NMDA receptor
The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a
The NMDA receptor is
Activity of the NMDA receptor is blocked by many
Overactivation of the receptor, causing excessive influx of Ca2+ can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.[16][17][18][19] However, hypofunction of NMDA receptors (due to glutathione deficiency or other causes) may be involved in impairment of synaptic plasticity[20] and could have other negative repercussions. The main problem with the utilization of NMDA receptor antagonists for neuroprotection is that the physiological actions of the NMDA receptor are essential for normal neuronal function. To be clinically useful NMDA antagonists need to block excessive activation without interfering with normal functions. Memantine has this property.[21]
History
The discovery of NMDA receptors was followed by the synthesis and study of N-methyl-D-aspartic acid (NMDA) in the 1960s by
In 2002, it was discovered by Hilmar Bading and co-workers that the cellular consequences of NMDA receptor stimulation depend on the receptor's location on the neuronal cell surface.[24][25] Synaptic NMDA receptors promote gene expression, plasticity-related events, and acquired neuroprotection. Extrasynaptic NMDA receptors promote death signaling; they cause transcriptional shut-off, mitochondrial dysfunction, and structural disintegration.[24][25] This pathological triad of extrasynaptic NMDA receptor signaling represents a common conversion point in the etiology of several acute and chronic neurodegenerative conditions.[26] The molecular basis for toxic extrasynaptic NMDA receptor signaling was uncovered by Hilmar Bading and co-workers in 2020.[27] Extrasynaptic NMDA receptors form a death signaling complex with TRPM4. NMDAR/TRPM4 interaction interface inhibitors (also known as interface inhibitors) disrupt the NMDAR/TRPM4 complex and detoxify extrasynaptic NMDA receptors.[27]
A fortuitous finding was made in 1968 when a woman was taking
Structure
Functional NMDA receptors are heterotetramers comprising different combinations of the GluN1, GluN2 (A-D), and GluN3 (A-B) subunits derived from distinct gene families (Grin1-Grin3). All NMDARs contain one or more of the obligatory GluN1 subunits, which when assembled with GluN2 subunits of the same type, give rise to canonical diheteromeric (d-) NMDARs (e.g., GluN1-2A-1-2A). Triheteromeric NMDARs, by contrast, contain three different types of subunits (e.g., GluN1-2A-1-2B), and include receptors that are composed of one or more subunits from each of the three gene families, designated t-NMDARs (e.g., GluN1-2A-3A-2A).[29] There is one GluN1, four GluN2, and two GluN3 subunit encoding genes, and each gene may produce more than one splice variant.
- GluN1 – GRIN1
- GluN2
- GluN3
Gating
The NMDA receptor is a glutamate and ion channel protein receptor that is activated when glycine and glutamate bind to it.[5] The receptor is a highly complex and dynamic heteromeric protein that interacts with a multitude of intracellular proteins via three distinct subunits, namely GluN1, GluN2, and GluN3. The GluN1 subunit, which is encoded by the GRIN1 gene, exhibits eight distinct isoforms owing to alternative splicing. On the other hand, the GluN2 subunit, of which there are four different types (A-D), as well as the GluN3 subunit, of which there are two types (A and B), are each encoded by six separate genes. This intricate molecular structure and genetic diversity enable the receptor to carry out a wide range of physiological functions within the nervous system.[30][31] All the subunits share a common membrane topology that is dominated by a large extracellular N-terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C-terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins.[30][32] Figure 1 shows a basic structure of GluN1/GluN2 subunits that forms the binding site for memantine, Mg2+ and ketamine.
Mg2+ blocks the NMDA receptor channel in a voltage-dependent manner. The channels are also highly permeable to Ca2+. Activation of the receptor depends on glutamate binding,
The GluN2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangements. The basic structure and functions associated with the NMDA receptor can be attributed to the GluN2B subunit. For example, the glutamate binding site and the control of the Mg2+ block are formed by the GluN2B subunit. The high affinity sites for glycine antagonist are also exclusively displayed by the GluN1/GluN2B receptor.[31]
GluN1/GluN2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists, but the transmembrane segments structures are not fully known as stated above. It is claimed that three binding sites within the receptor, A644 on the GluNB subunit and A645 and N616 on the GluN1 subunit, are important for binding of memantine and related compounds as seen in figure 2.[32]
The NMDA receptor forms a
Each receptor subunit has modular design and each structural module, also represents a functional unit:
- The
- The agonist-binding module links to a membrane domain, which consists of three transmembrane 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 phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.
