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Its name is derived from the ability to be activated by the artificial glutamate analog [[AMPA]]. The receptor was first named the "[[Quisqualic acid|quisqualate]] receptor" by Watkins and colleagues after a naturally occurring agonist [[quisqualic acid|quisqualate]] and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen.<ref>{{cite journal | vauthors = Honoré T, Lauridsen J, Krogsgaard-Larsen P | title = The binding of [3H]AMPA, a structural analogue of glutamic acid, to rat brain membranes | journal = Journal of Neurochemistry | volume = 38 | issue = 1 | pages = 173–8 | date = January 1982 | pmid = 6125564 | doi = 10.1111/j.1471-4159.1982.tb10868.x | s2cid = 42753770 }}</ref> The ''GRIA2''-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be [[protein crystal|crystallized]].<ref>{{Cite journal|title=Armstrong and Gouaux (2000) Mechanisms for Activation and Antagonism of an AMPA-Sensitive Glutamate Receptor: Crystal Structures of the GluR2 Ligand Binding Core. |doi=10.1016/S0896-6273(00)00094-5|pmid=11086992 |volume=28|year=2000|journal=Neuron|pages=165–181|vauthors=Armstrong N|issue=1 |s2cid=3128719|doi-access=free}}</ref> ==Structure and function== ===Subunit composition=== AMPARs are composed of four types of subunits encoded by different genes, designated as ''[[GRIA1]]'' (also named GluA1 or GluR1), ''[[GRIA2]]'' (also named GluA2 or GluR2), ''[[GRIA3]]'' (Also named GluA3 or GluR3), and ''[[GRIA4]]'' (also called GluA4 or GluRA-D2 ), which combine to form [[tetramer protein|tetramer]]s.<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 domains (parts of the protein that pass through the plasma membrane), proteins interacting with the subunit indicated that the [[N-terminus]] seemed to be extracellular, while the [[C-terminus]] seemed to be 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 does not in fact cross the membrane at all, but 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. 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]], 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 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> ===Ion channel function=== Each AMPAR has four sites to which an [[agonist]] (such as glutamate) can bind, one for each subunit.<ref name="Glutamate receptor ion channels"/> The binding site is believed to be formed by the N-terminal tail and the extracellular loop between transmembrane domains three and four.<ref>{{cite journal | vauthors = Armstrong N, Sun Y, Chen GQ, Gouaux E | title = Structure of a glutamate-receptor ligand-binding core in complex with kainate | journal = Nature | volume = 395 | issue = 6705 | pages = 913–7 | date = October 1998 | pmid = 9804426 | doi = 10.1038/27692 | bibcode = 1998Natur.395..913A | s2cid = 4405926 }}</ref> When an agonist binds, these two loops move towards each other, opening the pore. The channel opens when two sites are occupied,<ref name="Platt2007">{{cite journal | vauthors = Platt SR | title = The role of glutamate in central nervous system health and disease--a review | journal = Veterinary Journal | volume = 173 | issue = 2 | pages = 278–86 | date = March 2007 | pmid = 16376594 | doi = 10.1016/j.tvjl.2005.11.007 }}</ref> and increases its current as more binding sites are occupied.<ref>{{cite journal | vauthors = Rosenmund C, Stern-Bach Y, Stevens CF | title = The tetrameric structure of a glutamate receptor channel | journal = Science | volume = 280 | issue = 5369 | pages = 1596–9 | date = June 1998 | pmid = 9616121 | doi = 10.1126/science.280.5369.1596 | bibcode = 1998Sci...280.1596R | hdl = 11858/00-001M-0000-0012-FDD8-B | hdl-access = free }}</ref> Once open, the channel may undergo rapid desensitization, stopping the current. The mechanism of desensitization is believed to be due to a small change in angle of one of the parts of the binding site, closing the pore.