Direct Activation of CFTR Chloride Channel by Natural Compound Theophylline

Theophylline has been widely used in the treatment of airway disease but molecular mechanism has not been clearly elucidated. Previous studies have manifested that theophylline increases intracellular cAMP concentration. Because cystic fibrosis transmembrane conductance regulator(CFTR) is a cAMP-dependent Cl- channel that plays key roles in fluid secretion in vivo, we postulated that theophylline activates CFTR channel gating. We found (1) theophylline stimulated CFTR-mediated anion transport in a concentration-dependent manner, and CFTR specific blocker completely reversed the effect; (2) theophylline had no effect on Delta F508 or G551D mutant CFTR chloride channel activity; (3) theophylline had additive effect with forskolin(FSK) and 3-isobutyl-xanthin(IBMX), thus a direct binding activation mechanism was suggested. In conclusion, the results may provide a clue to elucidating the molecular mechanism of theophylline activities and theophylline may present a novel lead drug in treating CFTR-related disease.