The glycine-binding modules of the GluN1 and GluN3 subunits and the glutamate-binding module of the GluN2A 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.
Mechanism of action
NMDA receptors are a crucial part of the development of the central nervous system. The processes of learning, memory, and
Overactivation of NMDA receptors, causing excessive influx of Ca2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.[16][17][18][19] Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.[16][17][18] It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptors ion channel when excessively open.[18]
Uncompetitive NMDA receptor antagonists, or channel blockers, enter the channel of the NMDA receptor after it has been activated and thereby block the flow of ions.
Memantine is an example of an uncompetitive channel blocker of the NMDA receptor, with a relatively rapid off-rate and low affinity. At physiological pH its amine group is positively charged and its receptor antagonism is voltage-dependent.[18] It thereby mimics the physiological function of Mg2+ as channel blocker.[15] Memantine only blocks NMDA receptor associated channels during prolonged activation of the receptor, as it occurs under excitotoxic conditions, by replacing magnesium at the binding site. During normal receptor activity the channels only stay open for several milliseconds and under those circumstances memantine is unable to bind within the channels and therefore doesn't interfere with normal synaptic activity.[21]
Variants
GluN1
There are eight variants of the GluN1 subunit produced by alternative splicing of GRIN1:[35]
- GluN1-1a, GluN1-1b; GluN1-1a is the most abundantly expressed form.
- GluN1-2a, GluN1-2b;
- GluN1-3a, GluN1-3b;
- GluN1-4a, GluN1-4b;
GluN2
While a single GluN2 subunit is found in
GluN2B to GluN2A switch
While
There are three hypothetical models to describe this switch mechanism:
- Increase in synaptic GluN2A along with decrease in GluN2B
- Extrasynaptic displacement of GluN2B away from the synapse with increase in GluN2A
- Increase of GluN2A diluting the number of GluN2B without the decrease of the latter.
The GluN2B and GluN2A subunits also have differential roles in mediating excitotoxic neuronal death.[47] The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.[48] Homozygous disruption of the gene for GluN2B in mice causes perinatal lethality, whereas disruption of the GluN2A gene produces viable mice, although with impaired hippocampal plasticity.[49] One study suggests that reelin may play a role in the NMDA receptor maturation by increasing the GluN2B subunit mobility.[50]
GluN2B to GluN2C switch
Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division[51] in the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they down-regulate GluN2B and activate GluN2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors.[52]
Role in excitotoxicity
NMDA receptors have been implicated by a number of studies to be strongly involved with excitotoxicity.[53][54][55] Because NMDA receptors play an important role in the health and function of neurons, there has been much discussion on how these receptors can affect both cell survival and cell death.[56] Recent evidence supports the hypothesis that overstimulation of extrasynaptic NMDA receptors has more to do with excitotoxicity than stimulation of their synaptic counterparts.[53][24] In addition, while stimulation of extrasynaptic NMDA receptors appear to contribute to cell death, there is evidence to suggest that stimulation of synaptic NMDA receptors contributes to the health and longevity of the cell. There is ample evidence to support the dual nature of NMDA receptors based on location, and the hypothesis explaining the two differing mechanisms is known as the "localization hypothesis".[53][56]
Differing cascade pathways
In order to support the localization hypothesis, it would be necessary to show differing cellular signaling pathways are activated by NMDA receptors based on its location within the cell membrane.[53] Experiments have been designed to stimulate either synaptic or non-synaptic NMDA receptors exclusively. These types of experiments have shown that different pathways are being activated or regulated depending on the location of the signal origin.[57] Many of these pathways use the same protein signals, but are regulated oppositely by NMDARs depending on its location. For example, synaptic NMDA excitation caused a decrease in the intracellular concentration of p38 mitogen-activated protein kinase (p38MAPK). Extrasynaptic stimulation NMDARs regulated p38MAPK in the opposite fashion, causing an increase in intracellular concentration.[58][59] Experiments of this type have since been repeated with the results indicating these differences stretch across many pathways linked to cell survival and excitotoxicity.[53]
