Editing AMPA receptor (section)

====Constitutive trafficking and changes in subunit composition====
AMPA receptors are continuously being trafficked (endocytosed, recycled, and reinserted) into and out of the [[plasma membrane]]. Recycling endosomes within the [[dendritic spine]] contain pools of AMPA receptors for such synaptic reinsertion.<ref name="Shepherd Huganir 2007">{{cite journal | vauthors = Shepherd JD, Huganir RL | s2cid = 7048661 | title = The cell biology of synaptic plasticity: AMPA receptor trafficking | journal = Annual Review of Cell and Developmental Biology | volume = 23 | pages = 613–43 | year = 2007 | pmid = 17506699 | doi = 10.1146/annurev.cellbio.23.090506.123516 }}</ref> Two distinct pathways exist for the trafficking of AMPA receptors: a regulated pathway and a constitutive pathway.<ref name="Malinow et al 2000">{{cite journal | vauthors = Malinow R, Mainen ZF, Hayashi Y | title = LTP mechanisms: from silence to four-lane traffic | journal = Current Opinion in Neurobiology | volume = 10 | issue = 3 | pages = 352–7 | date = June 2000 | pmid = 10851179 | doi = 10.1016/S0959-4388(00)00099-4 | s2cid = 511079 }}</ref><ref name="Malenka 2003">{{cite journal | vauthors = Malenka RC | title = Synaptic plasticity and AMPA receptor trafficking | journal = Annals of the New York Academy of Sciences | volume = 1003 | pages = 1–11 | date = November 2003 | issue = 1 | pmid = 14684431 | doi = 10.1196/annals.1300.001 | bibcode = 2003NYASA1003....1M | s2cid = 22696062 }}</ref>

In the regulated pathway, GluA1-containing AMPA receptors are trafficked to the synapse in an activity-dependent manner, stimulated by [[NMDA receptor]] activation.<ref name="Hayashi et al 2000"/> Under basal conditions, the regulated pathway is essentially inactive, being transiently activated only upon the induction of [[long-term potentiation]].<ref name="Shepherd Huganir 2007"/><ref name="Malinow et al 2000"/> This pathway is responsible for synaptic strengthening and the initial formation of new memories.<ref name="Kessels Malinow 2009">{{cite journal | vauthors = Kessels HW, Malinow R | title = Synaptic AMPA receptor plasticity and behavior | journal = Neuron | volume = 61 | issue = 3 | pages = 340–50 | date = February 2009 | pmid = 19217372 | pmc = 3917551 | doi = 10.1016/j.neuron.2009.01.015 }}</ref>

In the constitutive pathway, GluA1-lacking AMPA receptors, usually GluR2-GluR3 heteromeric receptors, replace the GluA1-containing receptors in a one-for-one, activity-independent manner,<ref name="McCormack et al 2006">{{cite journal | vauthors = McCormack SG, Stornetta RL, Zhu JJ | title = Synaptic AMPA receptor exchange maintains bidirectional plasticity | journal = Neuron | volume = 50 | issue = 1 | pages = 75–88 | date = April 2006 | pmid = 16600857 | doi = 10.1016/j.neuron.2006.02.027 | s2cid = 17478776 | doi-access = free }}</ref><ref name="Zhu et al. 2000">{{cite journal | vauthors = Zhu JJ, Esteban JA, Hayashi Y, Malinow R | title = Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity | journal = Nature Neuroscience | volume = 3 | issue = 11 | pages = 1098–106 | date = November 2000 | pmid = 11036266 | doi = 10.1038/80614 | hdl = 10261/47079 | s2cid = 16116261 | hdl-access = free }}</ref> preserving the total number of AMPA receptors in the synapse.<ref name="Shepherd Huganir 2007"/><ref name="Malinow et al 2000"/> This pathway is responsible for the maintenance of new memories, sustaining the transient changes resulting from the regulated pathway. Under basal conditions, this pathway is routinely active, as it is necessary also for the replacement of damaged receptors.

