{{Short description|Protein found in humans}} {{Infobox_gene}} '''Excitatory amino acid transporter 2''' ('''EAAT2''') also known as '''solute carrier family 1 member 2''' ('''SLC1A2''') and '''glutamate transporter 1''' ('''GLT-1''') is a protein that in humans is encoded by the ''SLC1A2'' gene.<ref name="pmid1448170">{{cite journal | vauthors = Pines G, Danbolt NC, Bjørås M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI | title = Cloning and expression of a rat brain L-glutamate transporter | journal = Nature | volume = 360 | issue = 6403 | pages = 464–7 | date = Dec 1992 | pmid = 1448170 | doi = 10.1038/360464a0 | bibcode = 1992Natur.360..464P | s2cid = 4243369 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC1A2 solute carrier family 1 (glial high affinity glutamate transporter), member 2| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=6506}}</ref> Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.<ref name="entrez"/>
== Function ==
SLC1A2 / EAAT2 is a member of a family of the solute carrier family of proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors.<ref name="entrez"/> EAAT2 is responsible for over 90% of glutamate reuptake within the brain.<ref name="EAAT2 and CNS glutamate uptake">{{cite journal | vauthors = Rao P, Yallapu MM, Sari Y, Fisher PB, Kumar S | title = Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction | journal = J. Pers. Nanomed. | volume = 1 | issue = 1 | pages = 3–9 | date = July 2015 | pmid = 26635971 | pmc = 4666545 | quote = The glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) is responsible for the reuptake of more than 90% glutamate in the CNS [12–14].}}</ref><ref name="Homseth et al. 2009">{{cite journal |author1=Holmseth S |author2=Scott HA |author3=Real K |author4=Lehre KP |author5=Leergaard TB |author6=Bjaalie JG |author7=Danbolt NC | title = The concentrations and distributions of three C-terminal variants of the GLT1 (EAAT2; slc1a2) glutamate transporter protein in rat brain tissue suggest differential regulation | journal = Neuroscience | volume = 162 | issue = 4 | pages = 1055–71 | year = 2009 | pmid = 19328838 | doi = 10.1016/j.neuroscience.2009.03.048 |s2cid=41615013 | quote = Since then, a family of five high-affinity glutamate transporters has been characterized that is responsible for the precise regulation of glutamate levels at both synaptic and extrasynaptic sites, although the glutamate transporter 1 (GLT1) is responsible for more than 90% of glutamate uptake in the brain.3 The importance of GLT1 is further highlighted by the large number of neuropsychiatric disorders associated with glutamate-induced neurotoxicity.<br /><br />Clarification of nomenclature<br />The major glial glutamate transporter is referred to as GLT1 in the rodent literature and excitatory amino acid transporter 2 (EAAT2) in the human literature. }}</ref> {{multiple image <!--Layout parameters--> | align = center | direction = vertical <!--Image 1--> | image1 = Glutamate reuptake via EAAT2 (GLT1).jpg | width1 = 450 | alt1 = EAAT2 reuptake diagram | caption1 = This diagram shows the tissue distribution of glutamate transporter 1 (EAAT2) in the brain.<ref name="EAAT2 and CNS glutamate uptake" /> }}
== Clinical significance ==
Mutations in and decreased expression of this protein are associated with amyotrophic lateral sclerosis (ALS).<ref name="entrez"/> The drug riluzole approved for the treatment of ALS upregulates EAAT2.<ref name="riluzole">{{cite journal | vauthors = Carbone M, Duty S, Rattray M | title = Riluzole elevates GLT-1 activity and levels in striatal astrocytes | journal = Neurochem. Int. | volume = 60 | issue = 1 | pages = 31–8 | year = 2012 | pmid = 22080156 | pmc = 3430367 | doi = 10.1016/j.neuint.2011.10.017 }}</ref>
