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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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AUTHOR INFORMATION Author notes * William B. Guggino: To whom correspondence should be addressed. AUTHORS AND AFFILIATIONS * Departments of Physiology and Pediatrics, Johns Hopkins

University School of Medicine, Baltimore, Maryland, 21205, USA Marie Egan, Terence Flotte, Pamela L. Zeitlin & William B. Guggino * Laboratory of Molecular and Cellular Biology, National

Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA Terence Flotte, Sandra Afione, Rikki Solow & Barrie J. Carter Authors *

Marie Egan View author publications You can also search for this author inPubMed Google Scholar * Terence Flotte View author publications You can also search for this author inPubMed Google

Scholar * Sandra Afione View author publications You can also search for this author inPubMed Google Scholar * Rikki Solow View author publications You can also search for this author

inPubMed Google Scholar * Pamela L. Zeitlin View author publications You can also search for this author inPubMed Google Scholar * Barrie J. Carter View author publications You can also

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 29 April 1992 * Accepted: 25 June 1992 * Issue Date: 13 August 1992 * DOI:

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