Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase

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.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

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).

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/361637a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing