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===AMPA receptor trafficking=== [[Image:RegulationOfAMPARTrafficking.jpg|thumb|left|x250px|alt=Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli|Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli]] ====Molecular and signaling response to LTP-inducing stimuli==== The mechanism for LTP has long been a topic of debate, but, recently, mechanisms have come to some consensus. AMPARs play a key role in this process, as one of the key indicators of LTP induction is the increase in the ratio of AMPAR to NMDARs following high-frequency stimulation. The idea is that AMPARs are trafficked from the dendrite into the synapse and incorporated through some series of signaling cascades. AMPARs are initially regulated at the transcriptional level at their 5' promoter regions. There is significant evidence pointing towards the transcriptional control of AMPA receptors in longer-term memory through cAMP response element-binding protein ([[CREB]]) and [[Mitogen-activated protein kinases]] (MAPK).<ref>{{cite journal | vauthors = Perkinton MS, Sihra TS, Williams RJ | title = Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons | journal = The Journal of Neuroscience | volume = 19 | issue = 14 | pages = 5861β74 | date = July 1999 | pmid = 10407026 | pmc = 6783096 | doi = 10.1523/JNEUROSCI.19-14-05861.1999 }}</ref> Messages are translated on the rough [[endoplasmic reticulum]] (rough ER) and modified there. Subunit compositions are determined at the time of modification at the rough ER.<ref name="Greger et al. 2002"/> After post-ER processing in the Golgi apparatus, AMPARs are released into the perisynaptic membrane as a reserve waiting for the LTP process to be initiated. The first key step in the process following glutamate binding to NMDARs is the influx of calcium through the NMDA receptors and the resultant activation of [[Ca2+/calmodulin-dependent protein kinase II|Ca<sup>2+</sup>/calmodulin-dependent protein kinase]] (CaMKII).<ref name="pmid8385124">{{cite journal | vauthors = Fukunaga K, Stoppini L, Miyamoto E, Muller D | title = Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II | journal = The Journal of Biological Chemistry | volume = 268 | issue = 11 | pages = 7863β7 | date = April 1993 | doi = 10.1016/S0021-9258(18)53037-4 | pmid = 8385124 | doi-access = free }}</ref> Blocking either this influx or the activation of CaMKII prevents LTP, showing that these are necessary mechanisms for LTP.<ref name="pmid11994750">{{cite journal | vauthors = Lisman J, Schulman H, Cline H | title = The molecular basis of CaMKII function in synaptic and behavioural memory | journal = Nature Reviews. Neuroscience | volume = 3 | issue = 3 | pages = 175β90 | date = March 2002 | pmid = 11994750 | doi = 10.1038/nrn753 | s2cid = 5844720 }}</ref> In addition, profusion of CaMKII into a synapse causes LTP, showing that it is a causal and sufficient mechanism.<ref name="pmid9405465">{{cite journal | vauthors = Mammen AL, Kameyama K, Roche KW, Huganir RL | title = Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II | journal = The Journal of Biological Chemistry | volume = 272 | issue = 51 | pages = 32528β33 | date = December 1997 | pmid = 9405465 | doi = 10.1074/jbc.272.51.32528 | doi-access = free }}</ref> CaMKII has multiple modes of activation to cause the incorporation of AMPA receptors into the perisynaptic membrane. CAMKII enzyme is eventually responsible for the development of the actin cytoskeleton of neuronal cells and, eventually, for the dendrite and axon development (synaptic plasticity).<ref>{{cite journal | vauthors = Ebert DH, Greenberg ME | title = Activity-dependent neuronal signalling and autism spectrum disorder | journal = Nature | volume = 493 | issue = 7432 | pages = 327β37 | date = January 2013 | pmid = 23325215 | pmc = 3576027 | doi = 10.1038/nature11860 | bibcode = 2013Natur.493..327E }}</ref> The first is direct phosphorylation of synaptic-associated protein 97([[SAP97]]), a [[Scaffold protein|scaffolding protein]].