Editing NMDA receptor (section)

==Role in excitotoxicity==
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NMDA receptors have been implicated by a number of studies to be strongly involved with [[excitotoxicity]].<ref name=":0" /><ref name="pmid2892896">{{cite journal | vauthors = Choi DW, Koh JY, Peters S | title = Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists | journal = The Journal of Neuroscience | volume = 8 | issue = 1 | pages = 185–196 | date = January 1988 | pmid = 2892896 | pmc = 6569373 | doi = 10.1523/JNEUROSCI.08-01-00185.1988 }}</ref><ref>{{Cite book|title=Handbook of Clinical Neurology| vauthors = Henchcliffe C |publisher=Weill Medical College of Cornell University, Department of Neurology and Neuroscience|year=2007|location=New York, NY, USA|pages=553–569}}</ref> Because NMDA receptors play an important role in the health and function of [[neuron]]s, there has been much discussion on how these receptors can affect both cell survival and cell death.<ref name=":2">{{cite journal | vauthors = Hardingham GE, Bading H | title = The Yin and Yang of NMDA receptor signalling | journal = Trends in Neurosciences | volume = 26 | issue = 2 | pages = 81–89 | date = February 2003 | pmid = 12536131 | doi = 10.1016/s0166-2236(02)00040-1 | s2cid = 26207057 }}</ref> Recent evidence supports the hypothesis that overstimulation of [[extrasynaptic NMDA receptor]]s has more to do with excitotoxicity than stimulation of their [[Synapse|synaptic]] counterparts.<ref name=":0" /><ref name="pmid11953750"/> In addition, while stimulation of [[extrasynaptic NMDA receptor]]s 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".<ref name=":0" /><ref name=":2" />

===Differing cascade pathways===
In order to support the localization hypothesis, it would be necessary to show differing [[Cell signaling|cellular signaling pathways]] are activated by NMDA receptors based on its location within the cell membrane.<ref name=":0" /> 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.<ref name="pmid20720132">{{cite journal | vauthors = Xia P, Chen HS, Zhang D, Lipton SA | title = Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses | journal = The Journal of Neuroscience | volume = 30 | issue = 33 | pages = 11246–11250 | date = August 2010 | pmid = 20720132 | pmc = 2932667 | doi = 10.1523/JNEUROSCI.2488-10.2010 }}</ref> Many of these pathways use the same [[Protein targeting|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 ([[p38 mitogen-activated protein kinases|p38MAPK]]). Extrasynaptic stimulation NMDARs regulated p38MAPK in the opposite fashion, causing an increase in intracellular concentration.<ref name="WangBriz2013">{{cite journal | vauthors = Wang Y, Briz V, Chishti A, Bi X, Baudry M | title = Distinct roles for μ-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration | journal = The Journal of Neuroscience | volume = 33 | issue = 48 | pages = 18880–18892 | date = November 2013 | pmid = 24285894 | pmc = 3841454 | doi = 10.1523/JNEUROSCI.3293-13.2013 }}</ref><ref name="pmid19625523">{{cite journal | vauthors = Xu J, Kurup P, Zhang Y, Goebel-Goody SM, Wu PH, Hawasli AH, Baum ML, Bibb JA, Lombroso PJ | display-authors = 6 | title = Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP | journal = The Journal of Neuroscience | volume = 29 | issue = 29 | pages = 9330–9343 | date = July 2009 | pmid = 19625523 | pmc = 2737362 | doi = 10.1523/JNEUROSCI.2212-09.2009 }}</ref> Experiments of this type have since been repeated with the results indicating these differences stretch across many pathways linked to cell survival and excitotoxicity.<ref name=":0" />

