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Potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- currents by the chemical solvent tetrahydrofuran.
- Source :
-
Molecular membrane biology [Mol Membr Biol] 2008 Sep; Vol. 25 (6-7), pp. 528-38. - Publication Year :
- 2008
-
Abstract
- The chemical solvent tetrahydrofuran (THF) increases short-circuit current (I(sc)) in renal epithelia endogenously expressing the cystic fibrosis transmembrane conductance regulator (CFTR). To understand how THF increases I(sc), we employed the Ussing chamber and patch-clamp techniques to study cells expressing recombinant human CFTR. THF increased I(sc) in Fischer rat thyroid (FRT) epithelia expressing wild-type CFTR with half-maximal effective concentration (K(D)) of 134 mM. This THF-induced increase in I(sc) was enhanced by forskolin (10 microM), inhibited by the PKA inhibitor H-89 (10 microM) and the thiazolidinone CFTR(inh)-172 (10 microM) and attenuated greatly in FRT epithelia expressing the cystic fibrosis mutants F508del- and G551D-CFTR. By contrast, THF (100 mM) was without effect on untransfected FRT epithelia, while other solvents failed to increase I(sc) in FRT epithelia expressing wild-type CFTR. In excised inside-out membrane patches, THF (100 mM) potentiated CFTR Cl(-) channels open in the presence of ATP (1 mM) alone by increasing the frequency of channel openings without altering their duration. However, following the phosphorylation of CFTR by PKA (75 nM), THF (100 mM) did not potentiate channel activity. Similar results were obtained with the triangle upR-S660A-CFTR Cl(-) channel that is not regulated by PKA-dependent phosphorylation and using 2'deoxy-ATP, which gates wild-type CFTR more effectively than ATP. Our data suggest that THF acts directly on CFTR to potentiate channel gating, but that its efficacy is weak and dependent on the phosphorylation status of CFTR.
- Subjects :
- Animals
Cell Line
Chlorine metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Cystic Fibrosis Transmembrane Conductance Regulator genetics
Cystic Fibrosis Transmembrane Conductance Regulator metabolism
Electrophysiology
Epithelial Cells
Humans
Ion Channel Gating
Mice
Mutation
Phosphorylation
Rats
Solvents
Cystic Fibrosis Transmembrane Conductance Regulator agonists
Cystic Fibrosis Transmembrane Conductance Regulator physiology
Furans pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-5203
- Volume :
- 25
- Issue :
- 6-7
- Database :
- MEDLINE
- Journal :
- Molecular membrane biology
- Publication Type :
- Academic Journal
- Accession number :
- 18989824
- Full Text :
- https://doi.org/10.1080/09687680802487967