Disease relevance of SLC1A2

• Loss of function of the glial glutamate transporter GLT1 (SLC1A2) has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), resulting in damage of adjacent motor neurons [1].
• Impaired glutamate transport after HIV-1 infection or gp120 exposure correlated with a 40-70% decline in steady-state levels of EAAT2 RNA and protein [2].
• In the present study, we examined whether traumatic brain injury (TBI) affects the cellular expression of glutamate transporters EAAT1 and EAAT2 [3].
• Moreover, they raise the intriguing possibility that the EAAT2 promoter may be useful for targeting gene expression in the brain and for identifying molecules capable of modulating glutamate transport that could potentially inhibit, ameliorate, or prevent various neurodegenerative diseases [4].
• RATIONALE: Altered expression of glutamate transporter EAAT2 protein has been reported in the hippocampus of patients with temporal lobe epilepsy (TLE) [5].
• This review describes what is currently known about the regulation of EAAT2 mRNA and protein isoforms and concludes with a summary of studies showing dysregulation of EAAT2 in psychiatric and neurological disorders [6].

Psychiatry related information on SLC1A2

• This study demonstrates that distinct subclasses of neurons exhibited EAAT-2 immunoreactivity in cases with Alzheimer's disease (AD) [7].
• Furthermore, gene transfer techniques using recombinant adenoviruses revealed that GLT-1 in the locus coeruleus and NAc shell plays inhibitory roles in physical and psychological morphine dependence, respectively [8].
• Ectopic expression of AEG-1 inhibits excitatory amino acid transporter 2 (EAAT2) promoter activity with the potential to promote glutamate excitotoxicity and consequently HIV-1-associated dementia (HAD) [9].
• These two consistent lines of evidence suggest that genetic variation of the EAAT2 gene confers vulnerability to risk-taking behavior in alcoholics [10].

High impact information on SLC1A2

• A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke [11].
• The antioxidant Mn(III)TBAP rescued GLT1 from inhibition [12].
• Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis [13].
• About 60%-70% of sporadic ALS patients have a 30%-95% loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord [13].
• Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1) [14].

Chemical compound and disease context of SLC1A2

• Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120 [2].
• There was a similar increase in mRNA levels after hypoxia in C6 cells transfected with human EAAT2, whereas reoxygenation normalized the expression levels of glutamate transporters [15].
• Finally, although the protein kinase C stimulator phorbol-12-myristate-13-acetate enhanced EAAT2 mRNA levels after hypoxia, protein kinase C inhibitor bisindolylmaleimide I had the opposite effect [15].
• Effects of deep hypothermia (22 to 23 degrees C) on uptake and release of L-glutamate via hGLT-1 were investigated by whole-cell patch-clamp [16].
• Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis [17].

Biological context of SLC1A2

• On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS [18].
• The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay [19].
• We conclude that the posttraumatic reduction in cellular EAAT 1 and EAAT2 expression is predominantly due to degeneration of astrocytes and to downregulation in surviving astrocytes [3].
• Astrocytes isolated from fetal tissues between 16 and 19 weeks of gestation expressed EAAT1 and EAAT2 RNA and proteins as detected by Northern blot analysis and immunoblotting, respectively, and the cells were capable of specific glutamate uptake [2].
• The glutamate transporters EAAT1, EAAT2 and EAAT3 are key components of the glutamate-glutamine cycle and responsible for active transport of glutamate over the cell membrane [20].

Anatomical context of SLC1A2

• The Kb values for human EAAT1 and EAAT2 expressed in X. laevis oocytes were 9.0 microM and 116 nM, respectively [21].
• These findings demonstrate that HIV-1 and gp120 induce transcriptional downmodulation of the EAAT2 transporter gene in human astrocytes and coordinately attenuate glutamate transport by the cells [2].
• Following traumatic injury of human brain (n = 55), the number of EAAT2-positive cells was decreased for a prolonged survival period within the traumatized neocortex and the pericontusional region [3].
• We demonstrated previously that human macrophages express the glutamate transporters excitatory amino acid transporter (EAAT)1 and EAAT2 (which do not transport cystine, X system) and overcome competition for the use of cystine transporters [22].
• EAAT2 was exclusively localised to astrocytes, with preferential expression in the caudate nucleus, nucleus basalis of Meynert, spinal ventral horn, cerebral cortex and hippocampus, but with lower levels of expression throughout many other CNS regions [23].

Associations of SLC1A2 with chemical compounds

• The glutamate transporter gene, EAAT2/GLT-1, is induced by epidermal growth factor (EGF) and downregulated by tumor necrosis factor alpha (TNFalpha) [24].
• The EAAT2 subtype was distinguishable from the EAAT1/EAAT3 subtypes by the potency of several inhibitors, but most notably by sensitivity to kainic acid (KA) and dihydrokainic acid (DHK) [25].
• With regard to the human excitatory amino acid transporter-2 (EAAT2), the inhibitory effect of DL-TBOA (Ki = 5.7 microM) was much more potent than that of dihydrokainate (Ki = 79 microM), which is well known as a selective blocker of this subtype [21].
• In contrast, a significant effect of diazepam on EAAT2-mediated uptake was only observed at 1000 micromol/l where uptake was inhibited by 60% [26].
• Here we used cysteine-scanning mutagenesis of the GLT-1 transporter to test the idea that this loop undergoes conformational changes following sodium and substrate binding [27].

Regulatory relationships of SLC1A2

• Post-translational regulation of EAAT2 function by co-expressed ubiquitin ligase Nedd4-2 is impacted by SGK kinases [28].
• However, even in the absence of L-glutamate, the membrane conductance of oocytes expressing EAAT1 was significantly increased relative to oocytes expressing EAAT2 or control oocytes [29].
• Treatment with dibutyryl-cAMP, epidermal growth factor (EGF) or other growth factors both induces expression of GLT-1 and increases expression of GLAST in astrocyte cultures [30].
• Consequently, a significant increase in CA1 neuronal damage was observed in slices over-expressing EAAT2 in neurons following an acute exposure to exogenous glutamate [31].

Other interactions of SLC1A2

• Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression [24].
• KA and DHK potently inhibited EAAT2 transport, but did not significantly affect transport by EAAT1/EAAT3 [25].
• Herein, we demonstrate that both TNFalpha-mediated repression and EGF-mediated activation of EAAT2 expression require NF-kappaB [24].
• Furthermore, TNFalpha can abrogate IKKbeta- and p65-mediated activation of EAAT2 [24].
• The results indicate an upregulation of EAAT2 protein expression in CA1 and CA2 in neurones in the non-HS group [32].

Analytical, diagnostic and therapeutic context of SLC1A2

• Double immunofluorescence examinations revealed a reduction in absolute numbers of GFAP-positive astrocytes coexpressing EAAT1 or EAAT2 at survival times up to 7 days [3].
• Western blotting of homogenates of human cortical tissue with the EAAT2 antibody produced a discrete band at 66 kDa [23].
• In this study, a monoclonal antibody, suitable for immunohistochemistry (IHC) in human post-mortem tissue, was produced to the human astrocytic glutamate transporter EAAT2 (excitatory amino acid transporter 2) [23].
• Non-radioactive in situ hybridization showed that not only astrocytes, but also neurones express EAAT2 mRNA [32].
• TWO novel transcripts of the human excitatory amino acid transporter EAAT2 (GLT-1) were cloned using PCR cloning techniques [33].

References