Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker.
FEBS Lett
; 558(1-3): 52-6, 2004 Jan 30.
Article
in En
| MEDLINE
| ID: mdl-14759515
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) approximately 0.6 microM. 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) approximately 0.5 microM) for inhibition of Cl(-) current in wild-type, G551D, and G1349D CFTR; however, K(i) was significantly reduced to 0.2 microM for DeltaF508 CFTR. Our studies provide evidence for CFTR inhibition by CFTR(inh)-172 by a mechanism involving altered CFTR gating.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiazoles
/
Ion Channel Gating
/
Chloride Channels
/
Cystic Fibrosis Transmembrane Conductance Regulator
Limits:
Animals
Language:
En
Journal:
FEBS Lett
Year:
2004
Document type:
Article