nmda receptor
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NMDA receptor 1
NMDA receptor
NMDA
Glutamic acid
Stylised depiction of an activated NMDAR.
Glutamate is in the glutamate-binding site and
glycine is in the glycine-binding site. Allosteric
sites that would cause inhibition of the receptor
are not occupied. NMDARs require the binding
of two molecules of glutamate or aspartate and
two of glycine.[]
The N-methyl-D-aspartate receptor (also known as the NMDA
receptor or NMDAR), a glutamate receptor, is the predominant
molecular device for controlling synaptic plasticity and memory
function.[1]
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 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+
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.[2]
Structure
The NMDA receptor forms a heterotetramer between two GluN1 and
two GluN2 subunits (the subunits were previously denoted as NR1 and
NR2), 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: amodulatory 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 aseries of protein kinases and protein phosphatases, as well as residues that interact with a large number of
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NMDA receptor 2
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
NR2 subunit in vertebrates (left) and
invertebrates (right). Ryan et al., 2008
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.[3]
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.[4] 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.[5]
This may in part account for
greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behindgenetically-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.[6]
One study suggests that reelin may
play a role in the NMDA receptor maturation by increasing the NR2B subunit mobility.[]
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NMDA receptor 3
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.[]
Ligands
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
Partial agonists
• N-Methyl-D-aspartic acid (NMDA)
• 3,5-dibromo-L-phenylalanine
[7]
•• GLYX-13
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, Dextrorphan (a metabolite of Dextromethorphan), and MK-801, as well as
some NDMA 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.[]
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NMDA receptor 4
Common NMDA receptor antagonists include:
• Amantadine[]
•• Ketamine
•• Methoxetamine
• Phencyclidine (PCP)
• Nitrous oxide (laughing gas)• Dextromethorphan and dextrorphan
•• Memantine
•• Ethanol
• Riluzole (used in ALS)[8]
•• Xenon
• HU-211 (also a cannabinoid)
• Lead (Pb2+)[9]
•• Conantokins
•• Huperzine A
• Atomoxetine[]
Dual opioid and NMDA receptor 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. Treatment with forms magnesium glycinate and magnesium taurinate
has been used to produce rapid recovery from depression.[]
• Na+, K
+and Ca
2+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.[citation needed ]
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,
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NMDA receptor 6
External links
• Media related to NMDA receptor at Wikimedia Commons
• NMDA receptor pharmacology[11]
• 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[12]
• A schematic diagram summarizes three potential models for the switching of NR2A and NR2B subunits at
developing synapses.[13]
- a figure from Liu et al., 2004[]
• Drosophila NMDA receptor 1 - The Interactive Fly[14]
References
[1] Clinical Implications of Basic Research: Memory and the NMDA receptors (http:/ / content. nejm. org/ cgi/ content/ full/ 361/ 3/ 302), Fei Li
and Joe Z. Tsien, N Engl J Med, 361:302, July 16, 2009
[4] Ryan, T. J. & Grant, S. G. N. (2009) The origin and evolution of synapses (vol 10, pg 701, 2009). Nat Rev Neurosci 10, Doi 10.1038/Nrn2748
[8] http:/ / www. clinicalpharmacology-ip. com
[9][9] Toxicol. Sci. 2010 116: 249-263;
[10][10] >
[11] http:/ / www. bris.ac. uk/ Depts/ Synaptic/ info/ pharmacology/ NMDA. html
[12] http:/ / www. jneurosci. org/ cgi/ content/ full/ 16/ 24/ 7859
[13] http:/ / www. jneurosci. org/ cgi/ content-nw/ full/ 24/ 40/ 8885/ FIG8
[14] http:/ / www. sdbonline. org/ fly/ hjmuller/ nmda1. htm
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Article Sources and Contributors 7
Article Sources and ContributorsNMDA receptor Source: http://en.wikipedia.org/w/index.php?oldid=567872222 Contributors: A. Rad, A314268, ABCD, AJVincelli, Abductive, Absg2011eur, Acdx, Alibobar,
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