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Evidence for Direct CFTR Inhibition by CFTR(inh)-172 Based on Arg347 Mutagenesis

Evidence for Direct CFTR Inhibition by CFTR(inh)-172 Based on Arg347 Mutagenesis

Emanuela Caci, Antonella Caputo, Alexandre Hinzpeter, Nicole Arous, Pascale Fanen, Nitin Sonawane, A S Verkman, Roberto Ravazzolo, Olga Zegarra-Moran, Luis J V Galietta

Biochem J. 2008 Jul 1;413(1):135-42.

PMID: 18366345

Abstract:

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 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 CFTR(inh)-172 interacts directly with CFTR, and that Arg347 is important for the interaction.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP307510925	CFTR(inh)-172		307510-92-5	Price

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