CFTR (cystic fibrosis transmembrane conductance regulator) is an epithelial Cl- channel inhibited with high affinity and selectivity by the thiazolidinone compound CFTRinh-172. In the present study, we provide evidence that CFTRinh-172 acts directly on the CFTR. We introduced mutations in amino acid residues of the sixth transmembrane helix of the CFTR protein, a domain that has an important role in the formation of the channel pore. Basic and hydrophilic amino acids at positions 334-352 were replaced with alanine residues and the sensitivity to CFTRinh-172 was assessed using functional assays. We found that an arginine-to-alanine change at position 347 reduced the inhibitory potency of CFTRinh-172 by 20-30-fold. Mutagenesis of Arg347 to other amino acids also decreased the inhibitory potency, with aspartate producing near total loss of CFTR inh-172 activity. The results of the present study provide evidence that CFTRinh-172 interacts directly with CFTR, and that Arg 347 is important for the interaction.
- Channel blocker
- Chloride channel
- Cystic fibrosis
- Cystic fibrosis transmembrane conductance regulator (CFTR)
ASJC Scopus subject areas