期刊
BIOCHEMICAL JOURNAL
卷 413, 期 -, 页码 135-142出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20080029
关键词
channel blocker; chloride channel; cystic fibrosis; cystic fibrosis transmembrane conductance regulator (CFTR); mutagenesis
资金
- Telethon [GGP05103] Funding Source: Medline
CFTR (cystic fibrosis transmembrane conductance regulator) is an epithelial Cl(-) channel inhibited with high affinity and selectivity by the thiazolidinone compound CFTR(inh)-172. In the present study, we provide evidence that CFTR(inh)-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 CFTR(inh)-172 was assessed using functional assays. We found that an arginine-to-alanine change at position 347 reduced the inhibitory potency of CFTR(inh)-172 by 20-30-fold. Mutagenesis of Arg(347) 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 CFTR(inh)-172 interacts directly with CFTR, and that Arg(347) is important for the interaction.
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