Two specific proteins have been identified as a major pathway responsible for these different cellular responses ERK1/2, and Jacob.[53] ERK1/2 is responsible for phosphorylation of Jacob when excited by synaptic NMDARs. This information is then transported to the nucleus. Phosphorylation of Jacob does not take place with extrasynaptic NMDA stimulation. This allows the transcription factors in the nucleus to respond differently based in the phosphorylation state of Jacob.[60]
Neural plasticity
NMDA receptors (NMDARs) critically influence the induction of synaptic plasticity. NMDARs trigger both long-term potentiation (LTP) and long-term depression (LTD) via fast synaptic transmission.[61] Experimental data suggest that extrasynaptic NMDA receptors inhibit LTP while producing LTD.[62] Inhibition of LTP can be prevented with the introduction of a NMDA antagonist.[53] A theta burst stimulation that usually induces LTP with synaptic NMDARs, when applied selectively to extrasynaptic NMDARs produces a LTD.[63] Experimentation also indicates that extrasynaptic activity is not required for the formation of LTP. In addition, both synaptic and extrasynaptic activity are involved in expressing a full LTD.[64]
Role of differing subunits
Another factor that seems to affect NMDAR induced toxicity is the observed variation in subunit makeup. NMDA receptors are heterotetramers with two GluN1 subunits and two variable subunits.[53][65] Two of these variable subunits, GluN2A and GluN2B, have been shown to preferentially lead to cell survival and cell death cascades respectively. Although both subunits are found in synaptic and extrasynaptic NMDARs there is some evidence to suggest that the GluN2B subunit occurs more frequently in extrasynaptic receptors. This observation could help explain the dualistic role that NMDA receptors play in excitotoxicity.[66][67] t-NMDA receptors have been implicated in excitotoxicity-mediated death of neurons in temporal lobe epilepsy.[68]
Despite the compelling evidence and the relative simplicity of these two theories working in tandem, there is still disagreement about the significance of these claims. Some problems in proving these theories arise with the difficulty of using pharmacological means to determine the subtypes of specific NMDARs.[53][69] In addition, the theory of subunit variation does not explain how this effect might predominate, as it is widely held that the most common tetramer, made from two GluN1 subunits and one of each subunit GluN2A and GluN2B, makes up a high percentage of the NMDARs.[53] The subunit composition of t-NMDA receptors has recently been visualized in brain tissue.[70]
Excitotoxicity in a clinical setting
Excitotoxicity has been thought to play a role in the degenerative properties of
Ligands
Agonists
Activation of NMDA receptors requires binding of
NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast
Examples
Some known NMDA receptor agonists include:
- Amino acids and amino acid derivatives
- Aspartic acid (aspartate) (D-aspartic acid, L-aspartic acid) – endogenous glutamate site agonist. The word N-methyl-D-aspartate (NMDA) is partially derived from D-aspartate.
- Glutamic acid (glutamate) – endogenous glutamate site agonist
- Tetrazolylglycine – synthetic glutamate site agonist
- Homocysteic acid – endogenous glutamate site agonist
- Ibotenic acid – naturally occurring glutamate site agonist found in Amanita muscaria
- Quinolinic acid (quinolinate) – endogenous glutamate site agonist
- Glycine – endogenous glycine site agonist
- Positive allosteric modulators
- Cerebrosterol– endogenous weak positive allosteric modulator
- Cholesterol – endogenous weak positive allosteric modulator
- Dehydroepiandrosterone (DHEA) – endogenous weak positive allosteric modulator
- Dehydroepiandrosterone sulfate (DHEA-S) – endogenous weak positive allosteric modulator
- Nebostinel(neboglamine) – synthetic positive allosteric modulator of the glycine site
- Pregnenolone sulfate – endogenous weak positive allosteric modulator
- Polyamines
- Spermidine – endogenous polyamine site agonist
- Spermine – endogenous polyamine site agonist
Neramexane
An example of memantine derivative is
Partial agonists
N-Methyl-D-aspartic acid (NMDA), which the NMDA receptor was named after, is a partial agonist of the active or glutamate recognition site.