<ref name="pmid15044483">{{cite journal | vauthors = Mauceri D, Cattabeni F, Di Luca M, Gardoni F | title = Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines | journal = The Journal of Biological Chemistry | volume = 279 | issue = 22 | pages = 23813β21 | date = May 2004 | pmid = 15044483 | doi = 10.1074/jbc.M402796200 | doi-access = free }}</ref> First, SAP-97 and Myosin-VI, a motor protein, are bound as a complex to the C-terminus of AMPARs. Following phosphorylation by CaMKII, the complex moves into the perisynaptic membrane.<ref name="pmid12050163">{{cite journal | vauthors = Wu H, Nash JE, Zamorano P, Garner CC | title = Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 30928β34 | date = August 2002 | pmid = 12050163 | doi = 10.1074/jbc.M203735200 | doi-access = free }}</ref> The second mode of activation is through the MAPK pathway. CaMKII activates the Ras proteins, which go on to activate p42/44 MAPK, which drives AMPAR insertion directly into the perisynaptic membrane.<ref name="pmid12202034">{{cite journal | vauthors = Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R | title = Ras and Rap control AMPA receptor trafficking during synaptic plasticity | journal = Cell | volume = 110 | issue = 4 | pages = 443β55 | date = August 2002 | pmid = 12202034 | doi = 10.1016/S0092-8674(02)00897-8 | s2cid = 12858091 | doi-access = free }}</ref> ====AMPA receptor trafficking to the PSD in response to LTP==== Once AMPA receptors are transported to the perisynaptic region through PKA or SAP97 phosphorylation, receptors are then trafficked to the [[postsynaptic density]] (PSD). However, this process of trafficking to the PSD still remains controversial. One possibility is that, during LTP, there is lateral movement of AMPA receptors from perisynaptic sites directly to the PSD.<ref name="Borgdorff Choquet 2002"/> Another possibility is that [[exocytosis]] of intracellular vesicles is responsible for AMPA trafficking to the PSD directly.<ref name="pmid15448273">{{cite journal | vauthors = Park M, Penick EC, Edwards JG, Kauer JA, Ehlers MD | title = Recycling endosomes supply AMPA receptors for LTP | journal = Science | volume = 305 | issue = 5692 | pages = 1972β5 | date = September 2004 | pmid = 15448273 | doi = 10.1126/science.1102026 | bibcode = 2004Sci...305.1972P | s2cid = 34651431 }}</ref> Recent evidence suggests that both of these processes are happening after an LTP stimulus; however, only the lateral movement of AMPA receptors from the perisynaptic region enhances the number of AMPA receptors at the PSD.<ref name="pmid19914186">{{cite journal | vauthors = Makino H, Malinow R | title = AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis | journal = Neuron | volume = 64 | issue = 3 | pages = 381β90 | date = November 2009 | pmid = 19914186 | pmc = 2999463 | doi = 10.1016/j.neuron.2009.08.035 }}</ref> The exact mechanism responsible for lateral movement of AMPA receptors to the PSD remains to be discovered; however, research has discovered several essential proteins for AMPA receptor trafficking. For example, overexpression of SAP97 leads to increased AMPA receptor trafficking to [[synapses]].<ref name="pmid20133708">{{cite journal | vauthors = Howard MA, Elias GM, Elias LA, Swat W, Nicoll RA | title = The role of SAP97 in synaptic glutamate receptor dynamics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 8 | pages = 3805β10 | date = February 2010 | pmid = 20133708 | pmc = 2840522 | doi = 10.1073/pnas.0914422107 | bibcode = 2010PNAS..107.3805H | doi-access = free }}</ref> In addition to influencing synaptic localization, SAP97 has also been found to influence AMPA receptor conductance in response to [[glutamate]].<ref name="pmid19357261">{{cite journal | vauthors = Waites CL, Specht CG, HΓ€rtel K, Leal-Ortiz S, Genoux D, Li D, Drisdel RC, Jeyifous O, Cheyne JE, Green WN, Montgomery JM, Garner CC | display-authors = 6 | title = Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate | journal = The Journal of Neuroscience | volume = 29 | issue = 14 | pages = 4332β45 | date = April 2009 | pmid = 19357261 | pmc = 3230533 | doi = 10.1523/JNEUROSCI.4431-08.2009 }}</ref> [[Myosin]] proteins are calcium sensitive motor proteins that have also been found to be essential for AMPA receptor trafficking. Disruption of myosin Vb interaction with Rab11 and Rab11-FIP2 blocks spine growth and AMPA receptor trafficking.