NMDA receptor

The NMDA receptor (NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.

The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl D-aspartate) is the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. A unique property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg2+ ions. This allows the flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell to be voltage-dependent.

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 two ways: First, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands - glutamate and glycine.

Structure
The NMDA receptor forms a heterotetramer between two NR1 and two NR2 subunits; 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 modules of the NR1 and NR3 subunits 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.

NR1
There are eight variants of the NR1 subunit produced by alternative splicing of :
 * NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form.
 * NR1-2a, NR1-2b;
 * NR1-3a, NR1-3b;
 * NR1-4a, NR1-4b;

NR2
While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2 subunit have been formed by gene duplication in vertebrates, and are referred to with the nomenclature NR2A through D (GRIN2A, GRIN2B, GRIN2C, GRIN2D). They contain the binding-site for the neurotransmitter glutamate. 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 hypothetical 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. One study suggests that reelin may play a role in the NMDA receptor maturation by increasing the NR2B subunit mobility.

NR2B to NR2C switch
Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division in the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they downregulate NR2B and activate NR2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors.

Agonists
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- agonist glycine 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, 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 can be released both by neurons and astrocytes to regulate NMDA receptors.

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.

Known NMDA receptor agonists include:
 * Aminocyclopropanecarboxylic acid
 * D-Cycloserine
 * cis-2,3-Piperidinedicarboxylic acid
 * L- aspartate
 * Quinolinate
 * Homocysterate
 * D-serine
 * ACPL
 * L-alanine
 * D-serine

Antagonists
Antagonists of the NMDA receptor are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs due to their hallucinogenic properties, in addition to their unique effects at elevated dosages such as dissociation. When NMDA receptor antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's Lesions. So far, the published research on Olney's Lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists.

Common NMDA receptor antagonists include:
 * Amantadine
 * Ketamine
 * Phencyclidine (PCP)
 * Nitrous oxide
 * Dextromethorphan and dextrorphan
 * Memantine
 * Ethanol
 * Riluzole (used in ALS)
 * Xenon
 * HU-211 (also a cannabinoid)
 * Lead (Pb2+)

Dual opioids and NMDA-Antagonists:
 * Ketobemidone
 * Methadone
 * Dextropropoxyphene
 * Tramadol
 * Kratom alkaloids
 * Ibogaine

Modulators
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 glycinate and magnesium taurinate 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+ and Cu2+ generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity. (Zinc and Copper Influence Excitability of Rat Olfactory Bulb Neurons by Multiple Mechanisms|http://jn.physiology.org/content/86/4/1652.short)


 * Pb2+ lead is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb2+ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.


 * 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 greatly 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.


 * Src kinase enhances NMDA receptor currents.
 * Reelin modulates NMDA function through Src family kinases and DAB1. significantly enhancing LTP in the hippocampus.
 * CDK5 regulates the amount of NR2B-containing NMDA receptors on the synaptic membrane, thus affecting synaptic plasticity.

Functional role
The NMDA receptor is a non-specific cation channel which can allow Ca2+, Na+, and K+ to pass into the cell. The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA receptor increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function as a second messenger in various signaling pathways. However, the NMDA receptor cation channel is blocked by Mg2+ at resting membrane potential. To unblock the channel, the postsynaptic cell must be depolarized.

The NMDA receptor therefore functions as a "molecular coincidence detector". Its ion channel only opens when the following two conditions are met simultaneously: glutamate is bound to the receptor, and the postsynaptic cell is depolarized (which removes the Mg2+ blocking the channel). This property of the NMDA receptor explains many aspects of long term potentiation (LTP) and synaptic plasticity.

NMDA receptors are modulated by a number of endogenous and exogenous compounds and play a key role in a wide range of physiological (e.g. memory) and pathological processes (e.g. excitotoxicity).

Clinical significance
Recently, NMDARs were associated with a rare autoimmune disease, Anti-NMDAR encephalitis, that usually occurs due to cross reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in teratoma.