Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase (original) (raw)

Nature volume 361, pages 637–641 (1993)Cite this article

Abstract

GLUTAMATE-GATED ion channels mediate most excitatory synaptic transmission in the central nervous system and play crucial roles in synaptic plasticity, neuronal development and some neuropathological conditions1–3. These ionotropic glutamate receptors have been classified according to their preferred agonists as NMDA (_N_-methyl-D-aspartate), AMPA (_α_-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and KA (kainate) receptors4. On the basis of sequence similarity and pharmacological properties, the recently cloned glutamate receptor subunits have been assigned as components of NMDA (NMDAR1, 2A–D), AMPA (GluRl–4) and KA (GluR5–7, KA1, KA2) receptors5–7. Protein phosphorylation of glutamate receptors by protein kinase C and cyclic AMP-dependent protein kinase (PKA) has been suggested to regulate their function8–18, possibly playing a prominent role in certain forms of synaptic plasticity such as long-term potentiation19 and long-term depression9. Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. These results provide evidence that direct phosphorylation of glutamate receptors modulates their function.

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References

  1. Collingridge, G. L. & Singer, W. Trends pharmacol. Sci. 11, 290–296 (1990).
    Article CAS Google Scholar
  2. Choi, D. W. Neuron 1, 623–634 (1988).
    Article CAS Google Scholar
  3. Olney, J. W. A. Rev. Pharmac. Toxicol. 30, 47–71 (1990).
    Article CAS Google Scholar
  4. Monaghan, D. T., Bridges, R. J. & Cotman, C. W. A. Rev. Pharmac. Toxicol. 29, 365–402 (1989).
    Article CAS Google Scholar
  5. Gasic, G. P. & Hollmann, M. A. Rev. Physiol. 54, 507–536 (1992).
    Article CAS Google Scholar
  6. Sommer, B. & Seeburg, P. Trends pharmacol. Sci. 13, 291–296 (1992).
    Article CAS Google Scholar
  7. Nakanishi, S. Science 258, 597–603 (1992).
    Article ADS CAS Google Scholar
  8. Kutsuwada, T. et al. Nature 358, 36–41 (1992).
    Article ADS CAS Google Scholar
  9. Linden, D. J. & Connor, J. A. Science 254, 1656–1659 (1991).
    Article ADS CAS Google Scholar
  10. Gerber, G. et al. J. Neurosci. 9, 3606–3617 (1989).
    Article CAS Google Scholar
  11. Chen, L. & Huang, L. M. Nature 356, 521–523 (1992).
    Article ADS CAS Google Scholar
  12. Chen, L. & Huang, L. M. Neuron 7, 319–326 (1991).
    Article Google Scholar
  13. Liman, E. R., Knapp, A. G. & Dowling, J. E. Brain Res. 481, 399–402 (1989).
    Article CAS Google Scholar
  14. Wang, L.-Y., Salter, M. W. & MacDonald, J. F. Science 253, 1132–1135 (1991).
    Article ADS CAS Google Scholar
  15. Greengard, P., Jen, J., Nairn, A. C. & Stevens, C. F. Science 253, 1135–1138 (1991).
    Article ADS CAS Google Scholar
  16. Chavez-Noriega, L. E. & Stevens, C. F. Brain Res. 574, 85–92 (1992).
    Article CAS Google Scholar
  17. Knapp, A. G. & Dowling, J. E. Nature 325, 437–439 (1987).
    Article ADS CAS Google Scholar
  18. Keller, B. U., Hollmann, M., Heinemann, S. & Konnerth, A. EMBO J. 11, 891–896 (1992).
    Article CAS Google Scholar
  19. Madison, D. V., Malenka, R. C. & Nicoll, R. A. A. Rev. Neurosci. 14, 379–397 (1991).
    Article CAS Google Scholar
  20. Egeojerg, J., Bettler, B., Hermans-Borgmeyer, I. & Heinemann, S. Nature 351, 745–748 (1991).
    Article ADS Google Scholar
  21. Swope, S. L., Moss, S. J., Blackstone, C. D. & Huganir, R. L. FASEB J. 6, 2514–2523 (1992).
    Article CAS Google Scholar
  22. Huganir, R. L., Miles, K. & Greengard, P. Proc. natn. Acad. Sci. U.S.A. 81, 6968–6972 (1984).
    Article ADS CAS Google Scholar
  23. Huettner, J. E. Neuron 5, 255–266 (1990).
    Article CAS Google Scholar
  24. Bettler, B. et al. Neuron 8, 257–265 (1992).
    Article CAS Google Scholar
  25. Blackstone, C. D. et al. J. Neurochem. 58, 1118–1126 (1992).
    Article CAS Google Scholar
  26. Hamill, O. P. et al. Pfluegers Arch 391, 85–100 (1981).
    Article CAS Google Scholar
  27. Tang, C.-M., Dichter, M. & Morad, M. Science 243, 1474–1477 (1989).
    Article ADS CAS Google Scholar
  28. Kunkel, T. A., Roberts, J. D. & Zabour, D. L. Meth. Enzym. 154, 367–382 (1987).
    Article CAS Google Scholar
  29. Wang, L.-Y., Taverna, F. A., Huang, X.-P., MacDonald, J. F. & Hampson, D. R. Science (in the press).

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Authors and Affiliations

  1. Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
    Craig D. Blackstone & Richard L. Huganir
  2. Department of Neurology, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
    Lynn A. Raymond

Authors

  1. Lynn A. Raymond
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  2. Craig D. Blackstone
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  3. Richard L. Huganir
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Raymond, L., Blackstone, C. & Huganir, R. Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase.Nature 361, 637–641 (1993). https://doi.org/10.1038/361637a0

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