Regulation of ion channels in cystic fibrosis (869.8)

Abstract

Cystic Fibrosis (CF) is an autosomal recessive disease, characterized by mutations in the CFTR gene, incorrect protein folding, and impaired chloride secretion. In addition to the maintenance of chloride secretion, CFTR is also suggested to be an important regulator of epithelial sodium channel (ENaC) activity. We previously identified the chloride channel ClCN2 as coexpressed with the mutant CFTR and hypothesized that in addition to restoring chloride secretion, ClCN2 can act as a negative regulator of ENaC. Coimmunoprecipitation analysis shows a novel physical interaction between ClCN2 and ENaC in pulmonary epithelium, which is accompanied by changes in ClCN2 and ENaC protein localization, as well as transepithelial resistance. Furthermore, ClCN2 has been shown to play an important role in the regulation of epithelial cell junctions and to this end, we show that changes in ClCN2 localization and activity may also affect cell junctions in CF cells. In conclusion, our data is the first to identify a novel interaction between ClCN2 and ENaC subunits. We also show potential changes in junction formation which may be regulated by changes in ClCN2 activity and localization. Therefore, when CFTR is nonfunctional, as in Cystic Fibrosis, ClCN2 may regulate ENaC activity and tight junction formation, which suggests that modulation of ClCN2 activity might be an advantageous target for treatment of the disease.Grant Funding Source: Supported by 5T32HL72748‐11: Ruth L Kirschstein National Research Service Award