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.

NMDA receptors: linking physiological output to biophysical operation

Key Points

  • NMDA receptor isoforms respond to glutamate with distinct kinetics and have dynamic, complex and incompletely delineated expression profiles; precise mechanistic information for specific receptor isoforms is derived from recombinant preparations.

  • Functional attributes of recombinant receptor current match well to those of the NMDA receptor-mediated response recorded from synaptic and non-synaptic native receptors.

  • Kinetic models derived from one-channel recordings reproduce all known features of the macroscopic response and reveal novel biophysical properties that underlie physiologically salient features of the synaptic current.

  • The NMDA receptor response amplitude and ionic charge transfer, which initiate synaptic plasticity, depend on stimulation frequency as predicted by the kinetic model.

  • The biphasic decay time of the NMDA receptor synaptic response, which sets the window for coincident depolarization, reflects the proportion of receptors gating in distinct kinetic modes. This insight was afforded by statistical evaluation of single-channel behaviour.

  • Assigning molecular structures to the kinetic states postulated by statistically derived models of NMDA receptor activation is an active area of research.

Abstract

NMDA receptors are preeminent neurotransmitter-gated channels in the CNS, which respond to glutamate in a manner that integrates multiple external and internal cues. They belong to the ionotropic glutamate receptor family and fulfil unique and crucial roles in neuronal development and function. These roles depend on characteristic response kinetics, which reflect the operation of the receptors. Here, we review biologically salient features of the NMDA receptor signal and its mechanistic origins. Knowledge of distinctive NMDA receptor biophysical properties, their structural determinants and physiological roles is necessary to understand the physiological and neurotoxic actions of glutamate and to design effective therapeutics.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Two members of the ionotropic glutamate receptor family have similar structures but distinctive functional output.
Figure 2: Observable features of the NMDA receptor output.
Figure 3: Models of NMDA receptor operation.
Figure 4: Insights from statistical models.

References

  1. Meldrum, B. S. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130, 1007S–1015S (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Traynelis, S. F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Attwell, D. & Gibb, A. Neuroenergetics and the kinetic design of excitatory synapses. Nat. Rev. Neurosci. 6, 841–849 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Karakas, E. & Furukawa, H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science 344, 992–997 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lee, C. H. et al. NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511, 191–197 (2014). Reference 4 and reference 5 are the first two papers to report the full GluN1–GluN2B-containing tetrameric receptor, revealing the unique architecture that distinguishes NMDARs from other iGluRs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sobolevsky, A. I., Rosconi, M. P. & Gouaux, E. X-Ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462, 745–756 (2009). This paper provides the first crystal structure of a tetrameric iGluR, which allowed researchers to directly explore structure–function relationships in AMPARs and to infer structural interpretations of NMDAR function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Durr, K. L. et al. Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell 158, 778–792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Meyerson, J. R. et al. Structural basis of kainate subtype glutamate receptor desensitization. Nature 537, 567–571 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Meyerson, J. R. et al. Structural mechanism of glutamate receptor activation and desensitization. Nature 514, 328–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383–400 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Pachernegg, S., Strutz-Seebohm, N. & Hollmann, M. GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci. 35, 240–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Zukin, R. S. & Bennett, M. V. Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci. 18, 306–313 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Seeburg, P. H. et al. The NMDA receptor channel: molecular design of a coincidence detector. Recent Prog. Horm. Res. 50, 19–34 (1995).

    CAS  PubMed  Google Scholar 

  14. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Glasgow, N. G., Siegler Retchless, B. & Johnson, J. W. Molecular bases of NMDA receptor subtype-dependent properties. J. Physiol. 593, 83–95 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Cull-Candy, S. G. & Leszkiewicz, D. N. Role of distinct NMDA receptor subtypes at central synapses. Sci. STKE 2004, re16 (2004).

