Editing NMDA receptor (section)

{{Short description|Glutamate receptor and ion channel protein found in nerve cells}}
{{Redirect|NR1|the submarine|NR-1}}
{{distinguish|NDMA (disambiguation)}}

[[File:Activated NMDAR.svg|right|thumb|Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site. The [[allosteric site]], which modulates receptor function when bound to a ligand, is not occupied. NMDARs require the binding of two molecules of [[glutamate]] or [[aspartate]] and two of [[glycine]]<ref name="Laube">{{cite journal | vauthors = Laube B, Hirai H, Sturgess M, Betz H, 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 | date = March 1997 | pmid = 9115742 | doi = 10.1016/S0896-6273(00)81249-0 | quote = 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. | doi-access = free }}</ref><ref name="Anson">{{cite journal | vauthors = Anson LC, Chen PE, Wyllie DJ, Colquhoun D, Schoepfer R | title = Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors | journal = The Journal of Neuroscience | volume = 18 | issue = 2 | pages = 581–589 | date = January 1998 | pmid = 9425000 | pmc = 6792534 | doi = 10.1523/JNEUROSCI.18-02-00581.1998 }}</ref>]]

The '''''N''-methyl-<small>D</small>-aspartate''' '''receptor''' (also known as the '''NMDA receptor''' or '''NMDAR'''), is a [[glutamate receptor]] and predominantly Ca<sup>2+</sup> [[ion channel]] found in [[neuron]]s.<ref>{{Cite journal |last1=Vyklicky |first1=V. |last2=Korinek |first2=M. |last3=Smejkalova |first3=T. |last4=Balik |first4=A. |last5=Krausova |first5=B. |last6=Kaniakova |first6=M. |last7=Lichnerova |first7=K. |last8=Cerny |first8=J. |last9=Krusek |first9=J. |last10=Dittert |first10=I. |last11=Horak |first11=M. |last12=Vyklicky |first12=L. |date=2014 |title=Structure, function, and pharmacology of NMDA receptor channels |journal=Physiological Research |volume=63 |issue=Suppl 1 |pages=S191–203 |doi=10.33549/physiolres.932678 |issn=1802-9973 |pmid=24564659|doi-access=free }}</ref><ref>{{Citation |last1=Jewett |first1=Benjamin E. |title=Physiology, NMDA Receptor |date=2024 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK519495/ |access-date=2024-03-04 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30137779 |last2=Thapa |first2=Bicky}}</ref> The NMDA receptor is one of three types of [[ionotropic glutamate receptor]]s, the other two being [[AMPA receptor|AMPA]] and [[kainate receptor]]s. Depending on its subunit composition, its [[Ligand (biochemistry)|ligands]] are [[Glutamate (neurotransmitter)|glutamate]] and [[glycine]] (or [[D-Serine|<small>D</small>-serine]]). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by [[Magnesium|Mg<sup>2+</sup>]] ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows [[cation|positively charged ions]] (cations) to flow through the [[cell membrane]].<ref name="Furukawa"/> The NMDA receptor is thought to be very important for controlling [[synaptic plasticity]] and mediating [[learning]] and [[memory]] functions.<ref name="pmid19605837">{{cite journal | vauthors = Li F, Tsien JZ | title = Memory and the NMDA receptors | journal = The New England Journal of Medicine | volume = 361 | issue = 3 | pages = 302–303 | date = July 2009 | pmid = 19605837 | pmc = 3703758 | doi = 10.1056/NEJMcibr0902052 }}</ref>