Ceftriaxone, an antibiotic, has been shown to induce/enhance the expression of EAAT2, resulting in reduced glutamate activity.<ref name="pmid18326497">{{cite journal | vauthors = Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB | title = Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes | journal = J. Biol. Chem. | volume = 283 | issue = 19 | pages = 13116–23 | date = May 2008 | pmid = 18326497 | pmc = 2442320 | doi = 10.1074/jbc.M707697200 | doi-access = free }}</ref> Ceftriaxone has been shown to reduce the development and expression of tolerance to opiates and other drugs of abuse. EAAT2 may possess an important role in drug addiction and tolerance to addictive drugs.<ref name="addiction">{{cite journal | vauthors = Reissner KJ, Kalivas PW | title = Using glutamate homeostasis as a target for treating addictive disorders | journal = Behav Pharmacol | volume = 21 | issue = 5–6 | pages = 514–22 | year = 2010 | pmid = 20634691 | pmc = 2932669 | doi = 10.1097/FBP.0b013e32833d41b2 }}</ref>
Upregulation of EAAT2 (GLT-1) causes impairment of prepulse inhibition, a sensory gating deficit present in schizophrenics and schizophrenia animal models.<ref name="eaat2ppi">{{cite journal | vauthors = Bellesi M, Melone M, Gubbini A, Battistacci S, Conti F | title = GLT-1 upregulation impairs prepulse inhibition of the startle reflex in adult rats | journal = Glia | volume = 57 | issue = 7 | pages = 703–13 | year = 2009 | pmid = 18985735 | doi = 10.1002/glia.20798 | s2cid = 3222131 }}</ref><ref name="mgluppi">{{cite journal | vauthors = Bellesi M, Conti F | title = The mGluR2/3 agonist LY379268 blocks the effects of GLT-1 upregulation on prepulse inhibition of the startle reflex in adult rats | journal = Neuropsychopharmacology | volume = 35 | issue = 6 | pages = 1253–60 | year = 2010 | pmid = 20072121 | pmc = 3055342 | doi = 10.1038/npp.2009.225 }}</ref> Some antipsychotics have been shown to reduce the expression of EAAT2.<ref name="eaatcloz">{{cite journal | vauthors = Schmitt A, Zink M, Petroianu G, May B, Braus DF, Henn FA | title = Decreased gene expression of glial and neuronal glutamate transporters after chronic antipsychotic treatment in rat brain | journal = Neurosci. Lett. | volume = 347 | issue = 2 | pages = 81–4 | year = 2003 | pmid = 12873733 | doi = 10.1016/S0304-3940(03)00653-0 | s2cid = 43706291 }}</ref><ref name="clozastro">{{cite journal | vauthors = Vallejo-Illarramendi A, Torres-Ramos M, Melone M, Conti F, Matute C | title = Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures | journal = Glia | volume = 50 | issue = 3 | pages = 276–9 | year = 2005 | pmid = 15739191 | doi = 10.1002/glia.20172 | s2cid = 18972974 }}</ref>
== Interactions ==
SLC1A2 has been shown to interact with JUB.<ref name="pmid11860269">{{cite journal | vauthors = Marie H, Billups D, Bedford FK, Dumoulin A, Goyal RK, Longmore GD, Moss SJ, Attwell D | title = The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba | journal = Mol. Cell. Neurosci. | volume = 19 | issue = 2 | pages = 152–64 | date = February 2002 | pmid = 11860269 | doi = 10.1006/mcne.2001.1066 | s2cid = 45768895 }}</ref>
== As a drug target ==
EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamate neurotransmission. Dysfunction of EAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression of EAAT2/GLT-1 could serve as a potential therapy for these conditions. Translational activators of EAAT2/GLT-1, such as ceftriaxone and LDN/OSU-0212320, have been described to have significant protective effects in animal models of ALS and epilepsy. In addition, pharmacological activators of the activity of EAAT2/GLT-1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators.<ref name="Current approaches">{{Cite journal|vauthors=Fontana AC |title=Current approaches to enhance glutamate transporter function and expression. |journal= Journal of Neurochemistry |date=June 20, 2015 |doi=10.1111/jnc.13200 |pmid=26096891 |volume=134 |issue=6 |pages=982–1007|url=https://zenodo.org/record/889649 |doi-access=free }}</ref>