    Article  PubMed  Google Scholar 

  17. Hansen, K. B., Ogden, K. K., Yuan, H. & Traynelis, S. F. Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81, 1084–1096 (2014). Because recombinant systems restricted functional studies to diheteromeric receptors, the authors of this paper develop a method to overcome this limitation and characterize for the first time the unique pharmacological properties of triheteromeric NMDARs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ceccon, M., Rumbaugh, G. & Vicini, S. Distinct effect of pregnenolone sulfate on NMDA receptor subtypes. Neuropharmacology 40, 491–500 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Rumbaugh, G. & Vicini, S. Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar granule neurons. J. Neurosci. 19, 10603–10610 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vicini, S. et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J. Neurophysiol. 79, 555–566 (1998). This is a complete functional characterization of molecularly pure NMDAR subtypes in a recombinant system that definitively revealed subtype-specific kinetics and pharmacological properties.

    Article  CAS  PubMed  Google Scholar 

  21. Tajima, N. et al. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature 534, 63–68 (2016). The authors of this paper, using cryo-electron microscopy, observe several unique closed-state molecular structures in the presence of an agonist, thus substantiating electrophysiological observations of complex close time distributions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kennedy, M. B., Beale, H. C., Carlisle, H. J. & Washburn, L. R. Integration of biochemical signalling in spines. Nat. Rev. Neurosci. 6, 423–434 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Paoletti, P. & Neyton, J. NMDA receptor subunits: function and pharmacology. Curr. Opin. Pharmacol. 7, 39–47 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Forsythe, I. D. & Westbrook, G. L. Slow excitatory postsynaptic currents mediated by N-methyl-D-aspartate receptors on cultured mouse central neurones. J. Physiol. 396, 515–533 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Collingridge, G. L., Herron, C. E. & Lester, R. A. Frequency-dependent N-methyl-D-aspartate receptor-mediated synaptic transmission in rat hippocampus. J. Physiol. 399, 301–312 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hogan-Cann, A. D. & Anderson, C. M. Physiological roles of non-neuronal NMDA receptors. Trends Pharmacol. Sci. 37, 750–767 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Bouvier, G., Bidoret, C., Casado, M. & Paoletti, P. Presynaptic NMDA receptors: roles and rules. Neuroscience 311, 322–340 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Clements, J. D., Lester, R. A., Tong, G., Jahr, C. E. & Westbrook, G. L. The time course of glutamate in the synaptic cleft. Science 258, 1498–1501 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Kalia, L. V., Pitcher, G. M., Pelkey, K. A. & Salter, M. W. PSD-95 is a negative regulator of the tyrosine kinase Src in the NMDA receptor complex. EMBO J. 25, 4971–4982 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ng, D. et al. Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol. 7, e41 (2009).

    PubMed  Google Scholar 

  32. Rycroft, B. K. & Gibb, A. J. Regulation of single NMDA receptor channel activity by alpha-actinin and calmodulin in rat hippocampal granule cells. J. Physiol. 557, 795–808 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bard, L. et al. Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. Proc. Natl Acad. Sci. USA 107, 19561–19566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vergnano, A. M. et al. Zinc dynamics and action at excitatory synapses. Neuron 82, 1101–1114 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Amico-Ruvio, S. A., Paganelli, M. A., Myers, J. M. & Popescu, G. K. Ifenprodil effects on GluN2B-containing glutamate receptors. Mol. Pharmacol. 82, 1074–1081 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Legendre, P. & Westbrook, G. L. Ifenprodil blocks N-methyl-D-aspartate receptors by a two-component mechanism. Mol. Pharmacol. 40, 289–298 (1991).

