NMDA Receptors

NMDA receptors are expressed alongside AMPA receptors on the postsynaptic membrane of excitatory synapses, where they initiate a two-component excitatory postsynaptic potential (EPSP). The activation of AMPA receptors produces a current that has rapid onset and decay, while activation of NMDA receptors leads to a current with slower onset and decay. The slow decay of NMDA-mediated currents is due to the slow dissociation of glutamate from NMDA receptors, compared with AMPA receptors. Unlike other ionotropic glutamate receptors, NMDA receptors are highly permeable to Ca²⁺.

NMDA Receptor Structure

NMDA receptors are heteromeric tetramers, with every endogenously expressed NMDA receptor containing at least one GluN1 subunit, in combination with one or more GluN2 or GluN3 subunits. There is high variability in the exact subunit combination of endogenous NMDA receptors, as there have been 9 splice variants of GluN1 identified, as well as four genes for GluN2 (A to D) and two genes for GluN3 (A and B). The exact subunit conformation of a NMDA receptor determines the ability of the receptor to bind different ligands and the Ca²⁺ permeability of the receptor.

During postnatal development the subunit combinations expressed in the brain change. In early postnatal development, NMDA receptors are primarily composed of N1 and N2B subunits, resulting in very long-lasting synaptic responses. However, during the first weeks of brain development, the N2B subunit is replaced with N2A or N2C, leading to a shorter synaptic response.

Unique features of NMDA Receptors

NMDA receptors have properties that set them apart from other ligand-gated ion channels:

• divalent cation block
• multiple ligands required for activation
• a third pharmacological binding site within the ion pore

At resting membrane potentials, extracellular Mg²⁺ and Zn²⁺ block the ion pore of NMDA receptors, so that even in the presence of glutamate there is very little ion flow. Depolarization of the postsynaptic membrane where NMDA receptors are expressed is required to remove this block. Repetitive stimulation of the postsynaptic neuron is required to relieve the Mg²⁺/Zn²⁺ block, suggesting that NMDA receptors can detect simultaneous activity at adjacent receptors on the synaptic membrane. However, this sustained activation of the postsynaptic membrane can lead to glutamate excitotoxicity, due to the large influx of Ca²⁺ through extrasynaptic NMDA receptors. This has been postulated as a cause of cell death in neurogenerative diseases, such as Alzheimer's disease and Parkinson's disease.

Another unique feature of NMDA receptors is the requirement for two ligands to bind for endogenous activation. Both glutamate and glycine are required to bind at their respective binding sites. These ligands are referred to as co-agonists, and neither can activate the receptor without the other. Both the glutamate and glycine binding sites are targets for drugs. D-serine can also activate NDMA receptors with glutamate by binding to the glycine binding site; it is more potent than glycine. D-serine is released from glial cells in the CNS, suggesting a critical role for glial cells in modulating NMDA synaptic function.

The third unique feature of NMDA receptors is the presence of a third pharmacological binding site, within the ion pore near the Mg²⁺/Zn²⁺ blocking point. Drugs that bind at this site, such as MK 801 and Ketamine, physically block ion flow through the ion channel pore, and are described as non-competitive antagonists. At lower concentrations these compounds are psychotomimetic causing cognitive impairments, hallucinations and delusions, while at higher concentrations they are dissociative anesthetics.

External sources of pharmacological information for NMDA Receptors :

• IUPHAR Receptor Code

• BJP Guide

Literature for NMDA Receptors

Tocris offers the following scientific literature for NMDA Receptors to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.

Huntington's Disease Research Product Guide

This product guide provides a background to Huntington's disease research and lists around 100 products for the study of:

• Somatic Instability
• Proteolysis and Inclusion Bodies
• Transcriptional Dysregulation
• Mitochondrial Dysfunction
• Nuclear-Cytoplasmic Transport Interference
• Excitotoxicity
• Stem Cells

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Alzheimer's Disease Poster

Alzheimer's disease (AD) is a debilitating and progressive neurodegenerative disease and the most common cause of dementia, affecting approximately 30% of individuals aged over 85 years. This poster summarizes the cellular and molecular mechanisms of AD.

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Depression Poster

Major depressive disorder is characterized by depressed mood and a loss of interest and/or pleasure. Updated in 2015 this poster highlights presynaptic and postsynaptic targets for the potential treatment of major depressive disorder, as well as outlining the pharmacology of currently approved antidepressant drugs.

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Huntington's Disease Poster

Huntington's disease (HD) is a severe monogenic neurodegenerative disorder, which is characterized by the prevalent loss of GABAergic medium spiny neurons (MSN) in the striatum. This poster summarizes the effects of mutant huntingtin aggregation implicated in the pathology of HD, as well as highlighting the use of iPSCs for HD modeling.

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Parkinson's Disease Poster

Parkinson's disease (PD) causes chronic disability and is the second most common neurodegenerative condition. This poster outlines the neurobiology of the disease, as well as highlighting current therapeutic treatments for symptomatic PD, and emerging therapeutic strategies to delay PD onset and progression.

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NMDA Receptor Gene Data