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 SLC1A2gene.[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 the solute carrier family of proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitterglutamate 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.[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 with amyotrophic lateral sclerosis (ALS).[6] The drug riluzole 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 of prepulse inhibition, a sensory 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 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.[17]
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 sarinoncholinesterase. 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, and nicotine) is correlated with a persistent reduction in the expression of EAAT2 in the nucleus 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 to relapse after re-exposure to the addictive drug or its associated drug cues.[19] 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.[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.
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Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (1998). "DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters". Mol. Pharmacol. 53 (2): 195–201. doi:10.1124/mol.53.2.195. PMID9463476.
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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