title: 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 Cl- permeability, increased mucous sulphation, increased Na+ absorption and defective acidification of lysosomal vesicles. The CF gene encodes a protein (the cystic fibrosis transmembrane conductance regulator, CFTR) that can function as a low-conductance Cl- channel with a linear current-voltage relationship whose regulation is defective in CF patients. 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. The role of the outwardly rectifying Cl- channel in CF has been questioned. 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.
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: M
authors.initials: M
authors.lastname: Egan
authors.forename: T
authors.initials: T
authors.lastname: Flotte
authors.forename: S
authors.initials: S
authors.lastname: Afione
authors.forename: R
authors.initials: R
authors.lastname: Solow
authors.forename: P L
authors.initials: PL
authors.lastname: Zeitlin
authors.forename: B J
authors.initials: BJ
authors.lastname: Carter
authors.forename: W B
authors.initials: WB
authors.lastname: Guggino
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004553:Electric Conductivity; D006801:Humans; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism*; D014162:Transfection
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D011494:Protein Kinases