NMDA Receptors


N‐methyl‐D‐aspartate (NMDA) receptors are activated during excitatory neurotransmission at most synapses in the central nervous system. Their unique properties allow them to play key roles in synaptic transmission and plasticity; the functional importance of some NMDAR subtypes is becoming clearer.

Keywords: NMDA receptor subunits; NMDA receptor subtypes; glutamate receptors; AMPA receptors; synaptic transmission; plasticity

Figure 1.

Schematic drawing of the NMDAR channel‐binding sites.

Figure 2.

NMDAR subunits making up tetramers, and splice sites on NR1.

Figure 3.

NMDAR subunit topology.

Figure 4.

An NR1–NR2 heterodimer forms the functional unit of the NMDAR.

Figure 5.

NMDAR functional properties.



Armstrong N, Sun Y, Chen GQ and Gouaux E (1998) Structure of a glutamate‐receptor ligand‐binding core in complex with kainate. Nature 395: 913–917.

Banke TG, Dravid SM and Traynelis SF (2005) Protons trap NR1/NR2B NMDA receptors in a nonconducting state. Journal of Neuroscience 25: 42–51.

Banke TG and Traynelis SF (2003) Activation of NR1/NR2BNMDA receptors. Nature Neuroscience 6: 144–152.

Barria A and Malinow R (2002) Subunit‐specific NMDA receptor trafficking to synapses. Neuron 35: 345–353.

Barria A and Malinow R (2005) NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48: 289–301.

Bartlett TE, Bannister NJ, Collett VJ et al. (2007) Differential roles of NR2A and NR2B‐containing NMDA receptors in LTP and LTD in the CA1 region of two‐week old rat hippocampus. Neuropharmacology 52: 60–70.

Berberich S, Punnakkal P, Jensen V et al. (2005) Lack of NMDA receptor subtype selectivity for hippocampal long‐term potentiation. Journal of Neuroscience 25: 6907–6910.

Bergles DE, Diamond JS and Jahr CE (1999) Clearance of glutamate inside the synapse and beyond. Current Opinion in Neurobiology 9: 293–298.

Brickley SG, Misra C, Mok MH et al. (2003) NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites. Journal of Neuroscience 23: 4958–4966.

Cathala L, Misra C and Cull‐Candy S (2000) Developmental profile of the changing properties of NMDA receptors at cerebellar mossy fiber‐granule cell synapses. Journal of Neuroscience 20: 5899–5905.

Chatterton JE, Awobuluyi M, Premkumar LS et al. (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415: 793–798.

Collingridge GL, Isaac JTR and Wang YT (2005) Receptor trafficking and synaptic plasticity. Nature Reviews Neuroscience 5: 952–962.

Cull‐Candy S, Brickley S and Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Current Opinion in Neurobiology 11: 327–335.

Cull‐Candy SG and Leszkiewicz DN (2004) Role of distinct NMDA receptor subtypes at central synapses. Science STKE 16: 1–9.

Cull‐Candy SG and Usowicz MM (1987) Multiple‐conductance channels activated by excitatory amino acids in cerebellar neurons. Nature 325: 525–528.

Furukawa H, Singh SK and Mancusso R (2005) Subunit arrangement and function in NMDA receptors. Nature 438: 185–192.

Gebhardt C and Cull‐Candy SG (2006) Influence of agonist concentration on AMPA and kainate channels in CA1 pyramidal cells in rat hippocampal slices. Journal of Physiology 573: 371–394.

Hatton CJ and Paoletti P (2005) Modulation of triheteromeric NMDA receptors by N‐terminal domain ligands. Neuron 46: 261–274.

Hollman M (1999) Structure of ionotropic glutamate receptors. In: Jonas P and Monyer H (eds) Ionotropic Glutamate Receptors in the CNS, pp. 1–98. London: Springer.

Horak M, Vlcek K, Petrovic M et al. (2004) Molecular mechanism of pregnenolone sulfate action at NR1/NR2B receptors. Journal of Neuroscience 24: 10318–10325.

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

Jahr CE and Stevens CF (1987) Glutamate activates multiple single channel conductances in hippocampal neurons. Nature 325: 522–525.

Jin R, Banke TG, Mayer ML et al. (2003) Structural basis for partial agonist action at ionotropic glutamate receptors. Nature Neuroscience 6: 803–810.

Johnson JW and Ascher P (1994) The NMDA receptor, its channel and its modulation by glycine. In: Collingridge GL and Watkins JC (eds) The NMDA Receptor, 2nd edn. Oxford: Oxford University Press.

Johnson JW and Kotermanski SE (2006) Mechanism of action of memantine. Current Opinion in Pharmacology 6: 61–67.