<ref>{{cite journal | vauthors = Armstrong N, Jasti J, Beich-Frandsen M, Gouaux E | title = Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor | journal = Cell | volume = 127 | issue = 1 | pages = 85–97 | date = October 2006 | pmid = 17018279 | doi = 10.1016/j.cell.2006.08.037 | s2cid = 16564029 | doi-access = free }}</ref> AMPARs open and close quickly (1ms), and are thus responsible for most of the fast excitatory [[synaptic transmission]] in the central nervous system.<ref name="Platt2007"/> The AMPAR's permeability to [[calcium]] and other [[cation]]s, such as [[sodium]] and [[potassium]], is governed by the GluA2 subunit. If an AMPAR lacks a GluA2 subunit, then it will be permeable to sodium, potassium, and calcium. The presence of a GluA2 subunit will almost always render the channel impermeable to calcium. This is determined by post-[[Transcription (genetics)|transcription]]al modification — [[RNA editing]] — of the [[glutamine|Q]]-to-[[arginine|R]] editing site of the GluA2 [[mRNA]]. Here, [[RNA editing#A-I editing|A→I editing]] alters the uncharged [[amino acid]] [[glutamine]] (Q) to the positively charged [[arginine]] (R) in the receptor's ion channel. The positively charged amino acid at the critical point makes it energetically unfavourable for calcium to enter the cell through the pore. Almost all of the GluA2 subunits in CNS are edited to the GluA2(R) form. This means that the principal ions gated by AMPARs are sodium and potassium, distinguishing AMPARs from [[NMDA receptor]]s (the other main ionotropic glutamate receptors in the brain), which also permit calcium influx. Both AMPA and NMDA receptors, however, have an [[equilibrium potential]] near 0 mV. The prevention of calcium entry into the cell on activation of GluA2-containing AMPARs is proposed to guard against [[excitotoxicity]].<ref name="pmid11414791">{{cite journal | vauthors = Kim DY, Kim SH, Choi HB, Min C, Gwag BJ | title = High abundance of GluR1 mRNA and reduced Q/R editing of GluR2 mRNA in individual NADPH-diaphorase neurons | journal = Molecular and Cellular Neurosciences | volume = 17 | issue = 6 | pages = 1025–33 | date = June 2001 | pmid = 11414791 | doi = 10.1006/mcne.2001.0988 | s2cid = 15351461 }}</ref> The subunit composition of the AMPAR is also important for the way this receptor is modulated. If an AMPAR lacks GluA2 subunits, then it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called [[polyamine]]s. Thus, when the neuron is at a [[Depolarization|depolarized]] membrane potential, polyamines will block the AMPAR channel more strongly, preventing the flux of potassium ions through the channel pore. GluA2-lacking AMPARs are, thus, said to have an inwardly rectifying [[I/V curve]], which means that they pass less outward current than inward current at equivalent distance from the reversal potential.<ref name=":0">{{Cite journal |last1=Kumar |first1=Sanjay S. |last2=Bacci |first2=Alberto |last3=Kharazia |first3=Viktor |last4=Huguenard |first4=John R. |date=2002-04-15 |title=A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons |journal=The Journal of Neuroscience|volume=22 |issue=8 |pages=3005–3015 |doi=10.1523/JNEUROSCI.22-08-03005.2002 |issn=1529-2401 |pmc=6757523 |pmid=11943803}}</ref> Calcium permeable AMPARs are found typically early during postnatal development on neocortical [[pyramidal neurons]],<ref name=":0" /> some interneurons, or in dopamine neurons of the [[ventral tegmental area]] after the exposure to an addictive drug.<ref>{{cite journal | vauthors = Lüscher C, Malenka RC | title = Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling | journal = Neuron | volume = 69 | issue = 4 | pages = 650–63 | date = February 2011 | pmid = 21338877 | pmc = 4046255 | doi = 10.1016/j.neuron.2011.01.017 }}</ref> Alongside [[RNA editing]], [[alternative splicing]] allows a range of functional AMPA receptor subunits beyond what is encoded in the [[genome]]. In other words, although one [[gene]] (''GRIA1''–''GRIA4'') is encoded for each subunit (GluA1–GluA4), splicing after transcription from [[DNA]] allows some [[exons]] to be translated interchangeably, leading to several functionally different subunits from each gene.