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^- permeability¹, increased mucous sulphation ², increased Na⁺ absorption³ and defective acidification of lysosomal vesicles⁴. The CF gene encodes a protein (the cystic fibrosis trans-membrane conductance regulator, CFTR⁵) 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 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.