Editing NMDA receptor (section)

===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>