Disease relevance of Slc1a3

• Hyperthyroidism in rats is related to an increase in cardiac expression of EAAT1 mRNA and protein [1].
• Correlation between myocardial malate/aspartate shuttle activity and EAAT1 protein expression in hyper- and hypothyroidism [1].
• Selective induction of glial glutamate transporter GLT-1 by hypertonic stress in C6 glioma cells [2].
• Finally, changes in GLAST and GLT-1 expression were not observed in the CA1 region after ischemia using immunohistochemical study or immunoblotting [3].
• We have investigated the effects of lateral fluid percussion on the levels of the glutamate transporter proteins GLT-1alpha, its splice variant GLT-1v, GLAST, and EAAC1 in the rat in order to evaluate their pathogenetic role in this model of traumatic brain injury (TBI) [4].

Psychiatry related information on Slc1a3

• The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: the role of Abeta1-42 [5].
• Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental Wernicke's encephalopathy [6].
• The expression of mRNAs for the glial glutamate transporters, GLT-1 and GLAST, in the rat brain accompanied with morphine dependence and naloxone-precipitated withdrawal was investigated by Northern blot analysis [7].
• Thus, A beta-induced actin-dependent GLAST redistribution and relevant synaptic malfunction may be a cellular basis for the amnesia of Alzheimer's disease [8].

High impact information on Slc1a3

• Excitatory synaptic events activate rapid electrogenic glial glutamate transporter currents similar to those elicited by exogenous glutamate in other preparations [9].
• Three glutamate transporters have been identified in rat, including astroglial transporters GLAST and GLT-1 and a neuronal transporter EAAC1 [10].
• Astroglial membrane GLAST densities ranked as follows: Bergmann > cerebellar granular layer approximately hippocampus > cerebellar white matter [11].
• GLAST is found in both neurons and astroglia [12].
• Analysis of such synaptic EAAT currents suggests that, on average, postsynaptic EAATs take up approximately 1,300,000 glutamate molecules in response to a single climbing fiber action potential [13].

Chemical compound and disease context of Slc1a3

• EAAT1 regulation by thyroid hormone may facilitate increased metabolic demands of the cardiomyocyte during hyperthyroidism and impact cardiac function in hyperthyroidism [1].
• Using immunohistochemical and Western blot analyses, the authors examined the expression of the glutamate transporters EAAC1, GLAST, and GLT-1 in the rat hippocampus and cerebral cortex 8 hours and 1 to 28 days after transient forebrain ischemia [3].
• In the present study, we examined the effects of gene transfer of a glial glutamate transporter, GLT-1, into the NAc shell by recombinant adenoviruses on methamphetamine- and morphine-induced conditioned place preference in rats [14].
• In this study we used immuno-blotting technique to measure the cortical levels of the astrocytic glutamate transport protein (GLT-1) and of the glutamate and aspartate transporting protein (GLAST) in an epilepsy model induced by ferrous chloride injection in the cortex of rats [15].
• Moreover, the increased secretion of neurotrophic factors and upregulation of L-glutamate/L-aspartate transporter (GLAST) expression in Müller cells may protect retinal neurons from glutamate toxicity [16].

Biological context of Slc1a3

• The amino acid sequence of GLAST suggests a distinctive structure and membrane topology, with some conserved motifs also present in prokaryotic glutamate transporters [17].
• A GLAST-specific cDNA clone was isolated from a rat brain cDNA library [17].
• Here we demonstrate that the complete open reading frame of GLAST-1 mRNA and corresponding 69 kDa protein are expressed in rat bone in vivo [18].
• Mouse excitatory amino acid transporter EAAT2: isolation, characterization, and proximity to neuroexcitability loci on mouse chromosome 2 [19].
• Therefore the 70-kDa isoform differs only in the degree of glycosylation from the 64-kDa GLAST-1 isoform [20].

