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

It is increasingly being recognized that cells coordinate the activity Of s eparate ion channels that allow electrolytes into the cell. However, a perp lexing problem in channel regulation has arisen in the fatal genetic diseas e cystic fibrosis, which results fi om the loss of a specific Cl- channel ( the CFTR channel) in epithelial cell membranes(1). Although this defect cle arly inhibits the absorption of Na+ in sweat gands(2,3), it is widely accep ted that Na+ absorption is abnormally elevated in defective airways in cyst ic fibrosis(4,5). The only frequently cited explanation for this hypertrans port 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 her e 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 sec ondarily by a Na+ conductance in this tissue that cannot: be activated. Thu s, reduced salt absorption in cystic fibrosis is due not only to poor Cl- c onductance but also to poor Na+ conductance.