Editing AMPA receptor (section)

===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>