Kemp JA and McKernan RM (2002) NMDA receptor pathways as drug targets. Nature Neuroscience 5: 1039–1042.

Kristensen AS, Geballe MT, Snyder J P and Traynelis SF (2006) Glutamate receptors: variation in structure–function coupling. Trends in Pharmacological Sciences 27: 65–69.

Laube B, Kuhse J and Betz H (1998) Evidence for a tetrameric structure of recombinant NMDA receptors. Journal of Neuroscience 18: 2954–2961.

Liu L, Wong TP, Pozza MF et al. (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304: 1021–1024.

Malayev A, Gibbs TT and Farb DH (2002) Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. British Journal of Pharmacology 135: 901–909.

Martina M, Krasteniakov NV and Bergeron R (2003) d‐Serine differently modulates NMDA receptor function in rat CA1 hippocampal pyramidal cells and interneurons. Journal of Physiology 548: 411–423.

Massey PV, Johnson BE, Moult PR et al. (2004) Differential roles of NR2A and NR2B‐containing NMDA receptors in cortical long‐term potentiation and long‐term depression. Journal of Neuroscience 24: 7821–7828.

Mayer ML (2006) Glutamate receptors at atomic resolution. Nature Reviews 440: 456–462.

Mayer ML and Armstrong N (2004) Structure and function of glutamate receptor ion channels. Annual Review of Physiology 66: 161–181.

Misra C, Brickley SG, Wyllie DJ and Cull‐Candy SG (2000) Slow deactivation kinetics of NMDA receptors containing NR1 and NR2D subunits in rat cerebellar Purkinje cells. Journal of Physiology 525: 299–305.

Morishita W, Lu W, Smith GB et al. (2007) Activation of NR2B‐containing NMDA receptors is not required for NMDA receptor‐dependent long‐term depression. Neuropharmacology 52: 71–76.

Mothet J‐P, Pollegioni L, Ouanounou G et al. (2005) Glutamate receptor activation triggers a calcium dependent and SNARE protein‐dependent release of the gliotransmitter d‐serine. Proceedings of the National Academy of Sciences of the USA 102: 5606–5611.

Mu Y, Otsuka T, Horton AC, Scott DB and Ehlers MD (2003) Activity‐dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors. Neuron 40: 581–594.

Neyton J and Paoletti P (2006) Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. Journal of Neuroscience 26: 1331–1333.

Paoletti P, Perin‐Dureau F, Fayyazuddin A et al. (2000) Molecular organization of a zinc binding N‐terminal modulatory domain in an NMDA receptor subunit. Neuron 28: 911–925.

Popescu G, Robert A, Howe JR and Auerbach A (2004) Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430: 790–793.

Prybylowski K and Wenthold RJ (2004) N‐Methyl‐d‐aspartate receptors: subunit assembly and trafficking to the synapse. Journal of Biological Chemistry 279: 9673–9676.

Rachline J, Perin‐Dureau F, Le Goff A et al. (2005) The micromolar zinc‐binding domain on the NMDA receptor subunit NR2B. Journal of Neuroscience 25: 308–317.

Rosenmund C, Stern‐Batch Y and Stevens CF (1998) The tetrameric structure of a glutamate receptor channel. Science 280: 1596–1599.

Schorge S and Colquhoun D (2003) Studies of NMDA receptor function and stoichiometry with truncated and tandem subunits. Journal of Neuroscience 23: 1151–1158.

Scott DB, Blanpied TA, Swanson GT et al. (2001) An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. Journal of Neuroscience 21: 3063–3072.

Smith TC and Howe JR (2000) Concentration‐dependent substate behavior of native AMPA receptors. Nature Neuroscience 3: 992–997.

Toyoda H, Zhao MG and Zhuo M (2005) Roles of NMDA receptor NR2A and NR2B subtypes for long‐term depression in the anterior cingulate cortex. European Journal of Neuroscience 22: 485–494.

Traynelis SF and Cull‐Candy SG (1990) Proton inhibition of N‐methyl‐d‐aspartate receptors in cerebellar neurons. Nature 345: 347–350.

Vicini S, Wang JF, Li JH et al. (1998) Functional and pharmacological differences between recombinant N‐methyl‐d‐aspartate receptors. Journal of Neurophysiology 79: 555–566.

Weitlauf C, Honse Y, Auberson YP et al. (2005) Activation of NR2A‐containing NMDA receptors is not obligatory for NMDA receptor‐dependent long‐term potentiation. Journal of Neuroscience 25: 8386–8390.

Wollmuth LP and Sobolevsky AI (2004) Structure and gating of the glutamate receptor ion channel. Trends in Neurosciences 27: 321–328.

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Cull‐Candy, Stuart G(Sep 2007) NMDA Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000254.pub2]