Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel function

It is increasingly being recognized that cells coordinate the activity Of separate ion channels that allow electrolytes into the cell. However, a perplexing problem in channel regulation has arisen in the fatal genetic disease cystic fibrosis, which results fi om the loss of a specific Cl- channel (the CFTR channel) in epithelial cell membranes(1). Although this defect clearly inhibits the absorption of Na+ in sweat gands(2,3), it is widely accepted that Na+ absorption is abnormally elevated in defective airways in cystic fibrosis(4,5). The only frequently cited explanation for this hypertransport is that the activity of an epithelial Na+ channel (ENaC) is inversely related to the activity of the CFTR Cl- channel(5-7). However we report here that, in freshly isolated normal sweat ducts, ENaC activity is dependent on, and increases with, CFTR activity. Surprisingly, we also find that the primary defect in Cl- permeability in cystic fibrosis(8) is accompanied secondarily by a Na+ conductance in this tissue that cannot: be activated. Thus, reduced salt absorption in cystic fibrosis is due not only to poor Cl- conductance but also to poor Na+ conductance.