DL-TBOA, WAY-213,613, and dihydrokainic acid are known inhibitors of the protein, and function as excitotoxins. They can be considered a novel class of nerve agent toxins, inducing toxic levels of glutamate through transport inhibition in a manner analogous to the effect of sarin on cholinesterase. Antidotes for such a poisoning have never been formally tested for efficacy and are not readily available for medical use.<ref>{{cite journal|url=http://molpharm.aspetjournals.org/content/molpharm/53/2/195.full.pdf|title=DL-threo-b-Benzyloxyaspartate, A Potent Blocker of Excitatory Amino Acid Transporters|author=KEIKO SHIMAMOTO, BRUNO LEBRUN, YOSHIMI YASUDA-KAMATANI, MASAHIRO SAKAITANI, YASUSHI SHIGERI, NOBORU YUMOTO, and TERUMI NAKAJIMA|journal=Molecular Pharmacology|date=February 1998|volume=53|issue=2|pages=195–201|doi=10.1124/mol.53.2.195|pmid=9463476}}</ref>
Addiction to certain drugs (e.g., cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of EAAT2 in the nucleus accumbens (NAcc);<ref name="pmid24442756" /> the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.<ref name="pmid24442756" /> In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.<ref name="pmid24442756" /> Drugs which help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.<ref name="pmid24442756">{{cite journal | vauthors = McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM | title = Potential role of N-acetylcysteine in the management of substance use disorders | journal = CNS Drugs | volume = 28 | issue = 2 | pages = 95–106 | year = 2014 | pmid = 24442756 | pmc = 4009342 | doi = 10.1007/s40263-014-0142-x }}</ref>
== See also == * Glutamate transporter * Solute carrier family
== References == {{reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Wang Z, Trillo-Pazos G, Kim SY, Canki M, Morgello S, Sharer LR, Gelbard HA, Su ZZ, Kang DC, Brooks AI, Fisher PB, Volsky DJ | title = Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis | journal = J. Neurovirol. | volume = 10 | pages = 25–32 | year = 2004 | pmid = 14982736 | doi = 10.1080/jnv.10.s1.25.32| series = 10 | issue = Suppl 1 }} * {{cite journal | vauthors = Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG | title = Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex | journal = J. Neurosci. | volume = 14 | issue = 9 | pages = 5559–69 | year = 1994 | pmid = 7521911 | pmc = 6577102 | doi = 10.1523/jneurosci.14-09-05559.1994}} * {{cite journal | vauthors = Manfras BJ, Rudert WA, Trucco M, Boehm BO | title = Cloning and characterization of a glutamate transporter cDNA from human brain and pancreas | journal = Biochim. Biophys. Acta | volume = 1195 | issue = 1 | pages = 185–8 | year = 1994 | pmid = 7522567 | doi = 10.1016/0005-2736(94)90026-4 }} * {{cite journal | vauthors = Li X, Francke U | title = Assignment of the gene SLC1A2 coding for the human glutamate transporter EAAT2 to human chromosome 11 bands p13-p12 | journal = Cytogenet. Cell Genet. | volume = 71 | issue = 3 | pages = 212–3 | year = 1995 | pmid = 7587378 | doi = 10.1159/000134111 }} * {{cite journal | vauthors = Shashidharan P, Wittenberg I, Plaitakis A | title = Molecular cloning of human brain glutamate/aspartate transporter II | journal = Biochim. Biophys. Acta | volume = 1191 | issue = 2 | pages = 393–6 | year = 1994 | pmid = 8172925 | doi = 10.1016/0005-2736(94)90192-9 }} * {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Anal. Biochem. | volume = 236 | issue = 1 | pages = 107–13 | year = 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }} * {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Res. | volume = 7 | issue = 4 | pages = 353–8 | year = 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }} * {{cite journal | vauthors = Milton ID, Banner SJ, Ince PG, Piggott NH, Fray AE, Thatcher N, Horne CH, Shaw PJ | title = Expression of the glial glutamate transporter EAAT2 in the human CNS: an immunohistochemical study | journal = Brain Res. Mol. Brain Res. | volume = 52 | issue = 1 | pages = 17–31 | year = 1997 | pmid = 9450673 | doi = 10.1016/S0169-328X(97)00233-7 }} * {{cite journal | vauthors = Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T | title = DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters | journal = Mol. Pharmacol. | volume = 53 | issue = 2 | pages = 195–201 | year = 1998 | pmid = 9463476 | doi = 