CFTR inhibition by glibenclamide requires a positive charge in cytoplasmic loop three.

Patricia Melin, Eric Hosy, Michel Vivaudou, Frédéric Becq
Biochimica et Biophysica Acta (BBA) - Biomembranes. 2007-10-01; 1768(10): 2438-2446
DOI: 10.1016/j.bbamem.2007.05.013

Lire sur PubMed

1. Biochim Biophys Acta. 2007 Oct;1768(10):2438-46. Epub 2007 May 21.

CFTR inhibition by glibenclamide requires a positive charge in cytoplasmic loop

Melin P(1), Hosy E, Vivaudou M, Becq F.

Author information:
(1)Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS
UMR 6187, 86022 Poitiers cedex, France.

The sulfonylurea glibenclamide is widely used as an open-channel blocker of the
CFTR chloride channel. Here, we used site-directed mutagenesis to identify
glibenclamide site of interaction: a positively charged residue K978, located in
the cytoplasmic loop 3. Charge-neutralizing mutations K978A, K978Q, K978S
abolished the inhibition of forskolin-activated CFTR chloride current by
glibenclamide but not by CFTR(inh)-172. The charge-conservative mutation K978R
did not alter glibenclamide sensitivity of CFTR current. Mutations of the
neighbouring R975 (R975A, R975S, R975Q) did not affect electrophysiological and
pharmacological properties of CFTR. No alteration of halide selectivity was
observed with any of these CFTR mutant channels. This study identifies a novel
potential inhibitor site within the CFTR molecule, and suggests a novel role of
cytoplasmic loop three, within the second transmembrane domain of CFTR protein.
This work is the first to report on the role of a residue in a cytoplasmic loop
in the mechanism of action of the channel blocker glibenclamide.

DOI: 10.1016/j.bbamem.2007.05.013
PMID: 17582383 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus