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:

Kinetic basis of partial agonism at NMDA receptors

Nature Neuroscience volume 12, pages 1114–1120 (2009)Cite this article

Abstract

Activation of ligand-gated channels is initiated by the binding of small molecules at extracellular sites and culminates with the opening of a membrane-embedded pore. To investigate how perturbations at ligand-binding domains influence the gating reaction, we examined current traces recorded from individual NMDA receptors in the presence of several subunit-specific partial agonists. We found that low-efficacy agonists acting at either the glycine-binding or the glutamate-binding NMDA receptor subunits had very similar effects on the receptor's activation reaction, possibly reflecting a high degree of coupling between the two subunit types during gating. In addition, we found that partial agonists increased the height of all energy barriers encountered by NMDA receptors during activation. This result stands in sharp contrast to the localized effects that have been observed for pentameric ligand-gated channels and may represent a previously unknown mechanism by which partial agonists reduce receptor activity.

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: NMDA receptor activities with GluN1 partial agonists.
Figure 2: NMDA receptor activities with GluN2A partial agonists.
Figure 3: Partial agonists specifically prolonged the shorter, more frequent closures.
Figure 4: Partial agonists decrease NMDA receptor open durations.
Figure 5: Kinetic mechanism of NMDA receptor activation by partial agonists.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Colquhoun, D. What have we learned from single ion channels? J. Physiol. (Lond.) 581, 425–427 (2007).

    Article  Google Scholar 

  2. Armstrong, N., Sun, Y., Chen, G.Q. & Gouaux, E. Structure of a glutamate receptor ligand–binding core in complex with kainate. Nature 395, 913–917 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Armstrong, N. & Gouaux, E. Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28, 165–181 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Grosman, C., Zhou, M. & Auerbach, A. Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403, 773–776 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Robert, A., Armstrong, N., Gouaux, J.E. & Howe, J.R. AMPA receptor binding cleft mutations that alter affinity, efficacy and recovery from desensitization. J. Neurosci. 25, 3752–3762 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lape, R., Colquhoun, D. & Sivilotti, L.G. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454, 722–727 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mukhtasimova, N., Lee, W.Y., Wang, H.L. & Sine, S.M. Detection and trapping of intermediate states priming nicotinic receptor channel opening. Nature 459, 451–454 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Howe, J.R., Colquhoun, D. & Cull-Candy, S.G. On the kinetics of large-conductance glutamate receptor ion channels in rat cerebellar granule neurons. Proc. R. Soc. Lond. B 233, 407–422 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Gibb, A.J. & Colquhoun, D. Glutamate activation of a single NMDA receptor channel produces a cluster of channel openings. Proc. Biol. Sci. 243, 39–45 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Banke, T.G. & Traynelis, S.F. Activation of NR1/NR2B NMDA receptors. Nat. Neurosci. 6, 144–152 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Popescu, G. & Auerbach, A. Modal gating of NMDA receptors and the shape of their synaptic response. Nat. Neurosci. 6, 476–483 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Auerbach, A. & Zhou, Y. Gating reaction mechanisms for NMDA receptor channels. J. Neurosci. 25, 7914–7923 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schorge, S., Elenes, S. & Colquhoun, D. Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits. J. Physiol. 569, 395–418 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dravid, S.M., Prakash, A. & Traynelis, S.F. Activation of recombinant NR1/NR2C NMDA receptors. J. Physiol. (Lond.) 586, 4425–4439 (2008).

    Article  CAS  Google Scholar 

  15. Erreger, K., Dravid, S.M., Banke, T.G., Wyllie, D.J. & Traynelis, S.F. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signaling profiles. J. Physiol. (Lond.) 563, 345–358 (2005).

    Article  CAS  Google Scholar 

  16. Zhang, W., Howe, J.R. & Popescu, G.K. Distinct gating modes determine the biphasic relaxation of NMDA receptor currents. Nat. Neurosci. 11, 1373–1375 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cull-Candy, S., Brickley, S. & Farrant, M. NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11, 327–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Collingridge, G.L., Olsen, R.W., Peters, J. & Spedding, M. A nomenclature for ligand-gated ion channels. Neuropharmacology 56, 2–5 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Monyer, H. et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256, 1217–1221 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Vicini, S. et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J. Neurophysiol. 79, 555–566 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Kleckner, N.W. & Dingledine, R. Requirement for glycine in activation of NMDA receptors expressed in Xenopus oocytes. Science 241, 835–837 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Jahr, C.E. High probability opening of NMDA receptor channels by L-glutamate. Science 255, 470–472 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Popescu, G., Robert, A., Howe, J.R. & Auerbach, A. Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430, 790–793 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Priestley, T. et al. Pharmacological properties of recombinant human N-methyl-D-aspartate receptors comprising NR1a/NR2A and NR1a/NR2B subunit assemblies expressed in permanently transfected mouse fibroblast cells. Mol. Pharmacol. 48, 841–848 (1995).