The GluA1 and GluA4 subunits consist of a long carboxy (C)-tail, whereas the GluA2 and GluA3 subunits consist of a short carboxy-tail. The two pathways are governed by interactions between the C termini of the AMPA receptor subunits and synaptic compounds and proteins. Long C-tails prevent GluR1/4 receptors from being inserted directly into the postsynaptic density zone (PSDZ) in the absence of activity, whereas the short C-tails of GluA2/3 receptors allow them to be inserted directly into the PSDZ.<ref name="Borgdorff Choquet 2002">{{cite journal | vauthors = Borgdorff AJ, Choquet D | title = Regulation of AMPA receptor lateral movements | journal = Nature | volume = 417 | issue = 6889 | pages = 649–53 | date = June 2002 | pmid = 12050666 | doi = 10.1038/nature00780 | bibcode = 2002Natur.417..649B | s2cid = 4422115 }}</ref><ref name="Passafaro et al. 2001">{{cite journal | vauthors = Passafaro M, Piëch V, Sheng M | title = Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons | journal = Nature Neuroscience | volume = 4 | issue = 9 | pages = 917–26 | date = September 2001 | pmid = 11528423 | doi = 10.1038/nn0901-917 | s2cid = 32852272 }}</ref> The GluA2 C terminus interacts with and binds to [[N-ethylmaleimide sensitive fusion protein]] (NSF),<ref name="Song et al. 1998">{{cite journal | vauthors = Song I, Kamboj S, Xia J, Dong H, Liao D, Huganir RL | title = Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors | journal = Neuron | volume = 21 | issue = 2 | pages = 393–400 | date = August 1998 | pmid = 9728920 | doi = 10.1016/S0896-6273(00)80548-6 | doi-access = free }}</ref><ref name="Osten et al. 1998">{{cite journal | vauthors = Osten P, Srivastava S, Inman GJ, Vilim FS, Khatri L, Lee LM, States BA, Einheber S, Milner TA, Hanson PI, Ziff EB | display-authors = 6 | title = The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs | journal = Neuron | volume = 21 | issue = 1 | pages = 99–110 | date = July 1998 | pmid = 9697855 | doi = 10.1016/S0896-6273(00)80518-8 | s2cid = 18569829 | doi-access = free }}</ref><ref name="Nishimune et al. 1998">{{cite journal | vauthors = Nishimune A, Isaac JT, Molnar E, Noel J, Nash SR, Tagaya M, Collingridge GL, Nakanishi S, Henley JM | display-authors = 6 | title = NSF binding to GluR2 regulates synaptic transmission | journal = Neuron | volume = 21 | issue = 1 | pages = 87–97 | date = July 1998 | pmid = 9697854 | doi = 10.1016/S0896-6273(00)80517-6 | hdl = 2433/180867 | s2cid = 18956893 | hdl-access = free }}</ref> which allows for the rapid insertion of GluR2-containing AMPA receptors at the synapse.<ref name="Beretta et al. 2005">{{cite journal | vauthors = Beretta F, Sala C, Saglietti L, Hirling H, Sheng M, Passafaro M | title = NSF interaction is important for direct insertion of GluR2 at synaptic sites | journal = Molecular and Cellular Neurosciences | volume = 28 | issue = 4 | pages = 650–60 | date = April 2005 | pmid = 15797712 | doi = 10.1016/j.mcn.2004.11.008 | s2cid = 46716417 }}</ref> In addition, GluR2/3 subunits are more stably tethered to the synapse than GluR1 subunits.<ref name="Cingolani et al. 2008">{{cite journal | vauthors = Cingolani LA, Thalhammer A, Yu LM, Catalano M, Ramos T, Colicos MA, Goda Y | title = Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3 integrins | journal = Neuron | volume = 58 | issue = 5 | pages = 749–62 | date = June 2008 | pmid = 18549786 | pmc = 2446609 | doi = 10.1016/j.neuron.2008.04.011 }}</ref><ref name="Saglietti et al. 2007">{{cite journal | vauthors = Saglietti L, Dequidt C, Kamieniarz K, Rousset MC, Valnegri P, Thoumine O, Beretta F, Fagni L, Choquet D, Sala C, Sheng M, Passafaro M | display-authors = 6 | title = Extracellular interactions between GluR2 and N-cadherin in spine regulation | journal = Neuron | volume = 54 | issue = 3 | pages = 461–77 | date = May 2007 | pmid = 17481398 | doi = 10.1016/j.neuron.2007.04.012 | s2cid = 14600986 | doi-access = free }}</ref><ref name="Silverman et al. 2007">{{cite journal | vauthors = Silverman JB, Restituito S, Lu W, Lee-Edwards L, Khatri L, Ziff EB | title = Synaptic anchorage of AMPA receptors by cadherins through neural plakophilin-related arm protein AMPA receptor-binding protein complexes | journal = The Journal of Neuroscience | volume = 27 | issue = 32 | pages = 8505–16 | date = August 2007 | pmid = 17687028 | pmc = 6672939 | doi = 10.1523/JNEUROSCI.1395-07.2007 }}</ref>