Defective regulation of outwardly rectifying cl− channels by protein kinase a corrected by insertion of cftr


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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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Article Open access 27 May 2022 REFERENCES * Frizzell, R. A. _Trends Neurosci._ 10, 190–193 (1987). Article  CAS  Google Scholar  * Cheng, P. W. _et al._ _J. clin. Invest._ 84, 68–72 (1989).


Article  ADS  CAS  Google Scholar  * Quinton, P. M. _FASEB J._ 4, 2709–2717 (1990). Article  CAS  Google Scholar  * Barasch, J. _et al._ _Nature_ 352, 70–73 (1991). Article  ADS  CAS 


Google Scholar  * Riordin, J. R. _et al._ _Science_ 245, 1066–1073 (1989). Article  ADS  Google Scholar  * Kartner, N. _et al._ _Cell_ 64, 681–691 (1991). Article  CAS  Google Scholar  *


Anderson, M. P. _et al._ _Science_ 253, 202–205 (1991). Article  ADS  CAS  Google Scholar  * Bear, C. E. _et al._ _J. biol. Chem._ 266, 19142–19145 (1991). CAS  PubMed  Google Scholar  * Li,


M. _et al._ _Nature_ 331, 358–360 (1988). Article  ADS  CAS  Google Scholar  * Li, M. _et al._ _Science_ 244, 1353–1356 (1989). Article  ADS  CAS  Google Scholar  * Schoumacher, R. A. _et


al._ _Nature_ 330, 752–754 (1987). Article  ADS  CAS  Google Scholar  * Chen, J. H., Schulman, H. & Gardner, P. _Science_ 243, 657–660 (1989). Article  ADS  CAS  Google Scholar  * Hwang,


T. C. _et al._ _Science_ 244, 1351–1353 (1989). Article  ADS  CAS  Google Scholar  * Ward, C. L. _et al._ _Proc. natn. Acad. Sci. U.S.A._ 88, 5277–5281 (1991). Article  ADS  CAS  Google


Scholar  * Zeitlin, P. L. _et al._ _Am. J. respir. Cell molec. Biol._ 4, 313–319 (1991). Article  CAS  Google Scholar  * Flotte, T. R. _et al._ _Am. J. respir. Cell molec. Biol._ (in the


press). * Rich, D. P. _et al._ _Nature_ 347, 358–363 (1990). Article  ADS  CAS  Google Scholar  * Drumm, M. L. _et al._ _Cell_ 62, 1227–1233 (1990). Article  CAS  Google Scholar  * Anderson,


M. P. _et al._ _Cell_ 67, 775–784 (1991). Article  CAS  Google Scholar  * Bridges, R. J., Worrell, R. T., Frizzell, R. A. & Benos, D. J. _Am. J. Physiol._ 2562, C902–C912 (1989).


Article  Google Scholar  * Anderson, M. P. & Welsh, M. J. _Proc. natn. Acad. Sci. U.S.A._ 88, 6003–6007 (1991). Article  ADS  CAS  Google Scholar  * Welsh, M. J., Li, M. & McCann, J.


D. _J. clin. Invest._ 84, 2002–2007 (1989). Article  CAS  Google Scholar  * Zeitlin, P. L. _et al._ _Proc. natn. Acad. Sci. U.S.A._ 89, 344–347 (1992). Article  ADS  CAS  Google Scholar  *


Trapnell, B. C. _et al._ _J. biol. Chem._ 266, 10319–10323 (1991). CAS  PubMed  Google Scholar  * Flotte, T. _et al._ _Ped. Pulm._ 6 (suppl.) 247 (1991). Google Scholar  Download references


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


search for this author inPubMed Google Scholar * William B. Guggino View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and


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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