Molecular mechanism of cyclic-nucleotide-gated channel activation (original) (raw)

Nature volume 372, pages 369–374 (1994)Cite this article

Abstract

STUDIES on the activation of ligand- and voltage-gated ion channels have identified regions involved in both ligand binding1 and voltage sensing2, but relatively little is known about how such domains are coupled to channel opening. Here we investigate the structural basis for the activation of cyclic-nucleotide-gated channels, which are directly opened by cytoplasmic cyclic nucleotides3,4 but are structurally homologous to voltage-gated channels5–7. By constructing chimaeras between cyclic-nucleotide-gated channels cloned from bovine retinal photoreceptors8 and catfish olfactory neurons7, we identify two distinct domains that are important for ligand binding and channel gating. A putative α-helix in the carboxy-terminal binding domain determines the selectivity of the channel for activation by cGMP relative to cAMP. A domain in the amino-terminal region determines the ease with which channels open and thus influences agonist efficacy. We propose that channel opening is coupled to an allosteric conformational change in the binding site which enhances agonist binding. Thus, cyclic nucleotides activate the channel by binding tightly to the open state and stabilizing it.

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References

  1. Karlin, A. Curr. Opin. Neurobiol. 2, 299–309 (1993).
    Article Google Scholar
  2. Stuhmer, W. et al. Nature 339, 597–603 (1989).
    Article ADS CAS Google Scholar
  3. Fesenko, E. E., Kaoesnikov, S. S. & Lyubarsky, A. L. Nature 313, 310–313 (1985).
    Article ADS CAS Google Scholar
  4. Nakamura, T. & Gold, G. H. Nature 325, 342–344 (1987).
    Article Google Scholar
  5. Jan, L. Y. & Jan, Y. N. Nature 345, 672 (1990).
    Article ADS CAS Google Scholar
  6. Guy, H. R., Durell, S. R., Warmke, J., Drysdale, R. & Ganetzky, B. Science 254, 730 (1991).
    Article ADS CAS Google Scholar
  7. Goulding, E. H. et al. Neuron 8, 45–58 (1992).
    Article CAS Google Scholar
  8. Kaupp, U. B. et al. Nature 342, 762–766 (1989).
    Article ADS CAS Google Scholar
  9. Castillo, J. & Katz, B. Proc. R. Soc. B 146, 369–381 (1957).
    ADS Google Scholar
  10. Fersht, A. Enzyme Structure and Mechanism 98–106, 311–317 (Freeman, New York, 1985).
    Google Scholar
  11. Avis, J. M. & Fersht, A. R. Biochemistry 32, 5321–5326 (1993).
    Article CAS Google Scholar
  12. Catterall, W. A. Science 243, 236–237 (1989).
    Article ADS CAS Google Scholar
  13. Jackson, M. B. Biophys. J. 63, 1443–1444 (1992).
    Article ADS CAS Google Scholar
  14. Weber, I. T. & Steitz, T. A. J. molec Biol. 198, 311–326 (1987).
    Article CAS Google Scholar
  15. Shabb, J. M. & Corbin, J. D. J. biol. Chem. 267, 5723–5726 (1992).
    CAS PubMed Google Scholar
  16. Miller, C. Science 252, 1092–1096 (1991).
    Article ADS CAS Google Scholar
  17. Monod, J., Wyman, J. & Changeux, J.-P. J. molec. Biol. 12, 88–118 (1965).
    Article CAS Google Scholar
  18. MacKinnon, R. Nature 350, 232–235 (1991).
    Article ADS CAS Google Scholar
  19. Li, M., Jan, Y. N. & Jan, L. Y. Science 257, 1225–1230 (1992).
    Article ADS CAS Google Scholar
  20. Shen, N. V., Chen, X., Boyer, M. M. & Pfaffinger, P. J. Neuron 11, 67–76 (1993).
    Article CAS Google Scholar
  21. Babila, T. et al. Neuron 12, 615–626 (1994).
    Article CAS Google Scholar
  22. Perutz, M. F. Nature 228, 726–739 (1990).
    Article ADS Google Scholar
  23. Unwin, P. N. T. & Ennis, P. D. Nature 307, 609–613 (1984).
    Article ADS CAS Google Scholar
  24. Goulding, E. H., Tibbs, G. R., Liu, D. & Siegelbaum, S. A. Nature 364, 61–64 (1993).
    Article ADS CAS Google Scholar
  25. Zagotta, W. N., Hoshi, Y. & Aldrich, R. W. Science 250, 568–571 (1990).
    Article ADS CAS Google Scholar
  26. Kramer, R. H., Goulding, E. & Siegelbaum, S. A. Neuron 12, 655–662 (1994).
    Article CAS Google Scholar
  27. Liman, E. R., Tytgat, J. & Hess, P. Neuron 9, 861–871 (1992).
    Article CAS Google Scholar
  28. Takio, K. et al. Biochemistry 23, 4207–4218 (1984).
    Article CAS Google Scholar
  29. Titani, K. et al. Biochemistry 23, 4193–4199 (1984).
    Article CAS Google Scholar
  30. Skoog, D. A. & West, D. M. Fundamentals of Analytical Chemistry 75–80 (CBS College, New York, 1982).
    Google Scholar

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Authors and Affiliations

  1. Center for Neurobiology and Behavior, Departments of Physiology and Pharmacology, Howard Hughes Medical Institute, Columbia University, 722 W. 168th Street, New York, New York, 10032, USA
    Evan H. Goulding, Gareth R. Tibbs & Steven A. Siegelbaum

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  1. Evan H. Goulding
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  2. Gareth R. Tibbs
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  3. Steven A. Siegelbaum
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Goulding, E., Tibbs, G. & Siegelbaum, S. Molecular mechanism of cyclic-nucleotide-gated channel activation.Nature 372, 369–374 (1994). https://doi.org/10.1038/372369a0

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