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Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor

Abstract

A VARIETY of ligand-gated ion channels undergo a fast activation process after the rapid application of agonist and also a slower transition towards desensitized or inactivated closed channel states when exposure to agonist is prolonged1–5. Desensitization involves at least two distinct closed states in the acetylcholine receptor, each with an affinity for agonists higher than those of the resting or active conformations1–5. Here we investigate how structural elements could be involved in the desensitization of the acetylcholine-gated ion channel from the chick brain α-bungarotoxin sensitive homo-oligomeric α7 receptor6,7, using site-directed mutagenesis and expression in Xenopus oocytes. Mutations of the highly conserved leucine 247 residue8,9 from the uncharged Mil segment of α7 suppress inhibition by the open-channel blocker QX-222 (ref. 10), indicating that this residue, like others from Mil (refs 11–22), faces the lumen of the channel. But, unexpectedly, the same mutations decrease the rate of desensitization of the response, increase the apparent affinity for acetylcholine and abolish current rectification. Moreover, unlike wild-type α7, which has channels with a single conductance level, the leucine-to-threonine mutant has an additional conducting state active at low acetylcholine concentrations. It is possible that mutation of Leu 247 renders conductive one of the high-affinity desensitized states of the receptor.

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References

  1. Katz, B. & Thesleff, S. J. Physiol. Lond. 138, 63–80 (1957).

    Article  CAS  Google Scholar 

  2. Heidmann, T. & Changeux, J. P. Eur. J. Biochem. 94, 281–296 (1979).

    Article  CAS  Google Scholar 

  3. Sakmann, B., Patlak, J. & Neher, E. Nature 286, 71–73 (1980).

    Article  ADS  CAS  Google Scholar 

  4. Neubig, R., Boyd, N. & Cohen, J. B. Biochemistry 21, 3460–3467 (1982).

    Article  CAS  Google Scholar 

  5. Heidmann, T., Bernhardt, J., Neumann, E. & Changeux, J. P. Biochemistry 22, 5452–5459 (1983).

    Article  CAS  Google Scholar 

  6. Schoepfer, R., Conroy, W. G., Whithing, P., Gore, M. & Lindstrom, J. M. Neuron 5, 35–48 (1990).

    Article  CAS  Google Scholar 

  7. Couturier, S. et al. Neuron 5, 847–856 (1990).

    Article  CAS  Google Scholar 

  8. Changeux, J. P. in Fidia Research Foundation Neuroscience Award Lectures 4, 21–168 (Raven, New York, 1990).

    Google Scholar 

  9. Betz, H. Neuron 5, 383–392 (1990).

    Article  CAS  Google Scholar 

  10. Neher, E. & Steinbach, J. J. Physiol., Lond. 277, 153–176 (1978).

    Article  CAS  Google Scholar 

  11. Giraudat, J., Dennis, M., Heidmann, T., Chang, J. Y. & Changeux, J. P. Proc. natn. Acad. Sci. U.S.A. 83, 2719–2723 (1986).

    Article  ADS  CAS  Google Scholar 

  12. Giraudat, J. et al. Biochemistry 26, 2410–2418 (1987).

    Article  CAS  Google Scholar 

  13. Giraudat, J. et al. FEBS Lett. 253, 190–198 (1989).

    Article  CAS  Google Scholar 

  14. Revah, F. et al. Proc. natn. Acad. Sci. U.S.A. 87, 4675–4679 (1990).

    Article  ADS  CAS  Google Scholar 

  15. Oberthur, W. et al. EMBO J. 5, 1815–1819 (1986).

    Article  CAS  Google Scholar 

  16. Hucho, F., Oberthur, W. & Lottspeich, F. FEBS Lett. 205, 137–142 (1986).

    Article  CAS  Google Scholar 

  17. Imoto, K. et al. Nature 324, 670–674 (1986).

    Article  ADS  CAS  Google Scholar 

  18. Imoto, K. et al. Nature 335, 645–648 (1988).

    Article  ADS  CAS  Google Scholar 

  19. Cooper, E., Couturier, S. & Ballivet, M. Nature 350, 235–238 (1991).

    Article  ADS  CAS  Google Scholar 

  20. Leonard, R. J., Labarca, C. G., Charnet, P., Davidson, N. & Lester, H. A. Science 242, 1578–1581 (1988).

    Article  ADS  CAS  Google Scholar 

  21. Charnet, P. et al. Neuron 4, 87–95 (1990).

    Article  CAS  Google Scholar 

  22. Villarroel, A., Herlitze, S., Koenen, M. & Sakmann, B. Proc. R. Soc. B243, 69–74 (1991).

    Article  ADS  CAS  Google Scholar 

  23. Woodhull, A. M. J. gen. Physiol. 61, 687–708 (1973).

    Article  CAS  Google Scholar 

  24. Johnson, J. W. & Ascher, P. Biophys. J. 57, 1085–1090 (1990).

    Article  CAS  Google Scholar 

  25. Bertrand, D., Cooper, E., Valera, S., Rungger, D. & Ballivet, M. in Methods in Neuroscience 4 (ed. Conn, P. M.) 174–193 (Academic, San Diego, 1991).

    Google Scholar 

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Revah, F., Bertrand, D., Galzi, JL. et al. Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor. Nature 353, 846–849 (1991). https://doi.org/10.1038/353846a0

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