<ref>{{cite journal | vauthors = Herbrechter R, Hube N, Buchholz R, Reiner A | title = Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data | journal = Cellular and Molecular Life Sciences | volume = 78 | issue = 14 | pages = 5605–5630 | date = July 2021 | pmid = 34100982 | pmc = 8257547 | doi = 10.1007/s00018-021-03865-z }}</ref> The flip/flop sequence is one such interchangeable exon. A 38-amino acid sequence found prior to (i.e., before the [[N-terminus]] of) the fourth membranous domain in all four AMPAR subunits, it determines the speed of desensitisation<ref name="pmid7973663">{{cite journal | vauthors = Mosbacher J, Schoepfer R, Monyer H, Burnashev N, Seeburg PH, Ruppersberg JP | title = A molecular determinant for submillisecond desensitization in glutamate receptors | journal = Science | volume = 266 | issue = 5187 | pages = 1059–62 | date = November 1994 | pmid = 7973663 | doi = 10.1126/science.7973663 | bibcode = 1994Sci...266.1059M }}</ref> of the receptor and also the speed at which the receptor is resensitised<ref name="pmid1699275">{{cite journal | vauthors = Sommer B, Keinänen K, Verdoorn TA, Wisden W, Burnashev N, Herb A, Köhler M, Takagi T, Sakmann B, Seeburg PH | display-authors = 6 | title = Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS | journal = Science | volume = 249 | issue = 4976 | pages = 1580–5 | date = September 1990 | pmid = 1699275 | doi = 10.1126/science.1699275 | bibcode = 1990Sci...249.1580S }}</ref> and the rate of channel closing.<ref name="pmid17256974">{{cite journal | vauthors = Pei W, Huang Z, Niu L | title = GluR3 flip and flop: differences in channel opening kinetics | journal = Biochemistry | volume = 46 | issue = 7 | pages = 2027–36 | date = February 2007 | pmid = 17256974 | doi = 10.1021/bi062213s }}</ref> The flip form is present in prenatal AMPA receptors and gives a sustained current in response to glutamate activation.<ref name="pmid9030702">{{cite journal | vauthors = Eastwood SL, Burnet PW, Harrison PJ | title = GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study | journal = Brain Research. Molecular Brain Research | volume = 44 | issue = 1 | pages = 92–8 | date = February 1997 | pmid = 9030702 | doi = 10.1016/s0169-328x(96)00195-7 }}</ref> ==Synaptic plasticity== AMPA receptors (AMPAR) are both [[glutamate receptor]]s and cation [[ion channel|channels]] that are integral to [[neuroplasticity|plasticity]] and [[synaptic transmission]] at many postsynaptic membranes. One of the most widely and thoroughly investigated forms of plasticity in the nervous system is known as [[long-term potentiation]] (LTP). There are two necessary components of LTP: presynaptic [[glutamate]] release and postsynaptic depolarization. Therefore, LTP can be induced experimentally in a paired [[electrophysiology|electrophysiological recording]] when a presynaptic cell is stimulated to release glutamate on a postsynaptic cell that is depolarized. The typical LTP induction protocol involves a "tetanus" stimulation, which is a 100&nbsp;Hz stimulation for 1 second. When one applies this protocol to a pair of cells, one will see a sustained increase of the amplitude of the [[excitatory postsynaptic potential]] (EPSP) following tetanus. This response is interesting because it is thought to be the physiological correlation for learning and memory in the cell. In fact, it has been shown that, following a single paired-avoidance paradigm in mice, LTP can be recorded in some [[hippocampus|hippocampal]] synapses ''in vivo''.