Editing NMDA receptor (section)

==Variants==

===GluN1===
There are eight variants of the [[GRIN1|GluN1]] subunit produced by alternative splicing of [[GRIN1]]:<ref name="Stephenson_2006">{{cite journal | vauthors = Stephenson FA | title = Structure and trafficking of NMDA and GABAA receptors | journal = Biochemical Society Transactions | volume = 34 | issue = Pt 5 | pages = 877–881 | date = November 2006 | pmid = 17052219 | doi = 10.1042/BST0340877 | s2cid = 24875113 }}</ref>
* 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===
[[File:Model of NR2 Subunit of NMDA receptor (vertebrate and invertebrate).jpg|thumb|NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008]]
While a single GluN2 subunit is found in [[invertebrate]] [[organism]]s, four distinct isoforms of the GluN2 subunit are expressed in [[vertebrate]]s and are referred to with the nomenclature GluN2A through GluN2D (encoded by [[GRIN2A]], [[GRIN2B]], [[GRIN2C]], [[GRIN2D]]). Strong evidence shows that the genes encoding the GluN2 subunits in vertebrates have undergone at least two rounds of [[gene duplication]].<ref name="pmid20976280">
{{cite journal | vauthors = Teng H, Cai W, Zhou L, Zhang J, Liu Q, Wang Y, Dai W, Zhao M, Sun Z | display-authors = 6 | title = Evolutionary mode and functional divergence of vertebrate NMDA receptor subunit 2 genes | journal = PLOS ONE | volume = 5 | issue = 10 | pages = e13342 | date = October 2010 | pmid = 20976280 | pmc = 2954789 | doi = 10.1371/journal.pone.0013342 | doi-access = free | bibcode = 2010PLoSO...513342T }}</ref> They contain the binding-site for [[glutamate]]. More importantly, each GluN2 subunit has a different intracellular C-terminal domain that can interact with different sets of signaling molecules.<ref name="Ryan2009">{{cite journal | vauthors = Ryan TJ, Grant SG | title = The origin and evolution of synapses | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 10 | pages = 701–712 | date = October 2009 | pmid = 19738623 | doi = 10.1038/nrn2717 | s2cid = 5164419 }}</ref> Unlike GluN1 subunits, GluN2 subunits are expressed differentially across various cell types and developmental timepoints and control the electrophysiological properties of the NMDA receptor. In classic circuits, GluN2B is mainly present in immature neurons and in extrasynaptic locations such as [[growth cone]]s,<ref name="Georgiev2008">{{cite journal | vauthors = Georgiev D, Taniura H, Kambe Y, Takarada T, Yoneda Y | title = A critical importance of polyamine site in NMDA receptors for neurite outgrowth and fasciculation at early stages of P19 neuronal differentiation | journal = Experimental Cell Research | volume = 314 | issue = 14 | pages = 2603–2617 | date = August 2008 | pmid = 18586028 | doi = 10.1016/j.yexcr.2008.06.009 }}</ref> and contains the binding-site for the selective inhibitor [[ifenprodil]].<ref name="Bunk2014">{{cite journal | vauthors = Bunk EC, König HG, Prehn JH, Kirby BP | title = Effect of the N-methyl-D-aspartate NR2B subunit antagonist ifenprodil on precursor cell proliferation in the hippocampus | journal = Journal of Neuroscience Research | volume = 92 | issue = 6 | pages = 679–691 | date = June 2014 | pmid = 24464409 | doi = 10.1002/jnr.23347 | s2cid = 18582691 | url = https://figshare.com/articles/journal_contribution/10798256 }}</ref> However, in [[pyramidal cell]] [[synapse]]s in the newly evolved primate [[dorsolateral prefrontal cortex]], GluN2B are exclusively within the [[postsynaptic density]], and mediate higher cognitive operations such as [[working memory]].<ref name="Wang2013">{{cite journal | vauthors = Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF | display-authors = 6 | title = NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex | journal = Neuron | volume = 77 | issue = 4 | pages = 736–749 | date = February 2013 | pmid = 23439125 | pmc = 3584418 | doi = 10.1016/j.neuron.2012.12.032 }}</ref> This is consistent with the expansion in GluN2B actions and expression across the cortical hierarchy in [[monkey]]s <ref name="Yang2018">{{cite journal | vauthors = Yang ST, Wang M, Paspalas CD, Crimins JL, Altman MT, Mazer JA, Arnsten AF | title = Core Differences in Synaptic Signaling Between Primary Visual and Dorsolateral Prefrontal Cortex | journal = Cerebral Cortex | volume = 28 | issue = 4 | pages = 1458–1471 | date = April 2018 | pmid = 29351585 | pmc = 6041807 | doi = 10.1093/cercor/bhx357 }}</ref> and [[human]]s <ref name="Burt2018">{{cite journal | vauthors = Burt JB, Demirtaş M, Eckner WJ, Navejar NM, Ji JL, Martin WJ, Bernacchia A, Anticevic A, Murray JD | display-authors = 6 | title = Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography | journal = Nature Neuroscience | volume = 21 | issue = 9 | pages = 1251–1259 | date = September 2018 | pmid = 30082915 | pmc = 6119093 | doi = 10.1038/s41593-018-0195-0 }}</ref> and across [[primate]] [[cerebral cortex|cortex]] [[evolution]].<ref name="Muntane2015">{{cite journal | vauthors = Muntané G, Horvath JE, Hof PR, Ely JJ, Hopkins WD, Raghanti MA, Lewandowski AH, Wray GA, Sherwood CC | display-authors = 6 | title = Analysis of synaptic gene expression in the neocortex of primates reveals evolutionary changes in glutamatergic neurotransmission | journal = Cerebral Cortex | volume = 25 | issue = 6 | pages = 1596–1607 | date = June 2015 | pmid = 24408959 | pmc = 4428301 | doi = 10.1093/cercor/bht354 }}</ref>