The NMDA receptor is [[ionotropic]], meaning it is a protein which allows the passage of ions through the cell membrane.<ref name="pmid1834949">{{cite journal | vauthors = Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S | title = Molecular cloning and characterization of the rat NMDA receptor | journal = Nature | volume = 354 | issue = 6348 | pages = 31–37 | date = November 1991 | pmid = 1834949 | doi = 10.1038/354031a0 | s2cid = 4368947 | bibcode = 1991Natur.354...31M }}</ref> The NMDA receptor is so named because the [[agonist]] molecule [[N-methyl-D-aspartate|''N''-methyl-<small>D</small>-aspartate]] (NMDA) binds selectively to it, and not to other [[glutamate receptor]]s. Activation of NMDA receptors results in the opening of the ion channel that is nonselective to [[ion|cations]], with a combined [[reversal potential]] near 0&nbsp;mV. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage-dependent. Specifically located on the receptor, extracellular magnesium (Mg<sup>2+</sup>) and zinc (Zn<sup>2+</sup>) ions can bind and prevent other cations from flowing through the open ion channel. A voltage-dependent flow of predominantly calcium (Ca<sup>2+</sup>), sodium (Na<sup>+</sup>), and potassium (K<sup>+</sup>) ions into and out of the cell is made possible by the depolarization of the cell, which displaces and repels the Mg<sup>2+</sup> and Zn<sup>2+</sup> ions from the pore.<ref name="pmid10049997">{{cite journal | vauthors = Dingledine R, Borges K, Bowie D, Traynelis SF | title = The glutamate receptor ion channels | journal = Pharmacological Reviews | volume = 51 | issue = 1 | pages = 7–61 | date = March 1999 | doi = 10.1016/S0031-6997(24)01394-2 | pmid = 10049997 | url = http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10049997 | archive-date = 2020-10-27 | access-date = 2008-12-17 | archive-url = https://web.archive.org/web/20201027013532/https://pharmrev.aspetjournals.org/content/51/1/7.long | url-status = dead | url-access = subscription }}</ref><ref name="pmid11775847">{{cite journal | vauthors = Liu Y, Zhang J | title = Recent development in NMDA receptors | journal = Chinese Medical Journal | volume = 113 | issue = 10 | pages = 948–956 | date = October 2000 | pmid = 11775847 }}</ref><ref name="pmid11399431">{{cite journal | vauthors = Cull-Candy S, Brickley S, Farrant M | title = NMDA receptor subunits: diversity, development and disease | journal = Current Opinion in Neurobiology | volume = 11 | issue = 3 | pages = 327–335 | date = June 2001 | pmid = 11399431 | doi = 10.1016/S0959-4388(00)00215-4 | s2cid = 11929361 }}</ref><ref name="pmid17088105">{{cite journal | vauthors = Paoletti P, Neyton J | title = NMDA receptor subunits: function and pharmacology | journal = Current Opinion in Pharmacology | volume = 7 | issue = 1 | pages = 39–47 | date = February 2007 | pmid = 17088105 | doi = 10.1016/j.coph.2006.08.011 | url = https://hal.archives-ouvertes.fr/hal-00115220/file/PaolettiNeyton_Curr_Op_Pharmacol_main_text_020806.pdf }}</ref> Ca<sup>2+</sup> flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca<sup>2+</sup> ions.

