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

Abstract

CYSTIC fibrosis (CF) is a lethal genetic disease resulting in a reduced CI permeability1, increased mucous sulphation2, 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 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.

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Egan, M., Flotte, T., Afione, S. et al. Defective regulation of outwardly rectifying Cl channels by protein kinase A corrected by insertion of CFTR. Nature 358, 581–584 (1992). https://doi.org/10.1038/358581a0

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