Editing AMPA receptor (section)

===Subunit composition===
AMPARs are composed of four types of subunits encoded by different genes, designated as ''[[GRIA1]]'' (GluA1 or GluR1), ''[[GRIA2]]'' (GluA2 or GluR2), ''[[GRIA3]]'' (GluA3 or GluR3), and ''[[GRIA4]]'' (GluA4 or GluRA-D2), which combine to form [[tetramer protein|a tetrameric structure]].<ref>{{cite web|url=http://www.bris.ac.uk/Depts/Synaptic/info/glutamate.html |title=Glutamate receptors: Structures and functions. University of Bristol Centre for Synaptic Plasticity. |access-date=2007-09-02 |archive-url=https://web.archive.org/web/20070915085831/http://www.bris.ac.uk/Depts/Synaptic/info/glutamate.html |archive-date=15 September 2007 }}</ref><ref name="pmid10364548">{{cite journal|author6-link=Karel Svoboda (scientist) | vauthors = Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R | title = Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation | journal = Science | volume = 284 | issue = 5421 | pages = 1811–6 | date = June 1999 | pmid = 10364548 | doi = 10.1126/science.284.5421.1811 | citeseerx = 10.1.1.376.3281 }}</ref><ref name="pmid12392933">{{cite journal | vauthors = Song I, Huganir RL | title = Regulation of AMPA receptors during synaptic plasticity | journal = Trends in Neurosciences | volume = 25 | issue = 11 | pages = 578–88 | date = November 2002 | pmid = 12392933 | doi = 10.1016/S0166-2236(02)02270-1 | s2cid = 1993509 }}</ref> Most AMPARs are [[Tetrameric protein|heterotetrameric]], consisting of symmetric 'dimer of dimers' of GluA2 and either GluA1, GluA3 or GluA4.<ref name="Glutamate receptor ion channels">{{cite journal | vauthors = Mayer ML | title = Glutamate receptor ion channels | journal = Current Opinion in Neurobiology | volume = 15 | issue = 3 | pages = 282–8 | date = June 2005 | pmid = 15919192 | doi = 10.1016/j.conb.2005.05.004 | s2cid = 39812856 | url = https://hal.archives-ouvertes.fr/hal-01591055/file/article.pdf }}</ref><ref name="Greger2007">{{cite journal | vauthors = Greger IH, Ziff EB, Penn AC | title = Molecular determinants of AMPA receptor subunit assembly | journal = Trends in Neurosciences | volume = 30 | issue = 8 | pages = 407–16 | date = August 2007 | pmid = 17629578 | doi = 10.1016/j.tins.2007.06.005 | s2cid = 7505830 }}</ref>  [[Dimer (chemistry)|Dimerization]] starts in the [[endoplasmic reticulum]] with the interaction of N-terminal LIVBP domains, then "zips up" through the ligand-binding domain into the transmembrane ion pore.<ref name="Greger2007"/>

The conformation of the subunit protein in the [[plasma membrane]] caused controversy for some time.  While the amino acid sequence of the subunit indicated that there seemed to be four [[transmembrane protein]] domains (parts of the protein that pass through the plasma membrane), proteins interacting with the subunit indicated that the [[N-terminus]] were extracellular, while the [[C-terminus]] were intracellular.  However, if each of the four transmembrane domains went ''all the way'' through the plasma membrane, then the two termini would have to be on the same side of the membrane.  It was eventually discovered that the second "transmembrane" domain (M2) does not fully traverse the membrane but instead forms a reentrant [[Basic helix–loop–helix|helix-loop]], contributing to the ion-conducting pore of the receptor.<ref name=":2" />  The domain kinks back on itself within the membrane and returns to the intracellular side.<ref name="pmid7993626">{{cite journal | vauthors = Hollmann M, Maron C, Heinemann S | title = N-glycosylation site tagging suggests a three transmembrane domain topology for the glutamate receptor GluR1 | journal = Neuron | volume = 13 | issue = 6 | pages = 1331–43 | date = December 1994 | pmid = 7993626 | doi = 10.1016/0896-6273(94)90419-7 | s2cid = 39682094 }}</ref>  When the four subunits of the tetramer come together, this second membranous domain forms the ion-permeable pore of the receptor.  The M2 loop plays a crucial role in forming the ion channel's selectivity filter, with the helical portions of M2 contributing to hydrophobic interfaces between AMPAR subunits in the ion channel.<ref>{{Cite journal |last1=Twomey |first1=Edward C. |last2=Yelshanskaya |first2=Maria V. |last3=Grassucci |first3=Robert A. |last4=Frank |first4=Joachim |last5=Sobolevsky |first5=Alexander I. |date=2017-09-07 |title=Channel opening and gating mechanism in AMPA-subtype glutamate receptors |journal=Nature |language=en |volume=549 |issue=7670 |pages=60–65 |doi=10.1038/nature23479 |issn=0028-0836 |pmc=5743206 |pmid=28737760|bibcode=2017Natur.549...60T }}</ref>

