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

BackgroundTRPC6 has been proposed to be responsible for the abnormal OAG-dependent Ca2 + 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.MethodsChinese 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).ResultsCFTR down regulates OAG Ca2 + response and OAG Ca2 + influx increases CFTR chloride efflux. Furthermore, we observed potentiation of G551D-CFTR activity when combining VX-770 and OAG.ConclusionTaking advantage of the functional coupling between OAG-dependent Ca2 + influx and CFTR, a combination of OAG and VX-770 could be a therapeutic strategy for homozygote patients bearing the G551D-CFTR mutation.