Chloride and potassium channels in cystic fibrosis airway epithelia

Abstract

Cystic fibrosis, the most common lethal genetic disease in Caucasians, is characterized by a decreased permeability in sweat gland duct and airway epithelia. In sweat duct epithelium, a decreased Cl⁻ permeability accounts for the abnormally increased salt content of sweat¹. In airway epithelia a decreased Cl⁻ permeability, and possibly increased sodium absorption, may account for the abnormal respiratory tract fluid^2,3. The Cl⁻ impermeability has been localized to the apical membrane of cystic fibrosis airway epithelial cells⁴. The finding that hormonally regulated Cl⁻ channels make the apical membrane Cl⁻ permeable in normal airway epithelial cells⁵ suggested abnormal Cl⁻ channel function in cystic fibrosis. Here we report that excised, cell-free patches of membrane from cystic fibrosis epithelial cells contain Cl⁻ channels that have the same conductive properties as Cl⁻ channels from normal cells. However, Cl⁻ channels from cystic fibrosis cells did not open when they were attached to the cell. These findings suggest defective regulation of Cl⁻ channels in cystic fibrosis epithelia; to begin to address this issue, we performed two studies. First, we found that isoprenaline, which stimulates Cl⁻ secretion, increases cellular levels of cyclic AMP in a similar manner in cystic fibrosis and non-cystic fibrosis epithelial cells. Second, we show that adrenergic agonists open calcium-activated potassium channels, indirectly suggesting that calcium-dependent stimulus–response coupling is intact in cystic fibrosis. These data suggest defective regulation of Cl⁻ channels at a site distal to cAMP accumulation.