<ref name="pmid16931756">{{cite journal | vauthors = Whitlock JR, Heynen AJ, Shuler MG, Bear MF | title = Learning induces long-term potentiation in the hippocampus | journal = Science | volume = 313 | issue = 5790 | pages = 1093–7 | date = August 2006 | pmid = 16931756 | doi = 10.1126/science.1128134 | bibcode = 2006Sci...313.1093W | s2cid = 612352 }}</ref> The molecular basis for LTP has been extensively studied, and AMPARs have been shown to play an integral role in the process. Both GluR1 and GluR2 play an important role in synaptic plasticity. It is now known that the underlying physiological correlation for the increase in EPSP size is a postsynaptic upregulation of AMPARs at the membrane,<ref name="pmid8415757">{{cite journal | vauthors = Maren S, Tocco G, Standley S, Baudry M, Thompson RF | title = Postsynaptic factors in the expression of long-term potentiation (LTP): increased glutamate receptor binding following LTP induction in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 20 | pages = 9654–8 | date = October 1993 | pmid = 8415757 | pmc = 47628 | doi = 10.1073/pnas.90.20.9654 | bibcode = 1993PNAS...90.9654M | doi-access = free }}</ref> which is accomplished through the interactions of AMPARs with many cellular proteins. The simplest explanation for LTP is as follows (see the [[long-term potentiation]] article for a much more detailed account). Glutamate binds to postsynaptic AMPARs and another glutamate receptor, the [[NMDA receptor]] (NMDAR). Ligand binding causes the AMPARs to open, and Na<sup>+</sup> flows into the postsynaptic cell, resulting in a depolarization. NMDARs, on the other hand, do not open directly because their pores are occluded at resting membrane potential by Mg<sup>2+</sup> ions. NMDARs can open only when a depolarization from the AMPAR activation leads to repulsion of the Mg<sup>2+</sup> cation out into the extracellular space, allowing the pore to pass current. Unlike AMPARs, however, NMDARs are permeable to both Na<sup>+</sup> and Ca<sup>2+</sup>. The Ca<sup>2+</sup> that enters the cell triggers the upregulation of AMPARs to the membrane, which results in a long-lasting increase in EPSP size underlying LTP. The calcium entry also phosphorylates [[CaMKII]], which phosphorylates AMPARs, increasing their single-channel conductance. ===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 = 5861–74 | 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 = 7863–7 | 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 = 175–90 | 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 = 32528–33 | 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 = 327–37 | 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]]).<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 = 23813–21 | 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 = 30928–34 | 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 = 443–55 | 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 = 1972–5 | 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 = 381–90 | 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 = 3805–10 | 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, Härtel 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 = 4332–45 | 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 = 535–48 | 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 proteins 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 = 1253–6 | 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 = 805–16 | 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 = 936–43 | 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 motion of AMPA receptors on the synaptic membrane are well approximated as a [[Brownian motion|Brownian]], which can however be stabilized at the PSD by retention forces. These forces can stabilize receptors transienstly, but allow a constant exchanges with the peri-synaptic domain.