10.1124/mol.53.2.195}} * {{cite journal | vauthors = Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD | title = Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis | journal = Neuron | volume = 20 | issue = 3 | pages = 589–602 | year = 1998 | pmid = 9539131 | doi = 10.1016/S0896-6273(00)80997-6 | doi-access = free }} * {{cite journal | vauthors = Aoki M, Lin CL, Rothstein JD, Geller BA, Hosler BA, Munsat TL, Horvitz HR, Brown RH | title = Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis | journal = Ann. Neurol. | volume = 43 | issue = 5 | pages = 645–53 | year = 1998 | pmid = 9585360 | doi = 10.1002/ana.410430514 | s2cid = 10885891 }} * {{cite journal | vauthors = Trotti D, Aoki M, Pasinelli P, Berger UV, Danbolt NC, Brown RH, Hediger MA | title = Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity | journal = J. Biol. Chem. | volume = 276 | issue = 1 | pages = 576–82 | year = 2001 | pmid = 11031254 | doi = 10.1074/jbc.M003779200 | doi-access = free }} * {{cite journal | vauthors = Münch C, Schwalenstöcker B, Hermann C, Cirovic S, Stamm S, Ludolph A, Meyer T | title = Differential RNA cleavage and polyadenylation of the glutamate transporter EAAT2 in the human brain | journal = Brain Res. Mol. Brain Res. | volume = 80 | issue = 2 | pages = 244–51 | year = 2000 | pmid = 11038258 | doi = 10.1016/S0169-328X(00)00139-X }} * {{cite journal | vauthors = Honig LS, Chambliss DD, Bigio EH, Carroll SL, Elliott JL | title = Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls | journal = Neurology | volume = 55 | issue = 8 | pages = 1082–8 | year = 2000 | pmid = 11071482 | doi = 10.1212/wnl.55.8.1082 | s2cid = 26759254 }} * {{cite journal | vauthors = Flowers JM, Powell JF, Leigh PN, Andersen P, Shaw CE | title = Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis | journal = Ann. Neurol. | volume = 49 | issue = 5 | pages = 643–9 | year = 2001 | pmid = 11357955 | doi = 10.1002/ana.1029 | s2cid = 25451450 }} * {{cite journal | vauthors = Rimaniol AC, Mialocq P, Clayette P, Dormont D, Gras G | title = Role of glutamate transporters in the regulation of glutathione levels in human macrophages | journal = Am. J. Physiol., Cell Physiol. | volume = 281 | issue = 6 | pages = C1964-70 | year = 2001 | pmid = 11698255 | doi = 10.1152/ajpcell.2001.281.6.C1964| s2cid = 3173417 }} * {{cite journal | vauthors = Tozaki H, Kanno T, Nomura T, Kondoh T, Kodama N, Saito N, Aihara H, Nagata T, Matsumoto S, Ohta K, Nagai K, Yajima Y, Nishizaki T | title = Role of glial glutamate transporters in the facilitatory action of FK960 on hippocampal neurotransmission | journal = Brain Res. Mol. Brain Res. | volume = 97 | issue = 1 | pages = 7–12 | year = 2001 | pmid = 11744157 | doi = 10.1016/S0169-328X(01)00304-7 }} * {{cite journal | vauthors = Palmada M, Kinne-Saffran E, Centelles JJ, Kinne RK | title = Benzodiazepines differently modulate EAAT1/GLAST and EAAT2/GLT1 glutamate transporters expressed in CHO cells | journal = Neurochem. Int. | volume = 40 | issue = 4 | pages = 321–6 | year = 2002 | pmid = 11792462 | doi = 10.1016/S0197-0186(01)00087-0 | s2cid = 23624873 }} * {{cite journal | vauthors = Marie H, Billups D, Bedford FK, Dumoulin A, Goyal RK, Longmore GD, Moss SJ, Attwell D | title = The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba | journal = Mol. Cell. Neurosci. | volume = 19 | issue = 2 | pages = 152–64 | year = 2002 | pmid = 11860269 | doi = 10.1006/mcne.2001.1066 | s2cid = 45768895 }} * {{cite journal | vauthors = Reye P, Sullivan R, Fletcher EL, Pow DV | title = Distribution of two splice variants of the glutamate transporter GLT1 in the retinas of humans, monkeys, rabbits, rats, cats, and chickens | journal = J. Comp. Neurol. | volume = 445 | issue = 1 | pages = 1–12 | year = 2002 | pmid = 11891650 | doi = 10.1002/cne.10095 | s2cid = 23382118 }} {{refend}}
{{NLM content}} {{Solute carrier family|bg|bg0}} {{Glutamate metabolism and transport modulators}}
Category:Solute carrier family Category:Neurotransmitter transporters Category:Glutamate (neurotransmitter)