Editing AMPA receptor (section)

==Structure and function==

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

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

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

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

===Mechanism of Action===
AMPA receptors are integral to fast excitatory neurotransmission in the CNS.  Each receptor is a tetramer composed of four subunits, each providing a binding site for [[Agonist|agonists]] like glutamate.<ref name="Glutamate receptor ion channels"/> The ligand-binding domain is 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>  The subunit composition significantly influences the receptor's functional properties, including ion permeability and gating kinetics. 
==== Agonist Binding and Channel Activation ====
Upon glutamate binding, these two loops move towards each other, leading to pore opening.  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>  This opening allows the influx of [[Sodium ion|sodium (Na⁺)]] and, depending on subunit composition, [[Calcium ion|calcium (Ca²⁺)]] ions into the postsynaptic neuron, leading to depolarization and the propagation of excitatory signals.<ref>{{Cite journal |last1=Hale |first1=W. Dylan |last2=Montaño Romero |first2=Alejandra |last3=Gonzalez |first3=Cuauhtemoc U. |last4=Jayaraman |first4=Vasanthi |last5=Lau |first5=Albert Y. |last6=Huganir |first6=Richard L. |last7=Twomey |first7=Edward C. |date=November 2024 |title=Allosteric competition and inhibition in AMPA receptors |journal=Nature Structural & Molecular Biology |language=en |volume=31 |issue=11 |pages=1669–1679 |doi=10.1038/s41594-024-01328-0 |issn=1545-9993 |pmc=11563869 |pmid=38834914}}</ref> Once open, the channel may undergo rapid desensitization, stopping the current.  

==== Desensitization Mechanism ====
The mechanism of desensitization is 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|postsynaptic transmission]] in the central nervous system.<ref name="Platt2007" /> 

==== Subunit Composition and Ion Permeability ====
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 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 unfavorable for calcium to enter the cell through the pore.<ref>{{Cite journal |last1=Cull-Candy |first1=Stuart G. |last2=Farrant |first2=Mark |date=May 2021 |title=Ca 2+ -permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease |journal=The Journal of Physiology |language=en |volume=599 |issue=10 |pages=2655–2671 |doi=10.1113/JP279029 |issn=0022-3751 |pmc=8436767 |pmid=33533533}}</ref>  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 desensitization<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 resensitized<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>