3,5-Dibromo-L-phenylalanine, a naturally occurring halogenated derivative of
Other partial agonists of the NMDA receptor acting on novel sites such as rapastinel (GLYX-13) and apimostinel (NRX-1074) are now viewed for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.[80]
Examples
- Aminocyclopropanecarboxylic acid(ACC) – synthetic glycine site partial agonist
- D-cycloserine) – naturally occurring glycine site partial agonist found in Streptomyces orchidaceus
- HA-966 – synthetic glycine site weak partial agonist
- Homoquinolinic acid – synthetic glutamate site partial agonist
- N-Methyl-D-aspartic acid (NMDA) – synthetic glutamate site partial agonist
Positive allosteric modulators include:
- Zelquistinel(AGN-241751) - synthetic novel site partial agonist
- Apimostinel (NRX-1074) – synthetic novel site partial agonist
- Rapastinel (GLYX-13) – synthetic novel site partial agonist[81]
Antagonists
Antagonists of the NMDA receptor are used as
Most NMDAR antagonists are
Examples
Common agents in which NMDA receptor antagonism is the primary or a major mechanism of action:
- 7-Chlorokynurenic acid – glycine site antagonist
- Agmatine – endogenous polyamine site antagonist[85][86]
- Argiotoxin-636 – naturally occurring dizocilpine or related site antagonist found in Argiope venom
- AP5 – glutamate site antagonist
- AP7 – glutamate site antagonist
- CGP-37849 – glutamate site antagonist
- D-serine - t-NMDA receptor antagonist / inverse co-agonist[76][68]
- Delucemine (NPS-1506) – dizocilpine or related site antagonist; derived from argiotoxin-636[87][88]
- Dextromethorphan (DXM) – dizocilpine site antagonist; prodrug of dextrorphan
- Dextrorphan (DXO) – dizocilpine site antagonist
- Dexanabinol – dizocilpine-related site antagonist[89][90][91]
- Diethyl ether – unknown site antagonist
- Diphenidine – dizocilpine site antagonist
- Dizocilpine (MK-801) – dizocilpine site antagonist
- Eliprodil – ifenprodil site antagonist
- Esketamine – dizocilpine site antagonist
- Hodgkinsine – undefined site antagonist
- Ifenprodil – ifenprodil site antagonist[92]
- Kaitocephalin – naturally occurring glutamate site antagonist found in Eupenicillium shearii
- Ketamine – dizocilpine site antagonist
- Kynurenic acid – endogenous glycine site antagonist
- Lanicemine – low-trapping dizocilpine site antagonist
- LY-235959 – glutamate site antagonist
- Memantine – low-trapping dizocilpine site antagonist
- Methoxetamine – dizocilpine site antagonist
- Midafotel – glutamate site antagonist
- Nitrous oxide (N2O) – undefined site antagonist
- PEAQX – glutamate site antagonist
- Perzinfotel – glutamate site antagonist
- Phencyclidine (PCP) – dizocilpine site antagonist
- Phenylalanine - a naturally occurring amino acid, glycine site antagonist[93][94]
- Psychotridine – undefined site antagonist
- Selfotel – glutamate site antagonist
- Tiletamine – dizocilpine site antagonist
- Traxoprodil – ifenprodil site antagonist
- Xenon – unknown site antagonist
Some common agents in which weak NMDA receptor antagonism is a secondary or additional action include:
- antiviral and antiparkinsonian drug; low-trapping dizocilpine site antagonist[95]
- ADHD[96]
- opioid analgesic
- euphoriant, sedative, and anxiolyticused recreationally; unknown site antagonist
- expectorant
- antidementiaagent
- antiaddictiveagent
- Ketobemidone – an opioid analgesic
- Methadone – an opioid analgesic
- Minocycline – an antibiotic[97]
- Tramadol – an atypical opioid analgesic and serotonin releasing agent
Nitromemantine
The NMDA receptor is regulated via
- 25-Hydroxycholesterol – endogenous weak negative allosteric modulator
- Conantokins – naturally occurring negative allosteric modulators of the polyamine site found in Conus geographus[99]
Modulators
Examples
The NMDA receptor is modulated by a number of
- Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.
- NR2B-containing NMDA receptors on the synaptic membrane, thus affecting synaptic plasticity.[101][102]
- Polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.
- .
- Src kinase enhances NMDA receptor currents.[104]
- Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.[105]
- 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.[106]
- Pb2+[107] is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb2+ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.
- Proteins of the
- The activity of NMDA receptors is also strikingly sensitive to the changes in pH, and partially inhibited by the ambient concentration of H+ under physiological conditions.[111] 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."[112] 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[citation needed].