AMPAR subunits differ most in their C-terminal sequence, which determines their interactions with scaffolding proteins.  All AMPARs contain PDZ-binding domains, but which [[PDZ domain]] they bind to differs.  For example, [[GLUT1|GluA1]] binds to [[SAP97]] through SAP97's class I PDZ domain,<ref>{{cite journal | vauthors = Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW | title = SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit | journal = The Journal of Biological Chemistry | volume = 273 | issue = 31 | pages = 19518–24 | date = July 1998 | pmid = 9677374 | doi = 10.1074/jbc.273.31.19518 | doi-access = free }}</ref> while GluA2 binds to [[PICK1]]<ref name="Greger et al. 2002">{{cite journal | vauthors = Greger IH, Khatri L, Ziff EB | title = RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum | journal = Neuron | volume = 34 | issue = 5 | pages = 759–72 | date = May 2002 | pmid = 12062022 | doi = 10.1016/S0896-6273(02)00693-1 | s2cid = 15936250 | doi-access = free }}</ref> and [[Glutamate receptor-interacting protein (GRIP)|GRIP/ABP]].  Of note, AMPARs cannot directly bind to the common synaptic protein [[PSD-95]] owing to incompatible PDZ domains, although they do interact with PSD-95 via [[CACNG2|stargazin]] (the prototypical member of the TARP family of AMPAR auxiliary subunits).<ref name="pmid17329211">{{cite journal | vauthors = Bats C, Groc L, Choquet D | title = The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking | journal = Neuron | volume = 53 | issue = 5 | pages = 719–34 | date = March 2007 | pmid = 17329211 | doi = 10.1016/j.neuron.2007.01.030 | s2cid = 16423733 | doi-access = free }}</ref>

[[Phosphorylation]] of AMPARs can regulate channel localization, conductance, and open probability.  GluA1 has four known phosphorylation sites at [[serine]] 818 (S818), S831, [[threonine]] 840, and S845 (other subunits have similar phosphorylation sites, but GluR1 has been the most extensively studied).  S818 is phosphorylated by [[protein kinase C]] (PKC) and is necessary for [[long-term potentiation]] (LTP; for GluA1's role in LTP, see below).<ref>{{cite journal | vauthors = Boehm J, Kang MG, Johnson RC, Esteban J, Huganir RL, Malinow R | title = Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1 | journal = Neuron | volume = 51 | issue = 2 | pages = 213–25 | date = July 2006 | pmid = 16846856 | doi = 10.1016/j.neuron.2006.06.013 | s2cid = 16208091 | doi-access = free }}</ref>  S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluA1-containing AMPAR to the [[synapse]],<ref name="Hayashi et al 2000">{{cite journal | vauthors = Hayashi Y, Shi SH, Esteban JA, Piccini A, Poncer JC, Malinow R | s2cid = 17001488 | title = Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction | journal = Science | volume = 287 | issue = 5461 | pages = 2262–7 | date = March 2000 | pmid = 10731148 | doi = 10.1126/science.287.5461.2262 | bibcode = 2000Sci...287.2262H }}</ref> and increases their single channel conductance.<ref>{{cite journal | vauthors = Derkach V, Barria A, Soderling TR | title = Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 3269–74 | date = March 1999 | pmid = 10077673 | pmc = 15931 | doi = 10.1073/pnas.96.6.3269 | doi-access = free }}</ref>  The T840 site was more recently discovered, and has been implicated in LTD.<ref>{{cite journal | vauthors = Delgado JY, Coba M, Anderson CN, Thompson KR, Gray EE, Heusner CL, Martin KC, Grant SG, O'Dell TJ | display-authors = 6 | title = NMDA receptor activation dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840 | journal = The Journal of Neuroscience | volume = 27 | issue = 48 | pages = 13210–21 | date = November 2007 | pmid = 18045915 | pmc = 2851143 | doi = 10.1523/JNEUROSCI.3056-07.2007 }}</ref>  Finally, S845 is phosphorylated by [[protein kinase A]] (PKA) which regulates its open probability.<ref>{{cite journal | vauthors = Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF | title = Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase | journal = The Journal of Neuroscience | volume = 20 | issue = 1 | pages = 89–102 | date = January 2000 | pmid = 10627585 | pmc = 6774102 | doi = 10.1523/JNEUROSCI.20-01-00089.2000 }}</ref>