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.

  • Article
  • Published:

Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG

Nature Neuroscience volume 3, pages 559–565 (2000)Cite this article

Abstract

In central neurons, the second messenger cGMP is believed to induce long-term changes in efficacy at glutamatergic synapses through activation of protein kinase G (PKG). Stimulating nitric oxide synthase, activating soluble guanylyl cyclase or elevating concentrations of intracellular cGMP depressed excitatory synaptic transmission in CA1 hippocampal neurons. Unexpectedly, intracellular cGMP depressed responses of AMPA receptors and inhibited excitatory postsynaptic currents in hippocampal neurons independently of phosphorylation. Our findings demonstrate that cGMP's modulation of excitatory transmission may involve a coupling of AMPA channel activity to levels of cGMP.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Depression of synaptic currents by SNP. (a) Averaged mEPSCs (n = 150).
Figure 2: Application of NO donors to acutely isolated CA1 neurons depressed Ip but enhanced Iss glutamate-evoked currents.
Figure 3: cGMP depressed the amplitude of mEPSCs, evoked field potentials and EPSCs in CA1 neurons.
Figure 4: Intracellular cGMP does not require phosphorylation to depress peak AMPA responses in isolated CA1 neurons.
Figure 5: Regulation of desensitization of AMPA receptor-mediated currents by intracellular cGMP.
Figure 6: Ca2+/calmodulin dependence of the NOS/sGC/cGMP-induced depression of AMPA responses.

Similar content being viewed by others

References

  1. Snyder, S. H., Jaffrey, S. R. & Zakhary, R. Nitric oxide and carbon monoxide: parallel roles as neural messengers. Brain Res. Rev. 26, 167–175 (1998).

    Article  CAS  Google Scholar 

  2. Levenes, C., Daniel, H. & Crepel, F. Long-term depression of synaptic transmission in the cerebellum: cellular and molecular mechanisms revisited. Prog. Neurobiol. 55, 79–91 (1998).

    Article  CAS  Google Scholar 

  3. Jaffrey, S. R. & Snyder, S. H. Nitric oxide: A neural messenger. Annu. Rev. Cell Biol. 11, 417–440 (1995).

    Article  CAS  Google Scholar 

  4. Garthwaite, J. & Boulton, C. L. Nitric oxide signaling in the central nervous system. Annu. Rev. Physiol. 57, 683–706 (1995).

    Article  CAS  Google Scholar 

  5. McBain, C. J. & Mayer, M. L. N-methyl-d-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–723 (1994).

    Article  CAS  Google Scholar 

  6. Barria, A., Derkach, V. & Soderling, T. Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor. J. Biol. Chem. 272, 32727–32730 (1997).

    Article  CAS  Google Scholar 

  7. Barria, A., Muller, D., Derkach, V., Griffith, L. C. & Soderling, T. R. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276, 2042–2045 (1997).

    Article  CAS  Google Scholar 

  8. Kameyama, K., Lee, H. K., Bear, M. F. & Huganir, R. L. Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression. Neuron 21, 1163–1175 (1998).

    Article  CAS  Google Scholar 

  9. Lee, H. K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162 (1998).

    Article  CAS  Google Scholar 

  10. Garthwaite, J. et al. Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Mol. Pharmacol. 48, 184–188 (1995).

    CAS  PubMed  Google Scholar 

  11. Allen, C. N., Brady, R., Swann, J., Hori, N. & Carpenter, D. O. N-methyl-d-aspartate (NMDA) receptors are inactivated by trypsin. Brain Res. 458, 147–150 (1988).

    Article  CAS  Google Scholar 

  12. Hjelmstad, G. O., Isaac, J. T., Nicoll, R. A. & Malenka, R. C. Lack of AMPA receptor desensitization during basal synaptic transmission in the hippocampal slice. J. Neurophysiol. 81, 3096–3099 (1999).

    Article  CAS  Google Scholar 

  13. Schmidt, M. J., Sawyer, B. D., Truex, L. L., Marshall, W. S. & Fleisch, J. H. LY83583: an agent that lowers intracellular levels of cyclic guanosine 3′,5′-monophosphate. J. Pharmacol. Exp. Ther. 232, 764–769 (1985).

    CAS  PubMed  Google Scholar 

  14. Kase, H. et al. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem. Biophys. Res. Commun. 142, 436–440 (1987).

    Article  CAS  Google Scholar 

  15. Boulton, C. L. et al. The nitric oxide–cyclic GMP pathway and synaptic depression in rat hippocampal slices. Eur. J. Neurosci. 6, 1528–1535 (1994).

    Article  CAS  Google Scholar 

  16. Bradley, J. et al. Functional expression of the heteromeric “olfactory” cyclic nucleotide- gated channel in the hippocampus: a potential effector of synaptic plasticity in brain neurons. J. Neurosci. 17, 1993–2005 (1997).

    Article  CAS  Google Scholar 

  17. Kawada, T., Toyosato, A., Islam, M. O., Yoshida, Y. & Imai, S. cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery. Eur. J. Pharmacol. 323, 75–82 (1997).

    Article  CAS  Google Scholar 

  18. Wei, J. Y., Cohen, E. D., Genieser, H. G. & Barnstable, C. J. Substituted cGMP analogs can act as selective agonists of the rod photoreceptor cGMP-gated cation channel. J. Mol. Neurosci. 10, 53–64 (1998).

