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J Cyst Fibros. 2013 Dec;12(6):584-91. doi: 10.1016/j.jcf.2013.05.008. Epub 2013 Jun 10.

Effect of VX-770 (ivacaftor) and OAG on Ca2+ influx and CFTR activity in G551D and F508del-CFTR expressing cells.

Author information

1
Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS FRE 3511, 86022 Poitiers, France.

Abstract

BACKGROUND:

TRPC6 has been proposed to be responsible for the abnormal OAG-dependent Ca(2+) influx in cystic fibrosis (CF) cells and we hypothesized that it interacts with CFTR. Here, we investigated how this functional complex operates in CF and non-CF epithelial cells.

METHODS:

Chinese hamster ovary (CHO) cells stably transfected with pNut vector containing wild type CFTR (CHO-WT), F508del-CFTR (CHO-F508del) or G551D-CFTR(CHO-G551D) were used. Calcium channel activity was recorded using Fluo-4 probe and CFTR activity was measured by iodide efflux technique in the presence of CFTR activators (forskolin, genistein) and VX-770, CFTR inhibitor (GPinh5a) and TRPC non-selective modulators (OAG, SKF96365).

RESULTS:

CFTR down regulates OAG Ca(2+) response and OAG Ca(2+) influx increases CFTR chloride efflux. Furthermore, we observed potentiation of G551D-CFTR activity when combining VX-770 and OAG.

CONCLUSION:

Taking advantage of the functional coupling between OAG-dependent Ca(2+) influx and CFTR, a combination of OAG and VX-770 could be a therapeutic strategy for homozygote patients bearing the G551D-CFTR mutation.

KEYWORDS:

CFTR; Calcium signaling; Cystic fibrosis; G551D-CFTR; OAG; TRPC6; VX-770

PMID:
23757361
DOI:
10.1016/j.jcf.2013.05.008
[Indexed for MEDLINE]
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