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

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.
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https://hal.archives-ouvertes.fr/hal-00990531
Contributor : Christelle Morillon Connect in order to contact the contributor
Submitted on : Tuesday, May 13, 2014 - 3:51:47 PM
Last modification on : Wednesday, October 20, 2021 - 3:22:05 AM

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Laura Vachel, Caroline Norez, Frédéric Becq, Clarisse Vandebrouck. Effect of VX-770 (ivacaftor) and OAG on Ca2+ influx and CFTR activity in G551D and F508del-CFTR expressing cells.. Journal of Cystic Fibrosis, Elsevier, 2013, 12 (6), pp.584-91. ⟨10.1016/j.jcf.2013.05.008⟩. ⟨hal-00990531⟩

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