The N-methyl-D-aspartate receptor, 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 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
with an equilibrium potential near 0 mV. A property of the NMDA receptor is its voltage-dependent
activation, a result of ion channel block by extracellular Mg2+ & Zn2+ 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
be critical 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 either D-serine or glycine.
Structure The NMDA receptor forms a heterotetramer between
two GluN1 and two GluN2 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. Variants
GluN1 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. NR1-2a, NR1-2b;
NR1-3a, NR1-3b; NR1-4a, NR1-4b;
GluN2
While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2
subunit are expressed in vertebrates and are referred to with the nomenclature NR2A through
D(coded by GRIN2A, GRIN2B, GRIN2C, GRIN2D). Strong evidence shows that the genes coding
the NR2 subunits in vertebrates have undergone at least two rounds of gene duplication. They
contain the binding-site for the neurotransmitter glutamate. More importantly, each NR2 subunit
has a different intracellular C-terminal domain that can interact with different sets of signalling
molecules. 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. For
instance, greater ratios of the NR2B subunit leads to NMDA receptors which remain open
longer compared to those with more NR2A. This may in part account for greater memory abilities
in the immediate postnatal period compared to late in life, which is the principle behind
genetically-altered 'doogie mice'. 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 latter. 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 of the cerebellum,
after undergoing symmetric cell division in the external granule-cell layer, migrate into
the internal granule-cell layer where they downregulate NR2B and activate NR2C, a process
that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors.
Ligands Agonists
Activation of NMDA receptors requires binding of glutamate or aspartate. 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.
NMDA receptor-mediated currents are directly related to membrane depolarization. NMDA agonists
therefore exhibit fast Mg2+ unbinding kinetics, increasing channel open probability with depolarization.
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.
Some known NMDA receptor agonists include: Aminocyclopropanecarboxylic acid
D-Cycloserine cis-2,3-Piperidinedicarboxylic acid
L-Aspartate Quinolinate
Homocysterate D-Serine
ACPL L-Alanine
Partial agonists N-Methyl-D-aspartic acid
3,5-dibromo-L-phenylalanine GLYX-13
NRX-1074 Glycine-site NMDA receptor partial agonists,
such as GLYX-13 and NRX-1074, are now viewed with great interest for the development of
new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.
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 certain NMDA receptor
antagonists are given to rodents in large doses, they can cause a form of brain damage
called Olney's lesions. NMDA receptor antagonists that have been shown to induce Olney's lesions
include ketamine, phencyclidine, and dextrorphan, as well as some NMDA receptor antagonists
used only in research environments. 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 agents in which NMDA receptor antagonism is the primary mechanism of action:
AP5 Conantokins
Dextromethorphan Dexanabinol
Dizocilpine Ketamine
Memantine Nitrous oxide
Phencyclidine Xenon
Some common agents in which weak NMDA receptor antagonism is a secondary or additional action
include: Amantadine
Atomoxetine Dextropropoxyphene
Ethanol Huperzine A
Ibogaine Ketobemidone
Methadone – an opioid analgesic Tramadol – an atypical analgesic
Kynurenic acid is an endogenous NMDA receptor antagonist.
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. Treatment with forms magnesium glycinate and magnesium taurinate 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.
Pb2+ 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. Proteins of the major histocompatibility complex
class I are endogenous negative regulators of NMDAR-mediated currents in the adult hippocampus,
and are required for appropriate NMDAR-induced changes in AMPAR trafficking and NMDAR-dependent
synaptic plasticity and learning and memory. Receptor modulation
The NMDA receptor is a non-specific cation channel that can allow the passage of Ca2+
and Na+ into the cell and K+ out of the cell. The excitatory postsynaptic potential 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.
Therefore, the NMDA receptor functions as a "molecular coincidence detector". Its ion
channel opens only when the following two conditions are met simultaneously: glutamate
is bound to the receptor, and the postsynaptic cell is depolarized. This property of the
NMDA receptor explains many aspects of long-term potentiation 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 and pathological processes.
Clinical significance Memantine is approved by the U.S. F.D.A and
the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease,
and has now received a limited recommendation by the UK's National Institute for Health
and Care Excellence for patients who fail other treatment options.
Cochlear NMDARs are the target of intense research to find pharmacological solutions
to treat tinnitus. 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.
NMDAR modulators, including esketamine, GLYX-13, NRX-1074, and CERC-301, are under development
for the treatment of mood disorders, including major depressive disorder and treatment-resistant
depression. In addition, ketamine is already employed for this purpose as an off-label
therapy in some clinics. Compared to dopaminergic stimulants, phencyclidine
can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers,
in what has led to the glutamate hypothesis of schizophrenia. Experiments in which rodents
are treated with NMDA receptor antagonist are today the most common model when it comes
to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs
already approved for treatment of schizophrenia. See also
Long-term potentiation and depression Category: NMDA receptor antagonists
NMDA AMPA
AMPA receptor Calcium/calmodulin-dependent protein kinases
Anti-glutamate receptor antibodies Anti-NMDA receptor encephalitis
External links Media related to NMDA receptor at Wikimedia
Commons 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
Drosophila NMDA receptor 1 - The Interactive Fly