<ref>{{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=201–205 |pmc=2715948 |doi=10.1126/science.1152089|pmid=18403705 |bibcode=2008Sci...320..201H }}</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=17052–17057 |doi=10.1073/pnas.1204589109 |pmid=23035245 |pmc=3479500 |bibcode=2012PNAS..10917052H |doi-access=free}}</ref> These forces may results from the PSD local organization, sometimes refer to as [[phase separation]]. ====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]],<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> ====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, Lüscher 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 = 14112–7 | 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 = 1291–300 | 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 = 25963–6 | 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 = 1129–36 | 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 = 873–86 | 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 = 511–25 | 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 = 407–21 | 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> ====Role in Epileptic Seizures==== AMPA receptors play a key role in the generation and spread of epileptic seizures.<ref> {{cite journal | vauthors = Rogawski MA | title = AMPA receptors as a molecular target in epilepsy therapy | journal = Acta Neurologica Scandinavica. Supplementum | volume = 127 | issue = 197 | pages = 9–18 | year = 2013 | pmid = 23480151 | pmc = 4506648 | doi = 10.1111/ane.12099 }}</ref> [[Kainate|Kainic acid]], a convulsant that is widely used in epilepsy research induces seizures, in part, via activation of AMPA receptors<ref>{{cite journal | vauthors = Fritsch B, Reis J, Gasior M, Kaminski RM, Rogawski MA | title = Role of GluK1 kainate receptors in seizures, epileptic discharges, and epileptogenesis | journal = The Journal of Neuroscience | volume = 34 | issue = 17 | pages = 5765–75 | date = April 2014 | pmid = 24760837 | pmc = 3996208 | doi = 10.1523/JNEUROSCI.5307-13.2014 }}</ref>. ====Molecular target for epilepsy therapy==== The noncompetitive AMPA receptor antagonists [[talampanel]] and [[perampanel]] have been demonstrated to have activity in the treatment of adults with partial seizures,<ref name="Bialer">{{cite journal | vauthors = Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T | title = Progress report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EILAT VIII) | journal = Epilepsy Research | volume = 73 | issue = 1 | pages = 1–52 | date = January 2007 | pmid = 17158031 | doi = 10.1016/j.eplepsyres.2006.10.008 | s2cid = 45026113 }}</ref><ref name="French">{{cite journal | vauthors = French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, Kumar D, Rogawski MA | display-authors = 6 | title = Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304 | journal = Neurology | volume = 79 | issue = 6 | pages = 589–96 | date = August 2012 | pmid = 22843280 | pmc = 3413761 | doi = 10.1212/WNL.0b013e3182635735 }}</ref> indicating that AMPA receptor antagonists represent a potential target for the treatment of epilepsy.<ref name="Rogawski">{{cite journal | vauthors = Rogawski MA | title = Revisiting AMPA receptors as an antiepileptic drug target | journal = Epilepsy Currents | volume = 11 | issue = 2 | pages = 56–63 | date = March 2011 | pmid = 21686307 | pmc = 3117497 | doi = 10.5698/1535-7511-11.2.56 }}</ref> <ref name="Rogawski-b">{{cite journal | vauthors = Sakai F, Igarashi H, Suzuki S, Tazaki Y | title = Cerebral blood flow and cerebral hematocrit in patients with cerebral ischemia measured by single-photon emission computed tomography | journal = Acta Neurologica Scandinavica. Supplementum | volume = 127 | pages = 9–13 | year = 1989 | pmid = 2631521 | doi = 10.1111/j.1600-0404.1989.tb01805.x | s2cid = 30934688 | doi-access = free }}</ref> Perampanel (trade name: Fycompa) received Marketing Authorisation Approval by the European Commission for the treatment of partial epilepsy on July 27, 2012. The drug was approved in the United States by the [[Food and Drug Administration]] (FDA) on October 22, 2012. As has been the case for most recently developed AEDs including [[pregabalin]], [[lacosamide]] and [[ezogabine]], the FDA recommended that perampanel be classified by the [[Drug Enforcement Administration]] (DEA) as a scheduled drug. It has been designated as a Schedule 3 controlled substance. [[Decanoic acid]] acts as a non-competitive AMPA receptor antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects.