full_unstemmed |
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_short |
Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_sort |
altered channel gating mechanism for cftr inhibition by a high‐affinity thiazolidinone blocker |
| topic |
Cell Biology Genetics Molecular Biology Biochemistry Structural Biology Biophysics |
| url |
http://dx.doi.org/10.1016/s0014-5793(04)00011-0 |
| publishDate |
2004 |
| physical |
52-56 |
| description |
<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 >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> |
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| author | Taddei, Alessandro, Folli, Chiara, Zegarra-Moran, Olga, Fanen, Pascale, Verkman, A.S, Galietta, Luis J.V |
| author_facet | Taddei, Alessandro, Folli, Chiara, Zegarra-Moran, Olga, Fanen, Pascale, Verkman, A.S, Galietta, Luis J.V, Taddei, Alessandro, Folli, Chiara, Zegarra-Moran, Olga, Fanen, Pascale, Verkman, A.S, Galietta, Luis J.V |
| author_sort | taddei, alessandro |
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| description | <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 >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> |
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| imprint | Wiley, 2004 |
| imprint_str_mv | Wiley, 2004 |
| institution | DE-Rs1, DE-Pl11, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15 |
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| spelling | Taddei, Alessandro Folli, Chiara Zegarra-Moran, Olga Fanen, Pascale Verkman, A.S Galietta, Luis J.V 0014-5793 1873-3468 Wiley Cell Biology Genetics Molecular Biology Biochemistry Structural Biology Biophysics http://dx.doi.org/10.1016/s0014-5793(04)00011-0 <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 >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> Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker FEBS Letters |
| spellingShingle | Taddei, Alessandro, Folli, Chiara, Zegarra-Moran, Olga, Fanen, Pascale, Verkman, A.S, Galietta, Luis J.V, FEBS Letters, Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker, Cell Biology, Genetics, Molecular Biology, Biochemistry, Structural Biology, Biophysics |
| title | Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_full | Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_fullStr | Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_full_unstemmed | Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_short | Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| title_sort | altered channel gating mechanism for cftr inhibition by a high‐affinity thiazolidinone blocker |
| title_unstemmed | Altered channel gating mechanism for CFTR inhibition by a high‐affinity thiazolidinone blocker |
| topic | Cell Biology, Genetics, Molecular Biology, Biochemistry, Structural Biology, Biophysics |
| url | http://dx.doi.org/10.1016/s0014-5793(04)00011-0 |