===GluN2B to GluN2A switch===
[[File: NR2B-NR2A switch in human cerebellum, microarrays, Bar-Shira et al 2015.png| thumb|The timecourse of GluN2B-GluN2A switch in human cerebellum. Bar-Shira et al., 2015 <ref name="pmid26636753">{{cite journal | vauthors = Bar-Shira O, Maor R, Chechik G | title = Gene Expression Switching of Receptor Subunits in Human Brain Development | journal = PLOS Computational Biology | volume = 11 | issue = 12 | pages = e1004559 | date = December 2015 | pmid = 26636753 | pmc = 4670163 | doi = 10.1371/journal.pcbi.1004559 | bibcode = 2015PLSCB..11E4559B | doi-access = free }}</ref>]]

While [[GRIN2B|GluN2B]] is predominant in the early postnatal brain, the number of GluN2A subunits increases during early development; eventually, [[GRIN2A|GluN2A]] subunits become more numerous than GluN2B. This is called the GluN2B-GluN2A developmental switch, and is notable because of the different kinetics each GluN2 subunit contributes to receptor function.<ref name="pmid15470155">
{{cite journal | vauthors = Liu XB, Murray KD, Jones EG | title = Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development | journal = The Journal of Neuroscience | volume = 24 | issue = 40 | pages = 8885–8895 | date = October 2004 | pmid = 15470155 | pmc = 6729956 | doi = 10.1523/JNEUROSCI.2476-04.2004 }}</ref> For instance, greater ratios of the GluN2B subunit leads to NMDA receptors which remain open longer compared to those with more GluN2A.<ref name="pmid10789248">{{cite journal | vauthors = Tsien JZ | title = Building a brainier mouse | journal = Scientific American | volume = 282 | issue = 4 | pages = 62–68 | date = April 2000 | pmid = 10789248 | doi = 10.1038/scientificamerican0400-62 | bibcode = 2000SciAm.282d..62T }}</ref> This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically altered '[[doogie mice]]'.
The detailed time course of this switch in the human cerebellum has been estimated using expression microarray and RNA seq and is shown in the figure on the right.

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 [[excitotoxicity|excitotoxic]] neuronal death.<ref name="pmid17360906">{{cite journal | vauthors = Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT | display-authors = 6 | title = NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo | journal = The Journal of Neuroscience | volume = 27 | issue = 11 | pages = 2846–2857 | date = March 2007 | pmid = 17360906 | pmc = 6672582 | doi = 10.1523/JNEUROSCI.0116-07.2007 }}</ref> The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.<ref name="pmid16540573">{{cite journal | vauthors = Zhou M, Baudry M | title = Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors | journal = The Journal of Neuroscience | volume = 26 | issue = 11 | pages = 2956–2963 | date = March 2006 | pmid = 16540573 | pmc = 6673978 | doi = 10.1523/JNEUROSCI.4299-05.2006 }}</ref> 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.<ref>{{cite journal | vauthors = Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim JJ, Thompson RF, Sun W, Webster LC, Grant SG, Eilers J, Konnerth A, Li J, McNamara JO, Seeburg PH | display-authors = 6 | title = Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo | journal = Cell | volume = 92 | issue = 2 | pages = 279–289 | date = January 1998 | pmid = 9458051 | doi = 10.1016/S0092-8674(00)80921-6 | s2cid = 9791935 | doi-access = free }}</ref> One study suggests that [[reelin]] may play a role in the NMDA receptor maturation by increasing the GluN2B subunit mobility.<ref name="pmid17881522">{{cite journal | vauthors = Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P | title = NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin | journal = The Journal of Neuroscience | volume = 27 | issue = 38 | pages = 10165–10175 | date = September 2007 | pmid = 17881522 | pmc = 6672660 | doi = 10.1523/JNEUROSCI.1772-07.2007 }}</ref>

===GluN2B to GluN2C switch===
Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division<ref name="pmid18322077">{{cite journal | vauthors = Espinosa JS, Luo L | title = Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells | journal = The Journal of Neuroscience | volume = 28 | issue = 10 | pages = 2301–2312 | date = March 2008 | pmid = 18322077 | pmc = 2586640 | doi = 10.1523/JNEUROSCI.5157-07.2008 }}</ref> 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.<ref name="pmid19244516">{{cite journal | vauthors = Gajendran N, Kapfhammer JP, Lain E, Canepari M, Vogt K, Wisden W, Brenner HR | title = Neuregulin signaling is dispensable for NMDA- and GABA(A)-receptor expression in the cerebellum in vivo | journal = The Journal of Neuroscience | volume = 29 | issue = 8 | pages = 2404–2413 | date = February 2009 | pmid = 19244516 | pmc = 6666233 | doi = 10.1523/JNEUROSCI.4303-08.2009 }}</ref>