    CAS  PubMed  Google Scholar 

  37. Blanpied, T. A., Clarke, R. J. & Johnson, J. W. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J. Neurosci. 25, 3312–3322 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang, S., Ehlers, M. D., Bernhardt, J. P., Su, C. T. & Huganir, R. L. Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors. Neuron 21, 443–453 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Tong, G., Shepherd, D. & Jahr, C. E. Synaptic desensitization of NMDA receptors by calcineurin. Science 267, 1510–1512 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Tingley, W. G. et al. Characterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. J. Biol. Chem. 272, 5157–5166 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Kaufman, A. M. et al. Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons. J. Neurosci. 32, 3992–4003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Wyllie, D. J., Behe, P. & Colquhoun, D. Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors. J. Physiol. 510, 1–18 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Amico-Ruvio, S. A. & Popescu, G. K. Stationary gating of GluN1/GluN2B receptors in intact membrane patches. Biophys. J. 98, 1160–1169 (2010). This paper, using stationary single-channel recordings, describes the first complete kinetic mechanism derived for GluN1–GluN2B diheteromeric receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Borschel, W. F. et al. Gating reaction mechanism of neuronal NMDA receptors. J. Neurophysiol. 108, 3105–3115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Clark, B. A., Farrant, M. & Cull-Candy, S. G. A direct comparison of the single-channel properties of synaptic and extrasynaptic NMDA receptors. J. Neurosci. 17, 107–116 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jahr, C. E. & Stevens, C. F. Glutamate activates multiple single channel conductances in hippocampal neurons. Nature 325, 522–525 (1987).

    Article  CAS  PubMed  Google Scholar 

  49. Ascher, P., Bregestovski, P. & Nowak, L. N-methyl-D-aspartate-activated channels of mouse central neurones in magnesium-free solutions. J. Physiol. 399, 207–226 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Stern, P., Behe, P., Schoepfer, R. & Colquhoun, D. Single-channel conductances of NMDA receptors expressed from cloned cDNAs: comparison with native receptors. Proc. Biol. Sci. 250, 271–277 (1992).

    Article  CAS  PubMed  Google Scholar 

  51. 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. Biol. Sci. 233, 407–422 (1988).

    Article  CAS  PubMed  Google Scholar 

  52. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. & Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984).

    Article  CAS  PubMed  Google Scholar 

  53. Vance, K. M., Hansen, K. B. & Traynelis, S. F. GluN1 splice variant control of GluN1/GluN2D NMDA receptors. J. Physiol. 590, 3857–3875 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Siegler Retchless, B., Gao, W. & Johnson, J. W. A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction. Nat. Neurosci. 15, 406–413 (2012).

    Article  PubMed  CAS  Google Scholar 

  55. Green, G. M. & Gibb, A. J. Characterization of the single-channel properties of NMDA receptors in laminae I and II of the dorsal horn of neonatal rat spinal cord. Eur. J. Neurosci. 14, 1590–1602 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Palecek, J. I., Abdrachmanova, G., Vlachova, V. & Vyklick, L. Jr. Properties of NMDA receptors in rat spinal cord motoneurons. Eur. J. Neurosci. 11, 827–836 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Cull-Candy, S. G. et al. NMDA receptor diversity in the cerebellum: identification of subunits contributing to functional receptors. Neuropharmacology 37, 1369–1380 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Gibb, A. J., Kojima, H., Carr, J. A. & Colquhoun, D. Expression of cloned receptor subunits produces multiple receptors. Proc. Biol. Sci. 242, 108–112 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. Colquhoun, D. Binding, gating, affinity and efficacy: the interpretation of structure–activity relationships for agonists and of the effects of mutating receptors. Br. J. Pharmacol. 125, 924–947 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Benveniste, M., Clements, J., Vyklicky, L. Jr & Mayer, M. L. A kinetic analysis of the modulation of N-methyl-D-aspartic acid receptors by glycine in mouse cultured hippocampal neurones. J. Physiol. 428, 333–357 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lester, R. A., Clements, J. D., Westbrook, G. L. & Jahr, C. E. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346, 565–567 (1990). The authors of this paper, using precisely timed application of competitive antagonists before and after application of an agonist, reveal that the intrinsic gating kinetics of the channel set the time course of synaptic decay rather than agonist affinity.

    Article  CAS  PubMed  Google Scholar 

  62. 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 

  63. Lester, R. A. & Jahr, C. E. NMDA channel behavior depends on agonist affinity. J. Neurosci. 12, 635–643 (1992). The authors of this paper develop the first minimal conceptual model needed to describe the macroscopic current in response to brief pulses of agonist with separate kinetic states for glutamate binding, desensitization and gating.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Clements, J. D. & Westbrook, G. L. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron 7, 605–613 (1991).