    Article  CAS  Google Scholar 

  19. Leidenheimer, N. J. Effect of PKG activation on recombinant GABAA receptors. Mol. Brain Res. 42, 131–134 (1996).

    Article  CAS  Google Scholar 

  20. Wang, L. Y. & MacDonald, J. F. Modulation by magnesium of the affinity of NMDA receptors for glycine in murine hippocampal neurones. J. Physiol. (Lond.) 486, 83–95 (1995).

    Article  CAS  Google Scholar 

  21. Sather, W., Dieudonne, S., MacDonald, J. F. & Ascher, P. Activation and desensitization of N-methyl-d-aspartate receptors in nucleated outside-out patches from mouse neurones. J. Physiol. (Lond.) 450, 643–672 (1992).

    Article  CAS  Google Scholar 

  22. Fleck, M. W., Bahring, R., Patneau, D. K. & Mayer, M. L. AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide. J. Neurophysiol. 75, 2322–2333 (1996).

    Article  CAS  Google Scholar 

  23. Partin, K. M., Patneau, D. K. & Mayer, M. L. Cyclothiazide differentially modulates desensitization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants. Mol. Pharmacol. 46, 129–138 (1994).

    CAS  PubMed  Google Scholar 

  24. Partin, K. M., Fleck, M. W. & Mayer, M. L. AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate. J. Neurosci. 16, 6634–6647 (1996).

    Article  CAS  Google Scholar 

  25. Bol'shakov, K. B. & Buldakova, S. L. [Pharmacologic analysis of the subunit composition of AMPA-receptors in the hippocampal neurons]. Ross. Fiziol. Zh. Im I. M. Sechenova 85, 1480–1488 (1999).

    CAS  PubMed  Google Scholar 

  26. Jia, Z. et al. Enhanced LTP in mice deficient in the AMPA receptor GluR2. Neuron 17, 945–956 (1996).

    Article  CAS  Google Scholar 

  27. Finn, J. T., Solessio, E. C. & Yau, K. W. A cGMP-gated cation channel in depolarizing photoreceptors of the lizard parietal eye. Nature 385, 815–819 (1997).

    Article  CAS  Google Scholar 

  28. Wei, J. Y., Roy, D. S., Leconte, L. & Barnstable, C. J. Molecular and pharmacological analysis of cyclic nucleotide-gated channel function in the central nervous system. Prog. Neurobiol. 56, 37–64 (1998).

    Article  Google Scholar 

  29. Diamond, J. S. & Jahr, C. E. Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC. Neuron 15, 1097–1107 (1995).

    Article  CAS  Google Scholar 

  30. Sah, P., Hestrin, S. & Nicoll, R. A. Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246, 815–818 (1989).

    Article  CAS  Google Scholar 

  31. Hsueh, Y. P. & Sheng, M. Anchoring of glutamate receptors at the synapse. Prog. Brain Res. 116, 123–131 (1998).

    Article  CAS  Google Scholar 

  32. Sattler, R. et al. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284, 1845–1848 (1999).

    Article  CAS  Google Scholar 

  33. Baltrons, M. A. & Garcia, A. AMPA receptors are coupled to the nitric oxide/cyclic GMP pathway in cerebellar astroglial cells. Eur. J. Neurosci. 9, 2497–2501 (1997).

    Article  CAS  Google Scholar 

  34. Wu, J., Wang, Y., Rowan, M. J. & Anwyl, R. Evidence for involvement of the cGMP-protein kinase G signaling system in the induction of long-term depression, but not long-term potentiation, in the dentate gyrus in vitro. J. Neurosci. 18, 3589–3596 (1998).

    Article  CAS  Google Scholar 

  35. Calabresi, P. et al. A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression. J. Neurosci. 19, 2489–2499 (1999).

    Article  CAS  Google Scholar 

  36. Johnson, J. W. & Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurones. Nature 325, 529–531 (1987).

    Article  CAS  Google Scholar 

  37. Bai, D., Pennefather, P. S., MacDonald, J. F. & Orser, B. A. The general anesthetic propofol slows deactivation and desensitization of GABA(A) receptors. J. Neurosci. 19, 10635–10646 (1999).

    Article  CAS  Google Scholar 

  38. Wang, L. Y., Salter, M. W. & MacDonald, J. F. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 253, 1132–1135 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y.-T. Wang, M. W. Salter and L.-Y. Wang for comments on this manuscript. We thank K. W. Yau for the gifts of KY9 and KY8. Supported by the Medical Research Council of Canada and the Ontario Neurotrauma Foundation. S.L. and M.J. are fellows of the Ontario Neurotrauma Foundation and NSERC, respectively.

Author information

Authors and Affiliations

  1. Departments of Physiology and Pharmacology, University of Toronto, Medical Sciences Bldg., 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Saobo Lei, Michael F. Jackson & John F. MacDonald

  2. Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, M5G 1X8, Ontario, Canada

    Zhengping Jia

  3. Mt. Sinai Research Institutes, University of Toronto, 600 University Ave, Toronto, M5G 1X5, Ontario, Canada

    John Roder

  4. Department of Anaesthesia, University of Toronto, Anaesthesia Research Laboratory, 1 King's College Circle, Toronto, M55 1A8, Ontario, Canada

    Donglin Bai & Beverley A. Orser

Authors
  1. Saobo Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael F. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengping Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Roder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donglin Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Beverley A. Orser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John F. MacDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John F. MacDonald.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lei, S., Jackson, M., Jia, Z. et al. Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG. Nat Neurosci 3, 559–565 (2000). https://doi.org/10.1038/75729

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/75729

This article is cited by

Search

Advanced 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