Editing NMDA receptor (section)

===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>