Activity of the NMDA receptor is blocked by many [[psychoactive]] drugs such as [[phencyclidine]] (PCP), [[Alcohol (drug)|alcohol]] ([[ethanol]]) and [[dextromethorphan]] (DXM).<ref>{{Citation |last1=Journey |first1=Jonathan D. |title=Dextromethorphan Toxicity |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK538502/ |access-date=2025-03-25 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30860737 |last2=Agrawal |first2=Suneil |last3=Stern |first3=Evan}}</ref> The [[anaesthetic]] and [[analgesic]] effects of the drugs [[ketamine]] and [[nitrous oxide]] are also partially due to their effects at blocking NMDA receptor activity. In contrast, overactivation of NMDAR by NMDA agonists increases the [[cytosol]]ic concentrations of [[calcium]] and [[zinc]], which significantly contributes to [[Neuron|neural]] [[Neurodegeneration|death]], an effect known to be prevented by [[cannabinoid]]s, mediated by activation of the [[Cannabinoid receptor type 1|CB<sub>1</sub> receptor]], which leads [[HINT1]] protein to counteract the toxic effects of NMDAR-mediated [[Nitric oxide|NO]] production and zinc release.<ref>{{cite journal | vauthors = Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J | title = Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate | journal = Antioxidants & Redox Signaling | volume = 19 | issue = 15 | pages = 1766–1782 | date = November 2013 | pmid = 23600761 | pmc = 3837442 | doi = 10.1089/ars.2012.5100 }}</ref> As well as preventing [[methamphetamine]]-induced [[neurotoxicity]] via inhibition of [[nitric oxide synthase]] (nNOS) expression and [[astrocyte]] activation, it is seen to reduce methamphetamine induced brain damage through CB1-dependent and independent mechanisms, respectively, and inhibition of methamphetamine induced [[astrogliosis]] is likely to occur through a [[Cannabinoid receptor type 2|CB<sub>2</sub> receptor]] dependent mechanism for [[Tetrahydrocannabinol|THC]].<ref>{{cite journal | vauthors = Castelli MP, Madeddu C, Casti A, Casu A, Casti P, Scherma M, Fattore L, Fadda P, Ennas MG | display-authors = 6 | title = Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity | journal = PLOS ONE | volume = 9 | issue = 5 | pages = e98079 | date = 2014-05-20 | pmid = 24844285 | pmc = 4028295 | doi = 10.1371/journal.pone.0098079 | doi-access = free | bibcode = 2014PLoSO...998079C }}</ref> Since 1989, [[memantine]] has been recognized to be an [[uncompetitive antagonist]] of the NMDA receptor, entering the channel of the receptor after it has been activated and thereby blocking the flow of ions.<ref name="Johnson">{{cite journal | vauthors = Johnson JW, Kotermanski SE | title = Mechanism of action of memantine | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 61–67 | date = February 2006 | pmid = 16368266 | doi = 10.1016/j.coph.2005.09.007 }}</ref><ref name="Dominguez">{{cite journal | vauthors = Dominguez E, Chin TY, Chen CP, Wu TY | title = Management of moderate to severe Alzheimer's disease: focus on memantine | journal = Taiwanese Journal of Obstetrics & Gynecology | volume = 50 | issue = 4 | pages = 415–423 | date = December 2011 | pmid = 22212311 | doi = 10.1016/j.tjog.2011.10.004 | doi-access = free }}</ref><ref name="Chen">{{cite journal | vauthors = Chen HS, Lipton SA | title = The chemical biology of clinically tolerated NMDA receptor antagonists | journal = Journal of Neurochemistry | volume = 97 | issue = 6 | pages = 1611–1626 | date = June 2006 | pmid = 16805772 | doi = 10.1111/j.1471-4159.2006.03991.x | s2cid = 18376541 | doi-access = free }}</ref>

Overactivation of the receptor, causing excessive influx of Ca<sup>2+</sup> 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.<ref name="Chen" /><ref name="Kemp">{{cite journal | vauthors = Kemp JA, McKernan RM | title = NMDA receptor pathways as drug targets | journal = Nature Neuroscience | volume = 5 | issue = 11 | pages = 1039–1042 | date = November 2002 | pmid = 12403981 | doi = 10.1038/nn936 | s2cid = 41383776 }}</ref><ref name="Lipton1">{{cite journal | vauthors = Lipton SA | title = Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond | journal = Nature Reviews. Drug Discovery | volume = 5 | issue = 2 | pages = 160–170 | date = February 2006 | pmid = 16424917 | doi = 10.1038/nrd1958 | s2cid = 21379258 }}</ref><ref name="Koch">{{cite journal | vauthors = Koch HJ, Szecsey A, Haen E | title = NMDA-antagonism (memantine): an alternative pharmacological therapeutic principle in Alzheimer's and vascular dementia | journal = Current Pharmaceutical Design | volume = 10 | issue = 3 | pages = 253–259 | date = 1 January 2004 | pmid = 14754385 | doi = 10.2174/1381612043386392 }}</ref> However, hypofunction of NMDA receptors (due to [[glutathione]] deficiency or other causes) may be involved in impairment of synaptic plasticity<ref name="pmid16330153">{{cite journal | vauthors = Steullet P, Neijt HC, Cuénod M, Do KQ | title = Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia | journal = Neuroscience | volume = 137 | issue = 3 | pages = 807–819 | date = February 2006 | pmid = 16330153 | doi = 10.1016/j.neuroscience.2005.10.014 | s2cid = 1417873 }}</ref> and could have other negative repercussions. The main problem with the utilization of [[NMDA receptor antagonist]]s 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.<ref name="Lipton2">{{cite journal | vauthors = Lipton SA | title = Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults | journal = NeuroRx | volume = 1 | issue = 1 | pages = 101–110 | date = January 2004 | pmid = 15717010 | pmc = 534915 | doi = 10.1602/neurorx.1.1.101 }}</ref>

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