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 Cl- permeability1, increased mucous sulphation2, increased Na+ absorption3 and defective acidification of lysosomal vesicles4. The CF gene encodes a protein (the cystic fibrosis transmembrane conductance regulator, CFTR5) that can function as a low-conductance Cl- channel with a linear current-voltage relationship whose regulation is defective in CF patients6-8. 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 C9-13. The role of the outwardly rectifying Cl- channel in CF has been questioned14. 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.