    Article  CAS  PubMed  Google Scholar 

  65. Rosenmund, C., Feltz, A. & Westbrook, G. L. Synaptic NMDA receptor channels have a low open probability. J. Neurosci. 15, 2788–2795 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Benveniste, M. & Mayer, M. L. Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors. Two binding sites each for glutamate and glycine. Biophys. J. 59, 560–573 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kampa, B. M., Clements, J., Jonas, P. & Stuart, G. J. Kinetics of Mg2+ unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity. J. Physiol. 556, 337–345 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nahum-Levy, R., Lipinski, D., Shavit, S. & Benveniste, M. Desensitization of NMDA receptor channels is modulated by glutamate agonists. Biophys. J. 80, 2152–2166 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dilmore, J. G. & Johnson, J. W. Open channel block and alteration of N-methyl-D-aspartic acid receptor gating by an analog of phencyclidine. Biophys. J. 75, 1801–1816 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chen, N., Li, B., Murphy, T. H. & Raymond, L. A. Site within N-methyl-D-aspartate receptor pore modulates channel gating. Mol. Pharmacol. 65, 157–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Kloda, A., Clements, J. D., Lewis, R. J. & Adams, D. J. Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors. Mol. Pharmacol. 65, 1386–1396 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Horak, M., Vlcek, K., Petrovic, M., Chodounska, H. & Vyklicky, L. Jr. Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors. J. Neurosci. 24, 10318–10325 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yuan, H., Hansen, K. B., Vance, K. M., Ogden, K. K. & Traynelis, S. F. Control of NMDA receptor function by the NR2 subunit amino-terminal domain. J. Neurosci. 29, 12045–12058 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Qian, A., Buller, A. L. & Johnson, J. W. NR2 subunit-dependence of NMDA receptor channel block by external Mg2+. J. Physiol. 562, 319–331 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Kleckner, N. W. & Pallotta, B. S. Burst kinetics of single NMDA receptor currents in cell-attached patches from rat brain cortical neurons in culture. J. Physiol. 486, 411–426 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. Niciu, M. J., Henter, I. D., Luckenbaugh, D. A., Zarate, C. A. Jr & Charney, D. S. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu. Rev. Pharmacol. Toxicol. 54, 119–139 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. O'Leary, T. & Wyllie, D. J. Single-channel properties of N-methyl-D-aspartate receptors containing chimaeric GluN2A/GluN2D subunits. Biochem. Soc. Trans. 37, 1347–1354 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. 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. 432, 143–202 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Stern, P., Cik, M., Colquhoun, D. & Stephenson, F. A. Single channel properties of cloned NMDA receptors in a human cell line: comparison with results from Xenopus oocytes. J. Physiol. 476, 391–397 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Popescu, G. & Auerbach, A. Modal gating of NMDA receptors and the shape of their synaptic response. Nat. Neurosci. 6, 476–483 (2003). This paper analyses stationary single-channel gating records, revealing robust heterogeneity in the kinetics, known as modal gating, over time and allowing the first complete kinetic mechanism of channel activation to be derived.

    Article  CAS  PubMed  Google Scholar 

  84. 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 

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

    Article  CAS  PubMed  Google Scholar 

  86. 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 signalling profiles. J. Physiol. 563, 345–358 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kussius, C. L. & Popescu, G. K. NMDA receptors with locked glutamate-binding clefts open with high efficacy. J. Neurosci. 30, 12474–12479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cummings, K. A. & Popescu, G. K. Glycine-dependent activation of NMDA receptors. J. Gen. Physiol. 145, 513–527 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Kussius, C. L. & Popescu, G. K. Kinetic basis of partial agonism at NMDA receptors. Nat. Neurosci. 12, 1114–1120 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bicknell, B. A. & Goodhill, G. J. Emergence of ion channel modal gating from independent subunit kinetics. Proc. Natl Acad. Sci. USA 113, E5288–E5297 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ji, S. et al. Voltage-dependent regulation of modal gating in the rat SkM1 sodium channel expressed in Xenopus oocytes. J. Gen. Physiol. 104, 625–643 (1994).

