NMDA receptor
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2008-06-20T17:52:23Z
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[[Image:Nmda.png|thumb|[[NMDA]]]]
[[Image:L-glutamic-acid-skeletal.png|thumb|170px|[[Glutamic acid]]]]
{{portalpar|Neuroscience|Neuro logo.png}}
[[Image:Activated NMDAR.PNG|right|thumb|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.<ref name="Laube ">{{cite journal | last =Laube | first =B | authorlink = | coauthors =Hirai H, Sturgess M, Betz H, and Kuhse J | title =Molecular determinants of agonist discrimination by NMDA receptor subunits: Analysis of the glutamate binding site on the NR2B subunit | journal =Neuron | volume =18 | issue = 3| pages =493–503 | publisher = | date =1997 | url = | doi = | pmid =9115742 | accessdate =2007-01-17 }} </ref>]]{{protein
| Name = [[GRIN1|glutamate receptor, ionotropic, N-methyl D-aspartate 1]]
| caption =
| image =
| width =
| HGNCid = 4584
| Symbol = GRIN1
| AltSymbols = NMDAR1
| EntrezGene = 2902
| OMIM = 138249
| RefSeq = NM_021569
| UniProt = Q05586
| PDB =
| ECnumber =
| Chromosome = 9
| Arm = q
| Band = 34.3
| LocusSupplementaryData =
}}
{{protein
| Name = [[GRIN2A|glutamate receptor, ionotropic, N-methyl D-aspartate 2A]]
| caption =
| image =
| width =
| HGNCid = 4585
| Symbol = GRIN2A
| AltSymbols = NMDAR2A
| EntrezGene = 2903
| OMIM = 138253
| RefSeq = NM_000833
| UniProt = Q12879
| PDB =
| ECnumber =
| Chromosome = 16
| Arm = p
| Band = 13.2
| LocusSupplementaryData =
}}
{{protein
| Name = [[GRIN2B|glutamate receptor, ionotropic, N-methyl D-aspartate 2B]]
| caption =
| image =
| width =
| HGNCid = 4586
| Symbol = GRIN2B
| AltSymbols = NMDAR2B
| EntrezGene = 2904
| OMIM = 138252
| RefSeq = NM_000834
| UniProt = Q13224
| PDB =
| ECnumber =
| Chromosome = 12
| Arm = p
| Band = 12
| LocusSupplementaryData =
}}
{{protein
| Name = [[GRIN2C|glutamate receptor, ionotropic, N-methyl D-aspartate 2C]]
| caption =
| image =
| width =
| HGNCid = 4587
| Symbol = GRIN2C
| AltSymbols = NMDAR2C
| EntrezGene = 2905
| OMIM = 138254
| RefSeq = NM_000835
| UniProt = Q14957
| PDB =
| ECnumber =
| Chromosome = 17
| Arm = q
| Band = 24
| LocusSupplementaryData = -q25
}}
{{protein
| Name = [[GRIN2D|glutamate receptor, ionotropic, N-methyl D-aspartate 2D]]
| caption =
| image =
| width =
| HGNCid = 4588
| Symbol = GRIN2D
| AltSymbols = NMDAR2D
| EntrezGene = 2906
| OMIM = 602717
| RefSeq = NM_000836
| UniProt = O15399
| PDB =
| ECnumber =
| Chromosome = 19
| Arm = q
| Band = 13.1
| LocusSupplementaryData = -qter
}}
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 [[ion|cations]]. This allows flow of Na<sup>+</sup> and small amounts of Ca<sup>2+</sup> ions into the cell and K<sup>+</sup> 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_ion_channel|ligand-gated]] and voltage-dependent.
==Structure==
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.<ref name=Stephenson>{{cite journal | author=Stephenson FA | title=Structure and trafficking of NMDA and GABAA receptors | journal=Biochem Soc Trans. | date= 2006 Nov | volume=34 | pages=877–81 | doi=10.1042/BST0340877}}</ref> A related [[gene]] family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor [[isoform]]s 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 (biology)|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.
==Variants==
===NR1===
There are eight variants of the [[GRIN1|NR1]] subunit produced by alternative splicing of {{Gene|GRIN1}}:<!--
---><ref name="Stephenson_2006_NMDA_GABA_structure">Stephenson FA. (2006)
''Structure and trafficking of NMDA and GABAA receptors.'' Biochem Soc Trans. 2006 Nov;34 (Pt 5):877-81. PMID 17052219 [http://www.biochemsoctrans.org/bst/034/0877/0340877.pdf free fulltext pdf]</ref><!--
--->
* 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===
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 [[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 [[GRIN2B|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.<!--
--><ref name="Liu_2004_NR2_switch">Liu XB, Murray KD, Jones EG.(2004) ''Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development.'' The Journal of Neuroscience, 24(40):8885-95.PMID 15470155[http://www.jneurosci.org/cgi/content/full/24/40/8885 free fulltext]</ref><!--
--> 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 [[excitotoxicity|excitotoxic]] neuronal death.<!--
--><ref name="Liu_2007_NR2_excitotoxicity">Y. Liu, T. P. Wong, M. Aarts, A. Rooyakkers, L. Liu, T. W. Lai, D. C. Wu, J. Lu, M. Tymianski, A. M. Craig, and Y. T. Wang (2007) ''NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo'' J. Neurosci., March 14, 2007; 27(11): 2846 - 2857. PMID 17360906 </ref><!--
--> The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.<!--
--><ref name="Zhou_2006_NR2_excitotoxicity">Miou Zhou, Michel Baudry (2006) ''Developmental Changes in NMDA Neurotoxicity Reflect Developmental changes in Subunit Composition of NMDA Receptors''The Journal of Neuroscience, March 15, 2006, 26(11):2956-2963; doi:10.1523/JNEUROSCI.4299-05.2006 PMID 16540573 [http://www.jneurosci.org/cgi/content/full/26/11/2956 free fulltext]
</ref><!--
--> 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.
