title: Direct interactions between ENaC gamma subunit and ClCN2 in cystic fibrosis epithelial cells.
abstract: Cystic fibrosis (CF) is a lethal disease caused by mutations in the chloride channel CFTR gene. The disease is characterized by decreased chloride secretion and unregulated sodium absorption through the epithelial sodium channel (ENaC) in the airway epithelium and other affected organs. We hypothesize that a non-CFTR alternative chloride channel ClCN2 can be activated to negatively regulate ENaC in CF epithelial cell cultures. We identified a novel interaction between ClCN2 and the ENaCγ subunit in CF airway epithelial cells and show that the upregulation of ClCN2 leads to decreased expression of ENaCγ via a K63 ubiquitination mechanism. These regulatory effects of ClCN2 on ENaCγ appear to be dependent on the CBS-1 domain located within the c-terminus of ClCN2, which is necessary for the targeting of ClCN2 to the apical surface. In sum, these results suggest the ability of ClCN2 to negatively regulate sodium absorption through ENaC, supporting its role as a therapeutic target for the treatment of CF.
authors: Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Katherine R
authors: KR
authors: Henry
authors: Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Seakwoo
authors: S
authors: Lee
authors: Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Douglas
authors: D
authors: Walker
authors: Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Pamela L
authors: PL
authors: Zeitlin
keywords: Chloride channel N2; chloride secretion; cystic fibrosis; epithelial sodium channel; sodium absorption; ubiquitination
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