Two specific proteins have been identified as a major pathway responsible for these different cellular responses [[extracellular signal-regulated kinases|ERK1/2]], and Jacob.<ref name=":0" /> ERK1/2 is responsible for phosphorylation of Jacob when excited by synaptic NMDARs. This information is then [[Nuclear transport|transported to the nucleus]]. Phosphorylation of Jacob does not take place with extrasynaptic NMDA stimulation. This allows the [[transcription factor]]s in the nucleus to respond differently based in the phosphorylation state of Jacob.<ref name="KarpovaMikhaylova2013">{{cite journal | vauthors = Karpova A, Mikhaylova M, Bera S, Bär J, Reddy PP, Behnisch T, Rankovic V, Spilker C, Bethge P, Sahin J, Kaushik R, Zuschratter W, Kähne T, Naumann M, Gundelfinger ED, Kreutz MR | display-authors = 6 | title = Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus | journal = Cell | volume = 152 | issue = 5 | pages = 1119–1133 | date = February 2013 | pmid = 23452857 | doi = 10.1016/j.cell.2013.02.002 | doi-access = free }}</ref>

===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.<ref>{{cite journal | vauthors = Hunt DL, Castillo PE | title = Synaptic plasticity of NMDA receptors: mechanisms and functional implications | journal = Current Opinion in Neurobiology | volume = 22 | issue = 3 | pages = 496–508 | date = June 2012 | pmid = 22325859 | pmc = 3482462 | doi = 10.1016/j.conb.2012.01.007 }}</ref>  Experimental data suggest that extrasynaptic NMDA receptors inhibit LTP while producing LTD.<ref name="pmid21543591">{{cite journal | vauthors = Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ | title = Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors | journal = The Journal of Neuroscience | volume = 31 | issue = 18 | pages = 6627–6638 | date = May 2011 | pmid = 21543591 | pmc = 3100898 | doi = 10.1523/JNEUROSCI.0203-11.2011 }}</ref> Inhibition of LTP can be prevented with the introduction of a [[NMDA receptor antagonist|NMDA antagonist]].<ref name=":0" /> A [[Transcranial magnetic stimulation|theta burst stimulation]] that usually induces LTP with synaptic NMDARs, when applied selectively to extrasynaptic NMDARs produces a LTD.<ref name="LiuYang2013">{{cite journal | vauthors = Liu DD, Yang Q, Li ST | title = Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons | journal = Brain Research Bulletin | volume = 93 | pages = 10–16 | date = April 2013 | pmid = 23270879 | doi = 10.1016/j.brainresbull.2012.12.003 | s2cid = 7836184 }}</ref> 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.<ref name="PapouinLadépêche2012">{{cite journal | vauthors = Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, Groc L, Pollegioni L, Mothet JP, Oliet SH | display-authors = 6 | title = Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists | journal = Cell | volume = 150 | issue = 3 | pages = 633–646 | date = August 2012 | pmid = 22863013 | doi = 10.1016/j.cell.2012.06.029 | doi-access = free | hdl = 11383/1788727 | hdl-access = free }}</ref>

===Role of differing subunits===
Another factor that seems to affect NMDAR induced toxicity is the observed variation in [[Protein subunit|subunit]] makeup. NMDA receptors are heterotetramers with two GluN1 subunits and two variable subunits.<ref name=":0" /><ref>{{cite journal | vauthors = Sanz-Clemente A, Nicoll RA, Roche KW | title = Diversity in NMDA receptor composition: many regulators, many consequences | journal = The Neuroscientist | volume = 19 | issue = 1 | pages = 62–75 | date = February 2013 | pmid = 22343826 | pmc = 3567917 | doi = 10.1177/1073858411435129 }}</ref> 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.<ref name="pmid20096331">{{cite journal | vauthors = Petralia RS, Wang YX, Hua F, Yi Z, Zhou A, Ge L, Stephenson FA, Wenthold RJ | display-authors = 6 | title = Organization of NMDA receptors at extrasynaptic locations | journal = Neuroscience | volume = 167 | issue = 1 | pages = 68–87 | date = April 2010 | pmid = 20096331 | pmc = 2840201 | doi = 10.1016/j.neuroscience.2010.01.022 }}</ref><ref name="pmid21310659">{{cite journal | vauthors = Lai TW, Shyu WC, Wang YT | title = Stroke intervention pathways: NMDA receptors and beyond | journal = Trends in Molecular Medicine | volume = 17 | issue = 5 | pages = 266–275 | date = May 2011 | pmid = 21310659 | doi = 10.1016/j.molmed.2010.12.008 }}</ref> t-NMDA receptors have been implicated in excitotoxicity-mediated death of neurons in [[temporal lobe epilepsy]].<ref name=":3">{{cite journal | vauthors = Beesley S, Sullenberger T, Crotty K, Ailani R, D'Orio C, Evans K, Ogunkunle EO, Roper MG, Kumar SS | display-authors = 6 | title = D-serine mitigates cell loss associated with temporal lobe epilepsy | journal = Nature Communications | volume = 11 | issue = 1 | pages = 4966 | date = October 2020 | pmid = 33009404 | pmc = 7532172 | doi = 10.1038/s41467-020-18757-2 | bibcode = 2020NatCo..11.4966B }}</ref>