Development of NMDA receptor antagonists
The main problem with the development of NMDA antagonists for neuroprotection is that physiological NMDA receptor activity is essential for normal neuronal function. Complete blockade of all NMDA receptor activity results in side effects such as
Competitive NMDA receptor antagonists
Noncompetitive NMDA receptor antagonists
Uncompetitive NMDA receptor antagonists block within the ion channel at the Mg2+ site (pore region) and prevent excessive influx of Ca2+. Noncompetitive antagonism refers to a type of block that an increased concentration of glutamate cannot overcome, and is dependent upon prior activation of the receptor by the agonist, i.e. it only enters the channel when it is opened by agonist.[21][114]
Because of these adverse side effects of high affinity blockers, the search for clinically successful NMDA receptor antagonists for neurodegenerative diseases continued and focused on developing low affinity blockers. However the affinity could not be too low and dwell time not too short (as seen with Mg2+) where membrane depolarization relieves the block. The discovery was thereby development of uncompetitive antagonist with longer dwell time than Mg2+ in the channel but shorter than MK-801. That way the drug obtained would only block excessively open NMDA receptor associated channels but not normal neurotransmission.[21][114] Memantine is that drug. It is a derivative of amantadine which was first an anti-influenza agent but was later discovered by coincidence to have efficacy in Parkinson's disease. Chemical structures of memantine and amantadine can be seen in figure 5. The compound was first thought to be dopaminergic or anticholinergic but was later found to be an NMDA receptor antagonist.[15][21]
Memantine is the first drug approved for treatment of severe and more advanced Alzheimer's disease, which for example anticholinergic drugs do not do much good for.[114] It helps recovery of synaptic function and in that way improves impaired memory and learning.[19] In 2015 memantine is also in trials for therapeutic importance in additional neurological disorders.[98]
Many second-generation memantine derivatives have been in development that may show even better neuroprotective effects, where the main thought is to use other safe but effective modulatory sites on the NMDA receptor in addition to its associated ion channel.[98]
Structure activity relationship (SAR)
Memantine (1-amino-3,5-dimethyladamantane) is an aminoalkyl cyclohexane derivative and an atypical drug compound with non-planar, three dimensional tricyclic structure. Figure 8 shows SAR for aminoalkyl cyclohexane derivative. Memantine has several important features in its structure for its effectiveness:
- Three-ring structure with a bridgehead amine, -NH2
- The -NH2 group is protonated under physiological pH of the body to carry a positive charge, -NH3+
- Two methyl (CH3) side groups which serve to prolong the dwell time and increase stability as well as affinity for the NMDA receptor channel compared with amantadine (1-adamantanamine).[18][114]
Despite the small structural difference between memantine and amantadine, two adamantane derivatives, the affinity for the binding site of NR1/NR2B subunit is much greater for memantine. In
Second generation derivative of memantine; nitromemantine
Several derivatives of Nitromemantine, a second-generation derivative of memantine, have been synthesized in order to perform a detailed
Therapeutic application
Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and
Memantine is an example of uncompetitive NMDA receptor antagonist that has approved indication for the neurodegenerative disease Alzheimer's disease. In 2015 memantine is still in clinical trials for additional neurological diseases.[32][98]
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
Therefore, the NMDA receptor functions as a "molecular coincidence detector". Its ion channel opens only when the following two conditions are met: 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.[118]
In a
Clinical significance
NMDAR antagonists like
NMDAR-targeted compounds, including ketamine,
Research suggests that
Memantine, a low-trapping NMDAR antagonist, is approved in the United States and Europe for the treatment of moderate-to-severe Alzheimer's disease,[128] 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.[129]
Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat
Compared to dopaminergic stimulants like methamphetamine, the NMDAR antagonist phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the glutamate hypothesis of schizophrenia.[131] 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.
NMDAR antagonists, for instance
See also
- Calcium/calmodulin-dependent protein kinases
References
- ^ PMID 9115742.
Since two molecules of glutamate and glycine each are thought to be required for channel activation (3, 6), this implies that the NMDA receptor should be composed of at least four subunits.
- ^ PMID 9425000.
- PMID 24564659.
- PMID 30137779, retrieved 2024-03-04
- ^ S2CID 4400777.
- PMID 19605837.
- S2CID 4368947.
- ^ PMID 10049997.
- PMID 11775847.
- S2CID 11929361.
- ^ PMID 17088105.
- PMID 23600761.
- PMID 24844285.
- ^ PMID 16368266.
- ^ PMID 22212311.
- ^ S2CID 18376541.
- ^ S2CID 41383776.
- ^ S2CID 21379258.
- ^ PMID 14754385.
- S2CID 1417873.
- ^ PMID 15717010.
- S2CID 24726102.
- PMID 16402093.
- ^ S2CID 659716.
- ^ PMID 20842175.
- PMID 28209726.
- ^ S2CID 222210921.