<ref name="pmid18984164">{{cite journal | vauthors = Wang Z, Edwards JG, Riley N, Provance DW, Karcher R, Li XD, Davison IG, Ikebe M, Mercer JA, Kauer JA, Ehlers MD | display-authors = 6 | title = Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity | journal = Cell | volume = 135 | issue = 3 | pages = 535β48 | date = October 2008 | pmid = 18984164 | pmc = 2585749 | doi = 10.1016/j.cell.2008.09.057 }}</ref> Therefore, it is possible that myosin may drive the lateral movement of AMPA receptors in the perisynaptic region to the PSD. Transmembrane AMPA receptor regulatory proteins (TARPs) are a family protein that associate with AMPA receptors and control their trafficking and conductance.<ref name="pmid16513974">{{cite journal | vauthors = Nicoll RA, Tomita S, Bredt DS | title = Auxiliary subunits assist AMPA-type glutamate receptors | journal = Science | volume = 311 | issue = 5765 | pages = 1253β6 | date = March 2006 | pmid = 16513974 | doi = 10.1126/science.1123339 | bibcode = 2006Sci...311.1253N | s2cid = 40782882 }}</ref> [[CACNG2]] (Stargazin) is one such protein and is found to bind AMPA receptors in the perisynaptic and postsynaptic regions.<ref name="pmid12771129">{{cite journal | vauthors = Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS | title = Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins | journal = The Journal of Cell Biology | volume = 161 | issue = 4 | pages = 805β16 | date = May 2003 | pmid = 12771129 | pmc = 2199354 | doi = 10.1083/jcb.200212116 }}</ref> The role of stargazin in trafficking between the perisynaptic and postsynaptic regions remains unclear; however, stargazin is essential for immobilizing AMPA receptors in the PSD by interacting with PSD-95.<ref name="pmid11140673">{{cite journal | vauthors = Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA | display-authors = 6 | title = Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms | journal = Nature | volume = 408 | issue = 6815 | pages = 936β43 | year = 2000 | pmid = 11140673 | doi = 10.1038/35050030 | bibcode = 2000Natur.408..936C | s2cid = 4427689 }}</ref> PSD-95 stabilizes AMPA receptors to the synapse and disruption of the stargazin-PSD-95 interaction suppressed synaptic transmission.<ref name="pmid17329211"/> ==== Biophysics of AMPA receptor trafficking ==== The movement of AMPA receptors within the neuronal membrane is commonly modeled as [[Brownian diffusion]], reflecting their lateral mobility across the lipid bilayer. However, at synaptic sitesβ particularly the [[postsynaptic density]] (PSD)βthis motion is modulated by retention forces that can transiently stabilize receptors.<ref name=":3">{{Cite journal |vauthors=Heine M, Groc L, Frischknecht R, Béïque JC, Lounis B, Rumbaugh G, Huganir RL, Cognet L, Choquet D |date=April 2008 |title=Surface Mobility of Postsynaptic AMPARs Tunes Synaptic Transmission |journal=Science |volume=320 |issue=5873 |pages=201β205 |bibcode=2008Sci...320..201H |doi=10.1126/science.1152089 |pmc=2715948 |pmid=18403705}}</ref><ref name=":4">{{Cite journal |last1=He |first1=Shao-Qiu |last2=Zhang |first2=Zhen-Ning |last3=Guan |first3=Ji-Song |last4=Liu |first4=Hong-Rui |last5=Zhao |first5=Bo |last6=Wang |first6=Hai-Bo |last7=Li |first7=Qian |last8=Yang |first8=Hong |last9=Luo |first9=Jie |last10=Li |first10=Zi-Yan |last11=Wang |first11=Qiong |last12=Lu |first12=Ying-Jin |last13=Bao |first13=Lan |last14=Zhang |first14=Xu |date=January 2011 |title=Facilitation of ΞΌ-Opioid Receptor Activity by Preventing Ξ΄-Opioid Receptor-Mediated Codegradation |url=https://linkinghub.elsevier.com/retrieve/pii/S0896627310009864 |journal=Neuron |language=en |volume=69 |issue=1 |pages=120β131 |doi=10.1016/j.neuron.2010.12.001|pmid=21220103 }}</ref><ref>{{Cite journal |vauthors=Hoze N, Nair D, Hosy E, Holcman D |date=October 2012 |title=Heterogeneity of AMPA receptor trafficking and molecular interactions revealed by superresolution analysis of live cell imaging |journal=Proceedings of the National Academy of Sciences |volume=109 |issue=42 |pages=17052β17057 |doi=10.1073/pnas.1204589109 |pmid=23035245 |pmc=3479500 |bibcode=2012PNAS..10917052H |doi-access=free}}</ref> These forces do not completely immobilize AMPARs but instead permit a dynamic exchange with receptors in the perisynaptic domain.