==Agonists==
Activation of NMDA receptors requires binding of [[glutamic acid|glutamate]] or [[aspartic acid|aspartate]] (aspartate does not stimulate the receptors as strongly.<ref>Philip E. Chen, Matthew T. Geballe, Phillip J. Stansfeld, Alexander R. Johnston, Hongjie Yuan, Amanda L. Jacob, James P. Snyder, Stephen F. Traynelis, and David J. A. Wyllie. 2005. [http://molpharm.aspetjournals.org/cgi/content/full/67/5/1470 Structural Features of the Glutamate Binding Site in Recombinant NR1/NR2A N-Methyl-D-aspartate Receptors Determined by Site-Directed Mutagenesis and Molecular Modeling]. ''Molecular Pharmacology''. Volume 67, Pages 1470-1484.</ref>) In addition, NMDARs also require the binding of the [[agonist|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]] 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 [[Mg ion (physiology)|Mg<sup>2+</sup>]] 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|Antagonists]]==
{{main|NMDA Receptor Antagonists}}
[[NMDA Receptor Antagonists]] are used as [[anesthetics]] for animals and sometimes humans, and are often used as [[recreational drug]]s 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.<ref>Anderson C. [http://www.erowid.org/chemicals/dxm/dxm_health2.shtml "The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment"]. Erowid.org, June 2003</ref>
Common NMDA Receptor Antagonists include:
* [[Memantine]]
* [[Amantadine]]<ref>[http://www.clinicaltrials.gov/ct/show/NCT00188383?order=4 "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy"], University Health Network, Toronto, September 2005</ref>
* [[Dextromethorphan]]
* [[Dextrorphan]]
* [[Ethanol]]
* [[Ibogaine]]<ref>Popik P, Layer RT, Skolnick P (1994): "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex." Psychopharmacology (Berl), 114(4), 672-4. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7531855&query_hl=20&itool=pubmed_docsum Abstract]</ref>
* [[Ketamine]]
* [[Nitrous oxide]]
* [[Phencyclidine]]
* [[Tramadol]]
* [[Methadone]]
==Modulators==
The NMDA receptor is modulated by a number of [[endogenous]] and [[exogenous]] compounds.<!--
---><ref name="NMDA_Receptor_Modulation_2005">Huggins DJ, Grant GH. (2005) The function of the amino terminal domain in NMDA receptor modulation..'' J Mol Graph Model. 2005 Jan;23(4):381-8 PMID 15670959 </ref><!--
--->:
* [[Mg ion (physiology)|Mg<sup>2+</sup>]] not only [[channel block|blocks]] the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive [[membrane potential]]s. Magnesium treatment has been used to produce rapid recovery from depression.<!--
---><ref name="Eby_2006_Mg">Eby GA, Eby KL. (2006) ''Rapid recovery from major depression using magnesium treatment.'' Med Hypotheses. 2006;67(2):362-70 PMID 16542786 </ref><!--
--->
* [[Sodium|Na<sup>+</sup>]], [[K ion (physiology)|K<sup>+</sup>]] and [[Ca ion (physiology)|Ca<sup>2+</sup>]] not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.
* [[Zinc#Biological role|Zn<sup>2+</sup>]] 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 ion (physiology)|H<sup>+</sup>]] concentration, and partially inhibited by the ambient concentration of H<sup>+</sup> under physiological conditions. The level of inhibition by H<sup>+</sup> 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.<ref> Aizenman, E., S.A. Lipton and R.H. Loring. Selective modulation of NMDA induced responses by reduction and oxidation. Neuron 1989;2:1257-1263.</ref>
==Role==
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 [[physiology|physiologic]] and [[pathology|pathologic]] processes. The role of the NMDA receptor in general, with regard to [[synaptic plasticity]], can be described as coincidence detection.
==See also==
*[[Long-term potentiation]]
*[[:Category:NMDA receptor antagonists|Category: NMDA receptor antagonists]]
*[[NMDA]]
*[[AMPA]]
*[[AMPA receptor]]
*[[Ca2+/calmodulin-dependent protein kinase|Calcium/calmodulin-dependent protein kinases]]
==References==
{{Reflist|2}}
==External links==
* {{cite journal |author=Liu Y, Zhang J |title=Recent development in NMDA receptors |journal=Chin. Med. J. |volume=113 |issue=10 |pages=948–56 |year=2000 |pmid=11775847 |doi=}}
* {{cite journal |author=Dingledine R, Borges K, Bowie D, Traynelis SF |title=The glutamate receptor ion channels |journal=Pharmacol. Rev. |volume=51 |issue=1 |pages=7–61 |year=1999 |pmid=10049997 |doi=}}
*[http://www.bris.ac.uk/Depts/Synaptic/info/pharmacology/NMDA.html NMDA receptor pharmacology]
*[http://www.jneurosci.org/cgi/content/full/16/24/7859 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]
* [http://www.jneurosci.org/cgi/content-nw/full/24/40/8885/FIG8 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<ref name="Liu_2004_NR2_switch"/>
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