Anatomical context of Slc1a3

• These data suggest that GLAST may be involved in the regulation of neurotransmitter concentration in central nervous system [17].
• In situ hybridization reveals a strikingly high density of GLAST mRNA in the Purkinje cell layer of cerebellum, presumably in the Bergmann glia cells, and a less dense distribution throughout the cerebrum [17].
• However, when neurons are seeded and co-cultured on a layer of hippocampal astrocytes, they do not develop any immunoreactivity towards GLAST or GLT antibodies [21].
• In apparent contrast, all factors completely failed to affect GLT-1 and GLAST expression in astroglial cultures from the cerebellum, mesencephalon, and spinal cord between 36 h and 7 days [22].
• This has led us to propose that GLAST-1a has an opposite orientation in the cell membrane to GLAST-1 [18].

Associations of Slc1a3 with chemical compounds

• GLAST is specific for L-glutamate and L-aspartate, shows strict dependence on Na+ ions, and is inhibited by DL-threo-3-hydroxy-aspartate [17].
• We describe here the structure and function of a 66-kDa glycoprotein that was purified from rat brain and identified as an L-glutamate/L-aspartate transporter (GLAST) [17].
• In myocytes overexpressing EAAT1, activity of the malate/aspartate shuttle increased by 33% compared to non-transfected cells (P = 0.004) [23].
• In this study, we hypothesize that EAAT1 is regulated by thyroid hormone [1].
• Moreover, dibutyryl cyclic AMP (dbcAMP) potently promoted GLT-1 and/or GLAST expression in mesencephalic, cerebellar and spinal cord glia, further indicating that extracellular factors regulate glial glutamate transporter expression throughout the CNS [22].

Regulatory relationships of Slc1a3

• RNase protection assays showed that of the two glial transporters, mRNA for GLAST was expressed at much higher level than was GLT-1 [24].
• In this study, we found that ET-1 (100 nM) inhibited the glutamate uptake in cultured astrocytes expressing the glutamate/aspartate transporter (GLAST); astrocytes did not express the glutamate transporter-1 (GLT-1) [25].
• GLT-1 and GLAST are expressed by morphologically distinct glial fibrillary acidic protein-positive astrocytes, and their expression correlates with the status of neuron differentiation/maturation and activity [26].
• Abeta-induced increase of the glutamate transporter GLAST expression was also enhanced by the presence of MEK inhibitors [27].
• The effective concentrations of MEK inhibitors in enhancing Abeta-induced promotion of glutamate clearance and GLAST expression were consistent with those in blocking Abeta-induced ERK phosphorylation [27].

Other interactions of Slc1a3

• In blocking experiments using neutralizing antibodies and by incubation of astrocytes with recombinant cytokines, tumor necrosis factor-alpha (TNF-alpha) was identified as being responsible for the down-modulation of GLAST [28].
• Intriguingly, alterations of caveolin gene expression in response to cAMP or TGF-alpha coincided with reciprocal and brain-region specific changes in glial glutamate transporter GLT-1 expression [29].
• Thus, long-term treatment with the group I mGluR agonist, DHPG, causes down-regulation of GLAST, whereas the group II agonist, DCG-IV, has an opposite effect on the expression of GLAST in astrocytes [30].
• In contrast, hypoxic preconditioning had no effect on the levels of EAAT1 and ERbeta in any of the brain regions studied at any of the time points analyzed [31].

Analytical, diagnostic and therapeutic context of Slc1a3

• Rat heart total RNA was screened by reverse transcriptase-polymerase chain reaction with an array of primer pairs derived from the rat brain EAAT1 cDNA sequence, yielding a 3786-bp cDNA comprising a 1638-bp open reading frame identical to rat brain EAAT1 with flanking 5'- and 3'-untranslated regions [23].
• Steady-state mRNA levels of EAAT1 and aralar1 and citrin (both cardiac mitochondrial aspartate-glutamate transporters) were determined by Northern blot analysis and normalized to 18S rRNA [1].
• Protein lysates from mitochondria were separated by SDS-PAGE and probed with a human anti-EAAT1 IgG [1].
• A 70-kDa isoform of GLAST-1 was isolated from whole brain by wheat germ lectin affinity chromatography [20].
• The expression of a glutamate/aspartate transporter (GLAST) was detected by DNA amplification with the polymerase chain reaction [32].

References