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.<ref name=":0">{{cite journal | vauthors = Parsons MP, Raymond LA | title = Extrasynaptic NMDA receptor involvement in central nervous system disorders | journal = Neuron | volume = 82 | issue = 2 | pages = 279–293 | date = April 2014 | pmid = 24742457 | doi = 10.1016/j.neuron.2014.03.030 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Fourie C, Li D, Montgomery JM | title = The anchoring protein SAP97 influences the trafficking and localisation of multiple membrane channels | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1838 | issue = 2 | pages = 589–594 | date = February 2014 | pmid = 23535319 | doi = 10.1016/j.bbamem.2013.03.015 | doi-access = free }}</ref> 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.<ref name=":0" /> The subunit composition of ''t''-NMDA receptors has recently been visualized in brain tissue.<ref>{{cite journal | vauthors = Beesley S, Gunjan A, Kumar SS | title = Visualizing the triheteromeric N-methyl-D-aspartate receptor subunit composition | journal = Frontiers in Synaptic Neuroscience | volume = 15 | pages = 1156777 | date = 2023 | pmid = 37292368 | pmc = 10244591 | doi = 10.3389/fnsyn.2023.1156777 | doi-access = free }}</ref>

===Excitotoxicity in a clinical setting===
Excitotoxicity has been thought to play a role in the degenerative properties of [[Neurodegeneration|neurodegenerative]] conditions since the late 1950s.<ref>{{cite journal | vauthors = Lucas DR, Newhouse JP | title = The toxic effect of sodium L-glutamate on the inner layers of the retina | journal = A.M.A. Archives of Ophthalmology | volume = 58 | issue = 2 | pages = 193–201 | date = August 1957 | pmid = 13443577 | doi = 10.1001/archopht.1957.00940010205006 }}</ref> NMDA receptors seem to play an important role in many of these degenerative diseases affecting the brain. Most notably, excitotoxic events involving NMDA receptors have been linked to Alzheimer's disease and Huntington's disease, as well as with other medical conditions such as strokes and epilepsy.<ref name=":0" /><ref name="pmid20152125">{{cite journal | vauthors = Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden MR, Murphy TH, Raymond LA | display-authors = 6 | title = Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice | journal = Neuron | volume = 65 | issue = 2 | pages = 178–190 | date = January 2010 | pmid = 20152125 | doi = 10.1016/j.neuron.2010.01.008 | s2cid = 12987037 | doi-access = free }}</ref> Treating these conditions with one of the many known NMDA receptor antagonists, however, leads to a variety of unwanted side effects, some of which can be severe. These side effects are, in part, observed because the NMDA receptors do not just signal for cell death but also play an important role in its vitality.<ref name=":2" /> Treatment for these conditions might be found in blocking NMDA receptors not found at the synapse.<ref name=":0" /><ref name=":4"/> One class of excitotoxicity in disease includes gain-of-function mutations in GRIN2B and GRIN1 associated with cortical malformations, such as [[polymicrogyria]].<ref>{{cite journal | vauthors = Smith RS, Walsh CA | title = Ion Channel Functions in Early Brain Development | journal = Trends in Neurosciences | volume = 43 | issue = 2 | pages = 103–114 | date = February 2020 | pmid = 31959360 | pmc = 7092371 | doi = 10.1016/j.tins.2019.12.004 }}</ref> D-serine, an antagonist/inverse co-agonist of ''t''-NMDA receptors, which is made in the brain, has been shown to mitigate neuron loss in an animal model of [[temporal lobe epilepsy]].<ref name=":3" />