    Article  CAS  PubMed  Google Scholar 

  92. Alzheimer, C., Schwindt, P. C. & Crill, W. E. Modal gating of Na+ channels as a mechanism of persistent Na+ current in pyramidal neurons from rat and cat sensorimotor cortex. J. Neurosci. 13, 660–673 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Popescu, G. Mechanism-based targeting of NMDA receptor functions. Cell. Mol. Life Sci. 62, 2100–2111 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Aman, T. K., Maki, B. A., Ruffino, T. J., Kasperek, E. M. & Popescu, G. K. Separate intramolecular targets for protein kinase A control N-methyl-D-aspartate receptor gating and Ca2+ permeability. J. Biol. Chem. 289, 18805–18817 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Borschel, W. F., Cummings, K. A., Tindell, L. K. & Popescu, G. K. Kinetic contributions to gating by interactions unique to N-methyl-D-aspartate (NMDA) receptors. J. Biol. Chem. 290, 26846–26855 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Borschel, W. F., Murthy, S. E., Kasperek, E. M. & Popescu, G. K. NMDA receptor activation requires remodelling of intersubunit contacts within ligand-binding heterodimers. Nat. Commun. 2, 498 (2011).

    Article  PubMed  CAS  Google Scholar 

  97. Kazi, R., Dai, J., Sweeney, C., Zhou, H. X. & Wollmuth, L. P. Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents. Nat. Neurosci. 17, 914–922 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Erreger, K. & Traynelis, S. F. Zinc inhibition of rat NR1/NR2A N-methyl-D-aspartate receptors. J. Physiol. 586, 763–778 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Vance, K. M., Hansen, K. B. & Traynelis, S. F. Modal gating of GluN1/GluN2D NMDA receptors. Neuropharmacology 71, 184–190 (2013). The authors of this paper use single-channel gating records to derive the first single-channel mechanism of GluN1–GluN2D diheteromeric receptors and identify heterogeneous modal gating behaviours for this subtype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kazi, R. et al. Asynchronous movements prior to pore opening in NMDA receptors. J. Neurosci. 33, 12052–12066 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 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). The authors of this paper deduce the first tiered model of NMDAR modal gating and experimentally validated it as a mechanism for the multicomponent synaptic response in neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kirson, E. D. & Yaari, Y. Synaptic NMDA receptors in developing mouse hippocampal neurones: functional properties and sensitivity to ifenprodil. J. Physiol. 497, 437–455 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lindlbauer, R., Mohrmann, R., Hatt, H. & Gottmann, K. Regulation of kinetic and pharmacological properties of synaptic NMDA receptors depends on presynaptic exocytosis in rat hippocampal neurones. J. Physiol. 508, 495–502 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Balu, D. T. & Coyle, J. T. The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. Curr. Opin. Pharmacol. 20, 109–115 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Sensi, S. L., Paoletti, P., Bush, A. I. & Sekler, I. Zinc in the physiology and pathology of the CNS. Nat. Rev. Neurosci. 10, 780–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Forsythe, I. D., Westbrook, G. L. & Mayer, M. L. Modulation of excitatory synaptic transmission by glycine and zinc in cultures of mouse hippocampal neurons. J. Neurosci. 8, 3733–3741 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Peters, S., Koh, J. & Choi, D. W. Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science 236, 589–593 (1987).

