Stimulation of transepithelial Cl- secretion by the airway epithelium requires activation of channels at the two opposite sides of the cell: the apical and basolateral membranes. At the apical membrane, the Cl- channel is regulated by phosphorylation with PKA and PKC. At the basolateral membrane, the KCLIC channel is regulated by [Ca2+]c. Addition of a secretagogue that increases cellular levels of cAMP also causes release of Ca2+ from intracellular stores. The Ca2+ may then regulate basolateral membrane KCLIC channels. The cAMP-induced increase in [Ca2+]c and activation of the KCLIC channel is transient, however, whereas activation of the Cl- channel and stimulation of secretion is a more sustained response. Those results suggest that the presence of a second Ca2(+)-independent K+ channel located at the basolateral membrane, which is only expressed in cells grown on permeable supports.