Excitatory amino acid transporter 2 (EAAT2) also known assolute carrier family 1 member 2 (SLC1A2) andglutamate transporter 1 (GLT-1) is aprotein that in humans is encoded by theSLC1A2gene.[5][6] Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.[6]
SLC1A2 / EAAT2 is a member of a family of thesolute carrier family of proteins. The membrane-bound protein is the principal transporter that clears the excitatoryneurotransmitterglutamate 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 ofglutamate receptors.[6] EAAT2 is responsible for over 90% of glutamate reuptake within the brain.[7][8]
This diagram shows the tissue distribution of glutamate transporter 1 (EAAT2) in the brain.[7]
Mutations in and decreased expression of this protein are associated withamyotrophic lateral sclerosis (ALS).[6] The drugriluzole approved for the treatment of ALS upregulates EAAT2.[9]
Ceftriaxone, an antibiotic, has been shown to induce/enhance the expression of EAAT2, resulting in reduced glutamate activity.[10] 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.[11]
Upregulation of EAAT2 (GLT-1) causes impairment ofprepulse inhibition, asensory gating deficit present in schizophrenics and schizophrenia animal models.[12][13] Some antipsychotics have been shown to reduce the expression of EAAT2.[14][15]
EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamateneurotransmission. 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 asceftriaxone 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.[17]
DL-TBOA,WAY-213,613, anddihydrokainic acid are known inhibitors of the protein, and function as excitotoxins. They can be considered a novel class ofnerve agent toxins, inducing toxic levels of glutamate through transport inhibition in a manner analogous to the effect ofsarin oncholinesterase. Antidotes for such a poisoning have never been formally tested for efficacy and are not readily available for medical use.[18]
Addiction to certain drugs (e.g.,cocaine,heroin,alcohol, andnicotine) is correlated with a persistent reduction in the expression of EAAT2 in thenucleus accumbens (NAcc);[19] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.[19] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability torelapse after re-exposure to the addictive drug or its associateddrug cues.[19] Drugs which help to normalize the expression of EAAT2 in this region, such asN-acetylcysteine, have been proposed as anadjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[19]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Pines G, Danbolt NC, Bjørås M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI (Dec 1992). "Cloning and expression of a rat brain L-glutamate transporter".Nature.360 (6403):464–7.Bibcode:1992Natur.360..464P.doi:10.1038/360464a0.PMID1448170.S2CID4243369.
^Holmseth S; Scott HA; Real K; Lehre KP; Leergaard TB; Bjaalie JG; Danbolt NC (2009). "The concentrations and distributions of three C-terminal variants of the GLT1 (EAAT2; slc1a2) glutamate transporter protein in rat brain tissue suggest differential regulation".Neuroscience.162 (4):1055–71.doi:10.1016/j.neuroscience.2009.03.048.PMID19328838.S2CID41615013.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.
Clarification of nomenclature 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.
^Bellesi M, Melone M, Gubbini A, Battistacci S, Conti F (2009). "GLT-1 upregulation impairs prepulse inhibition of the startle reflex in adult rats".Glia.57 (7):703–13.doi:10.1002/glia.20798.PMID18985735.S2CID3222131.
^Schmitt A, Zink M, Petroianu G, May B, Braus DF, Henn FA (2003). "Decreased gene expression of glial and neuronal glutamate transporters after chronic antipsychotic treatment in rat brain".Neurosci. Lett.347 (2):81–4.doi:10.1016/S0304-3940(03)00653-0.PMID12873733.S2CID43706291.
^Vallejo-Illarramendi A, Torres-Ramos M, Melone M, Conti F, Matute C (2005). "Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures".Glia.50 (3):276–9.doi:10.1002/glia.20172.PMID15739191.S2CID18972974.
^Marie H, Billups D, Bedford FK, Dumoulin A, Goyal RK, Longmore GD, Moss SJ, Attwell D (February 2002). "The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba".Mol. Cell. Neurosci.19 (2):152–64.doi:10.1006/mcne.2001.1066.PMID11860269.S2CID45768895.
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 (2004). "Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis".J. Neurovirol. 10.10 (Suppl 1):25–32.doi:10.1080/jnv.10.s1.25.32.PMID14982736.
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Aoki M, Lin CL, Rothstein JD, Geller BA, Hosler BA, Munsat TL, Horvitz HR, Brown RH (1998). "Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis".Ann. Neurol.43 (5):645–53.doi:10.1002/ana.410430514.PMID9585360.S2CID10885891.
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