Defective regulation of outwardly rectifying Cl− channels by protein kinase A corrected by insertion of CFTR

CYSTIC fibrosis (CF) is a lethal genetic disease resulting in a reduced CI − permeability 1 , increased mucous sulphation 2 , increased Na + absorption 3 and defective acidification of lysosomal vesicles 4 . The CF gene encodes a protein (the cystic fibrosis trans-membrane conductance regulator, CFTR 5 ) that can function as a low-conductance Cl − channel with a linear current-voltage relationship whose regulation is defective in CF patients 6–8 . Larger conductance, outwardly rectifying Cl − channels are also defective in CF and fail to activate when exposed either to cyclic AMP-dependent protein kinase A or to protein kinase C 9–13 . The role of the outwardly rectifying Cl − channel in CF has been questioned 14 . We report here that expression of recombinant CF genes using adeno-associated virus vectors in CF bronchial epithelial cells corrects defective Cl − secretion, that it induces the appearance of small, linear conductance Cl − channels, and restores protein kinase A activation of outwardly rectifying Cl − channels. These results re-establish an involvement of outwardly rectifying Cl − channels in CF and suggest that CFTR regulates more than one conductance pathway in airway tissues.