- ^ PMID 23432396.
- PMID 37437688.
- ^ PMID 12493535.
- ^ PMID 17097347.
- ^ PMID 23421676.
- ISBN 978-1-60913-345-0.
- S2CID 14852616.
- S2CID 24875113.
- ^
Teng H, Cai W, Zhou L, Zhang J, Liu Q, Wang Y, et al. (October 2010). "Evolutionary mode and functional divergence of vertebrate NMDA receptor subunit 2 genes". PLOS ONE. 5 (10): e13342. PMID 20976280.
- S2CID 5164419.
- PMID 18586028.
- S2CID 18582691.
- PMID 23439125.
- PMID 29351585.
- PMID 30082915.
- PMID 24408959.
- PMID 26636753.
- ^
Liu XB, Murray KD, Jones EG (October 2004). "Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development". The Journal of Neuroscience. 24 (40): 8885–8895. PMID 15470155.
- PMID 10789248.
- PMID 17360906.
- PMID 16540573.
- S2CID 9791935.
- PMID 17881522.
- PMID 18322077.
- PMID 19244516.
- ^ PMID 24742457.
- PMID 2892896.
- ^ Henchcliffe C (2007). Handbook of Clinical Neurology. New York, NY, USA: Weill Medical College of Cornell University, Department of Neurology and Neuroscience. pp. 553–569.
- ^ S2CID 26207057.
- PMID 20720132.
- PMID 24285894.
- PMID 19625523.
- PMID 23452857.
- PMID 22325859.
- PMID 21543591.
- S2CID 7836184.
- PMID 22863013.
- PMID 22343826.
- PMID 20096331.
- PMID 21310659.
- ^ PMID 33009404.
- PMID 23535319.
- PMID 37292368.
- PMID 13443577.
- S2CID 12987037.
- PMID 31959360.
- S2CID 13505187.
- S2CID 39125762.
- ^ PMID 37437688.
- S2CID 11672391.
- PMID 18221208.
- PMID 20050189.
- ^ J. Moskal, D. Leander, R. Burch (2010). Unlocking the Therapeutic Potential of the NMDA Receptor. Drug Discovery & Development News. Retrieved 19 December 2013.
- PMID 30544218.
- ^ Anderson C (2003-06-01). "The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid DXM Vaults : Health. Retrieved 2008-12-17.
- ^ S2CID 33113283.
- ^ S2CID 31914015.
- PMID 10785653.
- S2CID 38065910.
- S2CID 2899648.
- PMID 26257776.
- PMID 10903397.
- PMID 2556719.
- S2CID 36689761.
- PMID 21677647.
- PMID 11986979.
- PMID 15634735.
- ^ Clinical trial number NCT00188383 for "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy" at ClinicalTrials.gov
- PMID 20423340.
- PMID 28616020.
- ^ S2CID 34931289.
- S2CID 25871948.
- PMID 15670959.
- PMID 17529984.
- PMID 18184784.
- PMID 16148228.
- S2CID 39275755.
- PMID 35022040.
- S2CID 6141092.
- PMID 20375082.
- ^ PMID 21135233.
- PMID 11118151.
- PMID 23959708.
- S2CID 4351139.
- S2CID 10324716.
- PMID 21204415.
- ^ PMID 15519530.
- PMID 26477507.
- ISBN 978-0-87893-697-7. Archived from the originalon 2011-09-27.
- PMID 15240809.
- ISBN 978-0-87893-697-7. Archived from the originalon 2011-09-27.
- S2CID 4344173.
- ISSN 2168-9709.
- ^ Poon L (2014). "Growing Evidence That A Party Drug Can Help Severe Depression". NPR.
- ^ Stix G (2014). "From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment". Scientific American.
- ^ PMID 19704408.
- S2CID 21953270.
- PMID 15753957.
- PMID 18221189. Archived from the originalon 2013-04-14. Retrieved 2020-04-12.
- ^ S2CID 30330824.
- PMID 16829947.
- ^ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
- ^ Todd A Hardy, Reddel, Barnett, Palace, Lucchinetti, Weinshenker, Atypical inflammatory demyelinating syndromes of the CNS, The lancet neurology, Volume 15, Issue 9, August 2016, Pages 967-981, doi: https://doi.org/10.1016/S1474-4422(16)30043-6, available at [1]
- PMID 18395805.
- PMID 31888772.
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
- Drosophila NMDA receptor 1 - The Interactive Fly