    CAS  PubMed  Google Scholar 

  26. Sheinin, A., Shavit, S. & Benveniste, M. Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine. Neuropharmacology 41, 151–158 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Inanobe, A., Furukawa, H. & Gouaux, E. Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron 47, 71–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Furukawa, H. & Gouaux, E. Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand–binding core. EMBO J. 22, 2873–2885 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, P.E. et al. Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. J. Physiol. (Lond.) 586, 227–245 (2008).

    Article  CAS  Google Scholar 

  30. Jin, R., Banke, T.G., Mayer, M.L., Traynelis, S.F. & Gouaux, E. Structural basis for partial agonist action at ionotropic glutamate receptors. Nat. Neurosci. 6, 803–810 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Howe, J.R., Cull-Candy, S.G. & Colquhoun, D. Currents through single glutamate receptor channels in outside-out patches from rat cerebellar granule cells. J. Physiol. (Lond.) 432, 143–202 (1991).

    Article  CAS  Google Scholar 

  32. Gibb, A.J. & Colquhoun, D. Activation of N-methyl-D-aspartate receptors by L-glutamate in cells dissociated from adult rat hippocampus. J. Physiol. (Lond.) 456, 143–179 (1992).

    Article  CAS  Google Scholar 

  33. Furukawa, H., Singh, S.K., Mancusso, R. & Gouaux, E. Subunit arrangement and function in NMDA receptors. Nature 438, 185–192 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Erreger, K. et al. Subunit-specific agonist activity at NR2A-, NR2B-, NR2C- and NR2D-containing N-methyl-D-aspartate glutamate receptors. Mol. Pharmacol. 72, 907–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. de Carvalho, L.P., Bochet, P. & Rossier, J. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neurochem. Int. 28, 445–452 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Blanke, M.L. & VanDongen, A.M. The NR1 M3 domain mediates allosteric coupling in the N-methyl-D-aspartate receptor. Mol. Pharmacol. 74, 454–465 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Erreger, K. et al. Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog. J. Neurosci. 25, 7858–7866 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schorge, S. & Colquhoun, D. Studies of NMDA receptor function and stoichiometry with truncated and tandem subunits. J. Neurosci. 23, 1151–1158 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, W., Robert, A., Vogensen, S. & Howe, J.R. The relationship between agonist potency and AMPA receptor kinetics. Biophys. J. 91, 1336–1346 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, W., Cho, Y., Lolis, E. & Howe, J.R. Structural and single-channel results indicate that the rates of ligand binding domain closing and opening directly impact AMPA receptor gating. J. Neurosci. 28, 932–943 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sun, Y. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Howe, J.R. Desensitization at the interface. ACS Chem. Biol. 1, 623–626 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Rosenmund, C., Stern-Bach, Y. & Stevens, C.F. The tetrameric structure of a glutamate receptor channel. Science 280, 1596–1599 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Shelley, C. & Magleby, K.L. Linking exponential components to kinetic states in Markov models for single-channel gating. J. Gen. Physiol. 132, 295–312 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J.M. Myers and A.M. Popescu for obtaining some of the single-channel records. This work was supported by the US National Institutes of Health (G.K.P.).

Author information

Authors and Affiliations

  1. Department of Biochemistry, University at Buffalo, Buffalo, New York, USA

    Cassandra L Kussius & Gabriela K Popescu

Authors
  1. Cassandra L Kussius
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriela K Popescu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.L.K. recorded the majority of the current traces and analyzed all of the data. C.L.K. and G.K.P designed the experiments, interpreted the results and wrote the manuscript.

Corresponding author

Correspondence to Gabriela K Popescu.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1–3 (PDF 335 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kussius, C., Popescu, G. Kinetic basis of partial agonism at NMDA receptors. Nat Neurosci 12, 1114–1120 (2009). https://doi.org/10.1038/nn.2361

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2361

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