<ref name= awv325>{{cite journal | vauthors = Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, Hardege JD, Chen PE, Walker MC, Williams RS | display-authors = 6 | title = Seizure control by decanoic acid through direct AMPA receptor inhibition | journal = Brain | volume = 139 | issue = Pt 2 | pages = 431–43 | date = February 2016 | pmid = 26608744 | pmc = 4805082 | doi = 10.1093/brain/awv325 }}</ref> This direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anticonvulsant effect of the [[medium-chain triglyceride]] [[ketogenic diet]].<ref name=awv325/> Decanoic acid and the AMPA receptor antagonist drug perampanel act at separate sites on the AMPA receptor, and so it is possible that they have a cooperative effect at the AMPA receptor, suggesting that perampanel and the ketogenic diet could be synergistic.<ref name=awv325/><ref>{{cite journal | doi=10.1111/epi.14578 | title=Perampanel and decanoic acid show synergistic action against <SCP>AMPA</SCP> receptors and seizures | date=2018 | last1=Augustin | first1=Katrin | last2=Williams | first2=Sophie | last3=Cunningham | first3=Mark | last4=Devlin | first4=Anita M. | last5=Friedrich | first5=Maximilian | last6=Jayasekera | first6=Ashan | last7=Hussain | first7=Mohammed A. | last8=Holliman | first8=Damian | last9=Mitchell | first9=Patrick | last10=Jenkins | first10=Alistair | last11=Chen | first11=Philip E. | last12=Walker | first12=Matthew C. | last13=Williams | first13=Robin S.B. | journal=Epilepsia | volume=59 | issue=11 | pages=e172–e178 | pmid=30324610 | doi-access=free }}</ref> Preclinical research suggest that several derivatives of aromatic amino acids with antiglutamatergic properties including AMPA receptor antagonism and inhibition of glutamate release such as 3,5-dibromo-D-tyrosine and 3,5-dibromo-L-phenylalnine exhibit strong anticonvulsant effect in animal models suggesting use of these compounds as a novel class of antiepileptic drugs.<ref>{{cite journal | vauthors = Cao W, Shah HP, Glushakov AV, Mecca AP, Shi P, Sumners C, Seubert CN, Martynyuk AE | display-authors = 6 | title = Efficacy of 3,5-dibromo-L-phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit | journal = British Journal of Pharmacology | volume = 158 | issue = 8 | pages = 2005–13 | date = December 2009 | pmid = 20050189 | pmc = 2807662 | doi = 10.1111/j.1476-5381.2009.00498.x }}</ref><ref>{{cite journal | vauthors = Cao W, Glushakov A, Shah HP, Mecca AP, Sumners C, Shi P, Seubert CN, Martynyuk AE | display-authors = 6 | title = Halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine produces beneficial effects in experimental stroke and seizures | journal = Amino Acids | volume = 40 | issue = 4 | pages = 1151–8 | date = April 2011 | pmid = 20839013 | doi = 10.1007/s00726-010-0739-4 | s2cid = 19852158 | pmc = 8396070 }}</ref> ===Agonists=== [[Image:L-glutamic-acid-skeletal.png|thumb|right|175px|[[Glutamate]], the [[endogenous agonist]] of the AMPAR.]] [[Image:AMPA.svg|thumb|right|175px|[[AMPA]], a synthetic agonist of the AMPAR.]] * [[5-Fluorowillardiine]] – a synthetic modification of [[willardiine]] * {{abbrlink|AMPA|α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid}} – a synthetic agonist after which the receptor is named * [[Domoic acid]] – a naturally occurring agonist that causes [[amnesic shellfish poisoning]] * [[Glutamic acid]] (glutamate) – the [[endogenous agonist]] * [[Ibotenic acid]] – a naturally occurring agonist found in ''[[Amanita muscaria]]'' * [[Quisqualic acid]] – a naturally occurring agonist found in certain species * [[Willardiine]] – a naturally occurring agonist ===Positive allosteric modulators=== {{Main|AMPA receptor positive allosteric modulator}} {{div