NMDA Receptors


N‐methyl‐D‐aspartate (NMDA) receptors are one type of glutamate receptor. They play key roles in synaptic transmission and plasticity in the central nervous system. They are uniquely activated by simultaneous binding of the amino acids glycine and l‐glutamate. These receptors are proteins that form an ion channel across the cell membrane, commonly formed by assembly of two glutamate‐binding GluN2 subunits and two glycine‐binding GluN1 subunits. The ion channel opens following receptor activation, allowing Na+ and Ca2+ ions to cross the cell membrane, thus translating the transient chemical signal provided by release of glutamate from a presynaptic neuron, into postsynaptic electrical and biochemical Ca2+ signals. Crucially, the characteristics of NMDA receptor signalling depend on the receptor subunit composition, particularly the nature of the GluN2 subunits which can be of four different types, creating unique and important variations in properties that provide a rich diversity of NMDA receptor signalling in the brain.

Key Concepts

  • NMDA receptor functional diversity is determined by the receptor subunit composition.
  • Key functional attributes of NMDA receptors are the Ca2+ permeability and Mg2+ block of the transmembrane ion channel and the slow kinetics of receptor activation which can last for hundreds of milliseconds.
  • The receptor subunits are somewhat modular in nature with key functional attributes depending on particular domains of the subunit protein.
  • Domain interactions are an emerging concept in understanding NMDA receptor structure–function relationships.
  • Allosteric modulators of NMDA receptors can both enhance or inhibit receptor function and provide the future possibility of novel therapeutic approaches to diseases of the nervous system associated with altered NMDA receptor function.

Keywords: NMDA receptor; subunit composition; receptor kinetics; channel properties; Ca2+ permeability; Mg2+ block; synaptic transmission; allosteric modulation

Figure 1. Schematic drawing of the NMDA receptor‐channel‐binding sites. Cull‐Candy . Reproduced with permission of John Wiley and Sons.
Figure 2. NMDAR subunits making up diheteromeric and triheteromeric tetramers, and splice sites on GluN1. Cull‐Candy . Reproduced with permission of John Wiley and Sons.
Figure 3. NMDAR subunit topology. Cull‐Candy . Reproduced with permission of John Wiley and Sons.
Figure 4. GluN1–GluN2 heterodimers form the NMDAR. Cull‐Candy . Reproduced with permission of John Wiley and Sons.
Figure 5. GluN2 subunits are key determinants of NMDAR functional properties. Cull‐Candy . Reproduced with permission of John Wiley and Sons.


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Further Reading

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

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

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

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

Farrant M, Feldmeyer D, Takahashi T and Cull‐Candy SG (1994) NMDA‐receptor channel diversity in the developing cerebellum. Nature 368: 335–339.

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 University Press: Oxford.

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

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.

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Gibb, Alasdair J(Jun 2019) NMDA Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000254.pub3]