    Article  CAS  PubMed  Google Scholar 

  108. Paoletti, P., Ascher, P. & Neyton, J. High-affinity zinc inhibition of NMDA NR1–NR2A receptors. J. Neurosci. 17, 5711–5725 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fayyazuddin, A., Villarroel, A., Le Goff, A., Lerma, J. & Neyton, J. Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors. Neuron 25, 683–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Paoletti, P. et al. Molecular organization of a zinc binding N-terminal modulatory domain in a NMDA receptor subunit. Neuron 28, 911–925 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Nozaki, C. et al. Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit. Nat. Neurosci. 14, 1017–1022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Amico-Ruvio, S. A., Murthy, S. E., Smith, T. P. & Popescu, G. K. Zinc effects on NMDA receptor gating kinetics. Biophys. J. 100, 1910–1918 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zheng, F. et al. Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A. Nat. Neurosci. 4, 894–901 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Sirrieh, R. E., MacLean, D. M. & Jayaraman, V. Amino-terminal domain tetramer organization and structural effects of zinc binding in the N-methyl-D-aspartate (NMDA) receptor. J. Biol. Chem. 288, 22555–22564 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sirrieh, R. E., MacLean, D. M. & Jayaraman, V. A conserved structural mechanism of NMDA receptor inhibition: a comparison of ifenprodil and zinc. J. Gen. Physiol. 146, 173–181 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Karakas, E., Simorowski, N. & Furukawa, H. Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. EMBO J. 28, 3910–3920 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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 

  118. Harsing, L. G. Jr & Matyus, P. Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: the role of synaptic and non-synaptic glycine transporters. Brain Res. Bull. 93, 110–119 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Bergeron, R., Meyer, T. M., Coyle, J. T. & Greene, R. W. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc. Natl Acad. Sci. USA 95, 15730–15734 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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 

  121. Cooper, D. R. et al. Conformational transitions in the glycine-bound GluN1 NMDA receptor LBD via single-molecule FRET. Biophys. J. 109, 66–75 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dolino, D. M. et al. Structural dynamics of the glycine-binding domain of the N-methyl-D-aspartate receptor. J. Biol. Chem. 290, 797–804 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Yao, Y., Belcher, J., Berger, A. J., Mayer, M. L. & Lau, A. Y. Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure 21, 1788–1799 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. Vargas-Caballero, M. & Robinson, H. P. Fast and slow voltage-dependent dynamics of magnesium block in the NMDA receptor: the asymmetric trapping block model. J. Neurosci. 24, 6171–6180 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Clarke, R. J., Glasgow, N. G. & Johnson, J. W. Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock. J. Neurosci. 33, 4140–4150 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lipton, S. A. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx 1, 101–110 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Dai, J. & Zhou, H. X. An NMDA receptor gating mechanism developed from MD simulations reveals molecular details underlying subunit-specific contributions. Biophys. J. 104, 2170–2181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sirrieh, R. E., MacLean, D. M. & Jayaraman, V. Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine. J. Biol. Chem. 290, 12812–12820 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Aow, J., Dore, K. & Malinow, R. Conformational signaling required for synaptic plasticity by the NMDA receptor complex. Proc. Natl Acad. Sci. USA 112, 14711–14716 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Dore, K., Aow, J. & Malinow, R. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow. Proc. Natl Acad. Sci. USA 112, 14705–14710 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Rambhadran, A., Gonzalez, J. & Jayaraman, V. Conformational changes at the agonist binding domain of the N-methyl-D-aspartic acid receptor. J. Biol. Chem. 286, 16953–16957 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, S., Vafabakhsh, R., Borschel, W. F., Ha, T. & Nichols, C. G. Structural dynamics of potassium-channel gating revealed by single-molecule FRET. Nat. Struct. Mol. Biol. 23, 31–36 (2016).

    Article  CAS  PubMed  Google Scholar 

  133. Dai, J. & Zhou, H. X. Semiclosed conformations of the ligand-binding domains of NMDA receptors during stationary gating. Biophys. J. 111, 1418–1428 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Nong, Y. et al. Glycine binding primes NMDA receptor internalization. Nature 422, 302–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Harris, J. J., Jolivet, R. & Attwell, D. Synaptic energy use and supply. Neuron 75, 762–777 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Tovar, K. R., McGinley, M. J. & Westbrook, G. L. Triheteromeric NMDA receptors at hippocampal synapses. J. Neurosci. 33, 9150–9160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 391, 85–100 (1981).