col|colwidth=22em}} * [[Aniracetam]] * [[Cyclothiazide]] * [[CX-516]] * [[CX-546]] * [[CX-614]] * [[Osavampator]] (TAK-653) * [[CX-717]] * [[Farampator]] (CX-691, ORG-24448) * [[IDRA-21]] * [[LY-404187]] * [[LY-503430]]<ref name="pmid12730350">{{cite journal | vauthors = Murray TK, Whalley K, Robinson CS, Ward MA, Hicks CA, Lodge D, Vandergriff JL, Baumbarger P, Siuda E, Gates M, Ogden AM, Skolnick P, Zimmerman DM, Nisenbaum ES, Bleakman D, O'Neill MJ | display-authors = 6 | title = LY503430, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor potentiator with functional, neuroprotective and neurotrophic effects in rodent models of Parkinson's disease | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 306 | issue = 2 | pages = 752–62 | date = August 2003 | pmid = 12730350 | doi = 10.1124/jpet.103.049445 | s2cid = 86751458 }}</ref><ref name="pmid15180479">{{cite journal | vauthors = O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES | title = AMPA receptor potentiators for the treatment of CNS disorders | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 3 | issue = 3 | pages = 181–94 | date = June 2004 | pmid = 15180479 | doi = 10.2174/1568007043337508 }}</ref> * [[Mibampator]] (LY-451395) * [[ORG-26576]] * [[Oxiracetam]] * [[PEPA (drug)|PEPA]] * [[Pesampator]] (BIIB-104) * [[Piracetam]] * [[Pramiracetam]] * [[Traneurocin]] (NA-831) * [[Tulrampator]] (S-47445, CX-1632) {{div col end}} ===Antagonists=== * [[Becampanel]] * [[CNQX]] * [[Dasolampanel]] * [[DNQX]] * [[Fanapanel]] (MPQX) * [[Kaitocephalin]] * [[Kynurenic acid]] – endogenous ligand * [[L-theanine]] * [[NBQX]] * 3,5-Dibromo-L-phenylalanine, a naturally occurring halogenated derivative of [[L-Phenylalanine|L-phenylalanine]]<ref>{{cite journal | vauthors = Yarotskyy V, Glushakov AV, Sumners C, Gravenstein N, Dennis DM, Seubert CN, Martynyuk AE | title = Differential modulation of glutamatergic transmission by 3,5-dibromo-L-phenylalanine | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1648–54 | date = May 2005 | pmid = 15687225 | doi = 10.1124/mol.104.005983 | s2cid = 11672391 }}</ref> * [[Perampanel]] * [[Selurampanel]] * [[Tezampanel]] * [[Zonampanel]] ===Negative allosteric modulators=== [[File:Perampanel structure.svg|thumb|right|175px|[[Perampanel]], a negative allosteric modulator of the AMPAR used to treat [[epilepsy]].]] * [[Barbiturate]]s (e.g., [[pentobarbital]], [[sodium thiopental]]) – non-selective * [[Ethanol]] – non-selective * [[Inhalational anaesthetic]]s (e.g., [[cyclopropane]], [[enflurane]], [[halothane]], [[isoflurane]], [[sevoflurane]]) – non-selective * [[GYKI-52466]] * [[Irampanel]] * [[Perampanel]] * [[Talampanel]] *PEP1-TGL : GluA1 subunit C-terminus peptide analog that inhibits AMPA receptor incorporation to the postsynaptic density<ref>{{Cite journal|url=https://www.science.org/doi/full/10.1126/science.287.5461.2262|title=Hayashi et al (200) Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction. Science 287; 2262-2267 |journal=Science |date=24 March 2000 |volume=287 |issue=5461 |pages=2262–2267 |doi=10.1126/science.287.5461.2262 |last1=Hayashi |first1=Yasunori |last2=Shi |first2=Song-Hai |last3=Esteban |first3=José A. |last4=Piccini |first4=Antonella |last5=Poncer |first5=Jean-Christophe |last6=Malinow |first6=Roberto |pmid=10731148 |bibcode=2000Sci...287.2262H }}</ref><ref>{{cite journal | vauthors = Tazerart S, Mitchell DE, Miranda-Rottmann S, Araya R | title = A spike-timing-dependent plasticity rule for dendritic spines | journal = Nature Communications | volume = 11 | issue = 1 | pages = 4276 | date = August 2020 | pmid = 32848151 | pmc = 7449969 | doi = 10.1038/s41467-020-17861-7 | bibcode = 2020NatCo..11.4276T }}</ref> == See also == * [[Arc (protein)|Arc/Arg3.1]] == References == {{Reflist|35em}} == External links == *[https://web.archive.org/web/20041213035007/http://www.bris.ac.uk/Depts/Synaptic/info/pharmacology/AMPA.html AMPA receptors - pharmacology] * 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