Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium (original) (raw)

Nature volume 331, pages 358–360 (1988)Cite this article

Abstract

Chloride (Cl–) secretion by the airway epithelium regulates, in part, the quantity and composition of the respiratory tract fluid, thereby facilitating mucociliary clearance. The rate of Cl– secretion is controlled by apical membrane Cl– channels1. Apical Cl– channels are opened and Cl– secretion is stimulated by a variety of hormones and neurotransmitters that increase intracellular levels of cyclic AMP (cAMP)1–2. In cystic fibrosis (CF), a common lethal genetic disease of Caucasians, airway3,4, sweat-gland duct5, secretory-coil6 and possibly other epithelia7 are anion impermeable. This abnormality may explain several of the clinical manifestations of the disease. The Cl– impermeability in CF-airway epithelia has been localized to the apical cell membrane4, where regulation of Cl– channels is abnormal8,9: hormonal secretagogues stimulate cAMP accumulation appropriately but Cl– channels fail to open. Here we report that the purified catalytic subunit of cAMP-dependent protein kinase plus ATP opens Cl– channels in excised, cell-free patches of membrane from normal cells, but fails to open Cl–; channels in CF cells. These results indicate that in normal cells, the cAMP-dependent protein kinase phosphorylates the Cl– channel or an associated regulatory protein, causing the channel to open. The failure of CF Cl– channels to open suggests a defect either in the channel or in such an associated regulatory protein.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Welsh, M. J. Physiol. Revs 67, 1143–1184 (1987).
    Article CAS Google Scholar
  2. Welsh, M. J. Science 232, 1648–1650 (1986).
    Article ADS CAS Google Scholar
  3. Knowles, M. R. et al. Science 221, 1067–1070 (1983).
    Article ADS CAS Google Scholar
  4. Widdicombe, J. H., Welsh, M. J. & Finkbeiner, W. E. Proc. natn. Acad. Sci. U.S.A. 82, 6167–6171 (1985).
    Article ADS CAS Google Scholar
  5. Quinton, P. M. Nature 301, 421–422 (1983).
    Article ADS CAS Google Scholar
  6. Sato, K. & Sato, F. J. clin. Invest. 73, 1763–1771 (1984).
    Article CAS Google Scholar
  7. Kopelman, H., Durie, P., Gaskin, K., Weizman, Z. & Forstner, G. N. Engl. J. Med. 312(6), 329–334 (1985).
    Article CAS Google Scholar
  8. Welsh, M. J. & Liedtke, C. M. Nature 322, 467–470 (1986).
    Article ADS CAS Google Scholar
  9. Frizzell, R. A., Rechkemmer, G. & Shoemaker, R. L. Science 233, 558–560 (1986).
    Article ADS CAS Google Scholar
  10. Krebs, E. G. & Beavo, J. A. A. Rev. Biochem. 48, 923–959 (1979).
    Article CAS Google Scholar
  11. Nestler, E. J. & Greengard, P. Protein Phosphorylation in the Nervous System (Wiley, New York, 1984).
    Google Scholar
  12. Levitan, I. B. J. Membrane Biol. 87, 177–190 (1985).
    Article CAS Google Scholar
  13. Flockhart, D. A. & Corbin, J. D. CRC Crit. Rev. Biochem. 12, 133–186 (1982).
    Article CAS Google Scholar
  14. Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Pflugers Arch. 391, 85–100 (1981).
    Article CAS Google Scholar
  15. Kaczraarek, L. K. et al. Proc. natn. Acad. Sci. U.S.A. 77, 7487–7491 (1980).
    Article ADS Google Scholar

Download references

Author information

Author notes

  1. Michael J. Welsh: To whom correspondence should be addressed.

Authors and Affiliations

  1. Laboratory of Epithelial Transport and Pulmonary Division, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, 52242, USA
    Ming Li, John D. McCann & Michael J. Welsh
  2. Cystic Fibrosis Center, Department of Pediatrics, Developmental Genetics and Anatomy, School of Medicine, Case Western Reserve, Cleveland, Ohio, 44106, USA
    Carole M. Liedtket
  3. Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021, USA
    Angus C. Nairn & Paul Greengard

Authors

  1. Ming Li
    You can also search for this author inPubMed Google Scholar
  2. John D. McCann
    You can also search for this author inPubMed Google Scholar
  3. Carole M. Liedtket
    You can also search for this author inPubMed Google Scholar
  4. Angus C. Nairn
    You can also search for this author inPubMed Google Scholar
  5. Paul Greengard
    You can also search for this author inPubMed Google Scholar
  6. Michael J. Welsh
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Li, M., McCann, J., Liedtket, C. et al. Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium.Nature 331, 358–360 (1988). https://doi.org/10.1038/331358a0

Download citation