    Article  CAS  PubMed  Google Scholar 

  138. Kumar, S. S. & Huguenard, J. R. Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex. J. Neurosci. 23, 10074–10083 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dzubay, J. A. & Jahr, C. E. The concentration of synaptically released glutamate outside of the climbing fiber–Purkinje cell synaptic cleft. J. Neurosci. 19, 5265–5274 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bengtson, C. P., Dick, O. & Bading, H. A quantitative method to assess extrasynaptic NMDA receptor function in the protective effect of synaptic activity against neurotoxicity. BMC Neurosci. 9, 11 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cho, C. H., St-Gelais, F., Zhang, W., Tomita, S. & Howe, J. R. Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents. Neuron 55, 890–904 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Sobczyk, A. & Svoboda, K. Activity-dependent plasticity of the NMDA-receptor fractional Ca2+ current. Neuron 53, 17–24 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Zito, K., Scheuss, V., Knott, G., Hill, T. & Svoboda, K. Rapid functional maturation of nascent dendritic spines. Neuron 61, 247–258 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bardoni, R., Magherini, P. C. & MacDermott, A. B. NMDA EPSCs at glutamatergic synapses in the spinal cord dorsal horn of the postnatal rat. J. Neurosci. 18, 6558–6567 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Nie, H. & Weng, H. R. Impaired glial glutamate uptake induces extrasynaptic glutamate spillover in the spinal sensory synapses of neuropathic rats. J. Neurophysiol. 103, 2570–2580 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank members of the Popescu laboratory and the reviewers for insights and helpful suggestions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gabriela K. Popescu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Excitatory postsynaptic current

(EPSC).The net flow of positively charged ions into a postsynaptic neuron observed in response to spontaneously occurring or experimentally evoked neurotransmitter release. In the mammalian CNS, this current is the glutamate-gated electrical output of multiple synaptic receptors (synaptic ionotropic glutamate receptors).

Gating reactions

Molecular isomerizations between inactive and active states; specifically, for ion channels, gating refers to the transitions that connect closed (non-conducting) to open (ion-conducting) conformations.

Binding reaction

The physical association between two initially separate entities; it describes the transition from apo (unbound) to liganded receptor states.

Rate constants

Numbers that define the frequency with which transitions occur. They are expressed in s−1 for isomerization reactions.

Reaction mechanism

The pathway of energy changes that are experienced by a molecule during a conformational or chemical transformation; it postulates numerous elementary states in which the system can be found, how these states can interconvert and the rates with which these steps occur.

Open states

Families of kinetic states defined functionally by their ability to pass current; for glutamate receptors, qualifying structures must have the glutamate-binding cleft in a contracted (closed) conformation, which is incompatible with agonist binding or agonist dissociation, and the pore open (conducting).

Desensitized states

Families of conformations defined functionally by their inability to bind to or dissociate from an agonist and their inability to pass current; for glutamate receptors, qualifying structures must have the glutamate-binding cleft in a tight binding-incompatible conformation and the pore closed (non-conducting).

Modes

Distinct patterns of activity that can be discerned in the single-channel record of almost all ion channels; each kinetic pattern or mode reflects a unique reaction mechanism, characterized by different numbers or arrangements of states or/and different values for particular rate constants.

Open probabilities

Parameters used to express quantitatively the activity of ion channels; they express the fraction of time during which the channel is open and allows ionic flow.

Single-channel record

Document that represents a digital sampling of electrical currents produced by the opening of individual channel proteins; it can register the activity of one or several simultaneously active channels.

Simulations

In silico calculations used to predict time-dependent occupancies for kinetic states given a reaction mechanism (model), initial state occupancies and a stimulus defined by duration and amplitude.

Bursts

Sequence of openings and brief closures; for ion channels with the single-channel record containing closures of n distinct durations, n–1 types of bursts can be defined to contain from 1 to n–1 types of closure durations.

Resting states

Families of conformations defined functionally by their ability to recognize and bind to an agonist and their inability to generate an electrical signal; for glutamate receptors, qualifying structures must have the glutamate-binding cleft in an extended binding-compatible conformation and the pore closed (non-conducting).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Iacobucci, G., Popescu, G. NMDA receptors: linking physiological output to biophysical operation. Nat Rev Neurosci 18, 236–249 (2017). https://doi.org/10.1038/nrn.2017.24

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2017.24

This article is cited by

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