<ref name=":3" /><ref name=":4" /> The molecular basis for this stabilization is believed to involve nanodomain organization within the PSD, including anchoring interactions with scaffolding proteins such as PSD-95 and transmembrane AMPA receptor regulatory proteins (TARPs).<ref name=":5">{{Cite journal |last1=Liu |first1=Zhikai |last2=Kimura |first2=Yukiko |last3=Higashijima |first3=Shin-ichi |last4=Hildebrand |first4=David G.C. |last5=Morgan |first5=Joshua L. |last6=Bagnall |first6=Martha W. |date=November 2020 |title=Central Vestibular Tuning Arises from Patterned Convergence of Otolith Afferents |journal=Neuron |language=en |volume=108 |issue=4 |pages=748β762.e4 |doi=10.1016/j.neuron.2020.08.019 |pmc=7704800 |pmid=32937099}}</ref><ref name=":6">{{Cite journal |last1=Anastasi |first1=Sergio |last2=Zhu |first2=Su-Jie |last3=BallarΓ² |first3=Costanza |last4=Manca |first4=Sonia |last5=Lamberti |first5=Dante |last6=Wang |first6=Li-Jun |last7=AlemΓ |first7=Stefano |last8=Yun |first8=Cai-Hong |last9=Segatto |first9=Oreste |date=May 2016 |title=Lack of Evidence that CYTH2/ARNO Functions as a Direct Intracellular EGFR Activator |url=https://linkinghub.elsevier.com/retrieve/pii/S0092867416305578 |journal=Cell |language=en |volume=165 |issue=5 |pages=1031β1034 |doi=10.1016/j.cell.2016.05.009|pmid=27203102 }}</ref> Recent evidence suggests that this compartmentalization may arise through liquid-liquid [[phase separation]] (LLPS), a biophysical process by which biomolecular condensates form via weak, multivalent interactions. LLPS may contribute to the formation of synaptic nanodomains that selectively retain or enrich AMPARs at functional sites within the PSD.<ref name=":5" /><ref name=":6" /> ====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 = 613β43 | 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 = 352β7 | 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 = 1β11 | 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 = 340β50 | 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 = 75β88 | 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 = 1098β106 | 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 = 649β53 | 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, PiΓ«ch 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 = 917β26 | 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 = 393β400 | 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 = 99β110 | 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 = 87β97 | 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 = 650β60 | 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 = 749β62 | 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 = 461β77 | 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 = 8505β16 | date = August 2007 | pmid = 17687028 | pmc = 6672939 | doi = 10.1523/JNEUROSCI.1395-07.2007 }}</ref> ====LTD-induced endocytosis of AMPA receptors==== [[Image:AMPAReceptorEndocytosis.jpg|thumb|x200px|alt=LTD-Induced AMPA Receptor Endocytosis|LTD-induced endocytosis of AMPA receptors]] [[Long-term depression]] enacts mechanisms to decrease AMPA receptor density in selected dendritic spines, dependent on [[clathrin]] and [[calcineurin]] and distinct from that of constitutive AMPAR trafficking. The starting signal for AMPAR [[endocytosis]] is an NMDAR-dependent calcium influx from low-frequency stimulation, which in turn activates protein phosphatases [[PP1]] and calcineurin. However, AMPAR endocytosis has also been activated by [[VDCC|voltage-dependent calcium channels]], agonism of AMPA receptors, and administration of [[insulin]], suggesting general calcium influx as the cause of AMPAR endocytosis.