Potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl¯ currents by the chemical solvent tetrahydrofuran

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Abstract

The chemical solvent tetrahydrofuran (THF) increases short-circuit current (Isc) in renal epithelia endogenously expressing the cystic fibrosis transmembrane conductance regulator (CFTR). To understand how THF increases Isc, we employed the Ussing chamber and patch-clamp techniques to study cells expressing recombinant human CFTR. THF increased Isc in Fischer rat thyroid (FRT) epithelia expressing wild-type CFTR with half-maximal effective concentration (KD) of 134 mM. This THF-induced increase in Isc was enhanced by forskolin (10 μM), inhibited by the PKA inhibitor H-89 (10 μM) and the thiazolidinone CFTRinh-172 (10 μM) 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 Isc 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 ΔR-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.
Translated title of the contributionPotentiation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl¯ currents by the chemical solvent tetrahydrofuran
Original languageEnglish
Pages (from-to)528 - 538
Number of pages11
JournalMolecular Membrane Biology
Volume25
DOIs
Publication statusPublished - Sep 2008

Bibliographical note

Publisher: Informa Healthcare
Other: Supplemental Data

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