The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl D-aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell.
Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in that it is both ligand-gated and voltage-dependent.
The NMDA receptor forms a heterodimer between NR1 and NR2 subunits, which explains why NMDA receptors contain two obligatory NR1 subunits and two regionally localized NR2 subunits. A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits.
Each receptor subunit has modular design and each structural module also represents a functional unit:
The extracellular domain contains two globular structures: a modulatory domain and a ligand binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate.
The agonist-binding module links to a membrane domain, which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels.
The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary conductance, high-calcium permeability, and voltage-dependent magnesium block.
Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.
The glycine-binding module of the NR1 subunit and the glutamate-binding module of the NR2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors.
There are eight variants of the NR1 subunit produced by alternative splicing of GRIN1:
NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form.
Various isoforms of NR2 subunits exist, and are referred to with the nomenclature NR2A through D (GRIN2A, GRIN2B, GRIN2C, GRIN2D). They contain the binding-site for the neurotransmitterglutamate. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil.
Whereas NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor. There are three hypothetic models to describe this switch mechanism:
Dramatic increase in synaptic NR2A along with decrease in NR2B
Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A
Increase of NR2A diluting the number of NR2B without the decrease of the former.
The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death. The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity. Disruption of the gene for NR2B in mice causes perinatal lethality, whereas the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity.
Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly.) In addition, NMDARs also require the binding of the co-agonistglycine for the efficient opening of the ion channel, which is a part of this receptor.
D-serine has also been found to co-agonize the NMDA receptor with even greater potency than glycine. D-serine is produced by serine racemase in astrocyte cells, and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine is also synthesized in neurons, indicating a role for neuron-derived D-serine in NMDA receptor regulation.
In addition, a third requirement is membrane depolarization. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission.
NMDA Receptor Antagonists are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs because of their hallucinogenic properties. When NMDA Receptor Antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's Lesions. However, there are fundamental differences between human and rodent brains. For now there is not enough research to show that large doses of NMDA antagonists cause Olney's Lesions in humans or monkeys.
The NMDA receptor is modulated by a number of endogenous and exogenous compounds:
Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium treatment has been used to produce rapid recovery from depression.
Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.
Zn2+ blocks the NMDA current in a noncompetitive and a voltage-independent manner.
It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.
Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.
The activity of NMDA receptors is also strikingly sensitive to the changes in H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions. The level of inhibition by H+ is greaty reduced in receptors containing the NR1a subtype, which contains the positively-charged insert Exon 5. The effect of this insert may be mimicked by positively-charged polyamines and aminoglycosides, explaining their mode of action.
NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site." Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone.
This channel complex contributes to excitatory synaptic transmission as well as synaptic plasticity at sites throughout the brain and the spinal cord, and is modulated by a number of endogenous and exogenous compounds. NMDA receptors play a key role in a wide range of physiologic and pathologic processes. The role of the NMDA receptor in general, with regard to syanptic plasicity, can be described as coincidence detection.
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NMDA receptor pharmacology
Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit
A schematic diagram summarizes three potential models for the switching of NR2A and NR2B subunits at developing synapses. - a figure from Liu et al., 2004