<ref name="Carroll et al.">{{cite journal | vauthors = Carroll RC, Beattie EC, Xia H, LΓΌscher C, Altschuler Y, Nicoll RA, Malenka RC, von Zastrow M | display-authors = 6 | title = Dynamin-dependent endocytosis of ionotropic glutamate receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 24 | pages = 14112β7 | date = November 1999 | pmid = 10570207 | pmc = 24199 | doi = 10.1073/pnas.96.24.14112 | bibcode = 1999PNAS...9614112C | doi-access = free }}</ref> Blockage of PP1 did not prevent AMPAR endocytosis, but antagonist application to calcineurin led to significant inhibition of this process.<ref name="Beattie et al.">{{cite journal | vauthors = Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC | title = Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD | journal = Nature Neuroscience | volume = 3 | issue = 12 | pages = 1291β300 | date = December 2000 | pmid = 11100150 | doi = 10.1038/81823 | doi-access = free }}</ref> Calcineurin interacts with an endocytotic complex at the postsynaptic zone, explaining its effects on LTD.<ref name="Lai et al.">{{cite journal | vauthors = Lai MM, Hong JJ, Ruggiero AM, Burnett PE, Slepnev VI, De Camilli P, Snyder SH | title = The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis | journal = The Journal of Biological Chemistry | volume = 274 | issue = 37 | pages = 25963β6 | date = September 1999 | pmid = 10473536 | doi = 10.1074/jbc.274.37.25963 | doi-access = free }}</ref> The complex, consisting of a clathrin-coated pit underneath a section of AMPAR-containing plasma membrane and interacting proteins, is the direct mechanism for reduction of AMPARs, in particular GluR2/GluR3 subunit-containing receptors, in the synapse. Interactions from calcineurin activate [[dynamin]] GTPase activity, allowing the clathrin pit to excise itself from the cell membrane and become a cytoplasmic vesicle.<ref name="pmid17547698">{{cite journal | vauthors = Jung N, Haucke V | title = Clathrin-mediated endocytosis at synapses | journal = Traffic | volume = 8 | issue = 9 | pages = 1129β36 | date = September 2007 | pmid = 17547698 | doi = 10.1111/j.1600-0854.2007.00595.x | doi-access = free }}</ref> Once the clathrin coat detaches, other proteins can interact directly with the AMPARs using [[PDZ domain|PDZ]] carboxyl tail domains; for example, glutamate receptor-interacting protein 1 ([[GRIP1 (gene)|GRIP1]]) has been implicated in intracellular sequestration of AMPARs.<ref name="Daw et al.">{{cite journal | vauthors = Daw MI, Chittajallu R, Bortolotto ZA, Dev KK, Duprat F, Henley JM, Collingridge GL, Isaac JT | display-authors = 6 | title = PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses | journal = Neuron | volume = 28 | issue = 3 | pages = 873β86 | date = December 2000 | pmid = 11163273 | doi = 10.1016/S0896-6273(00)00160-4 | hdl = 2262/89240 | s2cid = 13727678 | hdl-access = free }}</ref> Intracellular AMPARs are subsequently sorted for degradation by lysosomes or recycling to the cell membrane.<ref name="Ehlers et al.">{{cite journal | vauthors = Ehlers MD | title = Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting | journal = Neuron | volume = 28 | issue = 2 | pages = 511β25 | date = November 2000 | pmid = 11144360 | doi = 10.1016/S0896-6273(00)00129-X | s2cid = 16333109 | doi-access = free }}</ref> For the latter, [[PICK1]] and PKC can displace GRIP1 to return AMPARs to the surface, reversing the effects of endocytosis and LTD. when appropriate.<ref name="pmid16055064">{{cite journal | vauthors = Lu W, Ziff EB | title = PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking | journal = Neuron | volume = 47 | issue = 3 | pages = 407β21 | date = August 2005 | pmid = 16055064 | doi = 10.1016/j.neuron.2005.07.006 | s2cid = 17100359 | doi-access = free }}</ref> Nevertheless, the highlighted calcium-dependent, dynamin-mediated mechanism above has been implicated as a key component of LTD. and as such may have applications to further behavioral research.<ref name="Yang et al.">{{cite journal | vauthors = Wang YT | title = Probing the role of AMPAR endocytosis and long-term depression in behavioural sensitization: relevance to treatment of brain disorders, including drug addiction | journal = British Journal of Pharmacology | volume = 153 Suppl 1 | issue = S1 | pages = S389-95 | date = March 2008 | pmid = 18059315 | pmc = 2268058 | doi = 10.1038/sj.bjp.0707616 }}</ref>
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