Calu-3 is a well differentiated human bronchial cell line with the characteristics of the serous cells of airway submucosal glands. The submucosal glands play a major role in mucociliary clearance because they secrete electrolytes that facilitate airway hydration. Given the significance of both long- and short-term β-adrenergic receptor agonists in the treatment of respiratory diseases, it is important to determine the role of these receptors and their ligands in normal physiological function. The current studies were designed to characterize the effect of epinephrine, the naturally occurring β-adrenergic receptor agonist, on electrolyte transport of the airway serous cells. Interestingly epinephrine stimulated two anion secretory channels, the cystic fibrosis transmembrane conductance regulator and a Ca²⁺-activated Cl^- channel, with the characteristics of TMEM16A, thereby potentially altering mucociliary clearance via multiple channels. Consistent with the dual channel activation, epinephrine treatment resulted in increases in both intracellular cAMP and Ca²⁺ Furthermore, the current results extend previous reports indicating that the two anion channels are functionally linked.