Disease relevance of SLC1A3

• RESULTS: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls [1].
• Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis [2].
• In the present study, we examined whether traumatic brain injury (TBI) affects the cellular expression of glutamate transporters EAAT1 and EAAT2 [3].
• Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures [1].
• CONCLUSION: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia [1].

Psychiatry related information on SLC1A3

• A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder [4].
• Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer's disease [5].
• Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder [6].
• Here we show that a glial glutamate transporter GLT-1 could be involved in physical and psychological morphine dependence [7].
• EAAT1 parameters were mutually correlated (p<0.01) and correlations were shown with dementia severity (p<0.05 MMSE-expression, p<0.005 MMSE-mRNA) [8].

High impact information on SLC1A3

• An excitatory amino-acid transporter with properties of a ligand-gated chloride channel [9].
• SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter [10].
• NFIA is both necessary and sufficient for GLAST induction in the VZ [11].
• We identified a family of transcription factors, called NFI genes, which are induced throughout the spinal cord ventricular zone (VZ) concomitantly with the induction of GLAST, an early marker of gliogenesis [11].
• Here, we report the results of a comprehensive evaluation of the C-terminal topology of EAAT1 determined by the chemical modification of introduced cysteine residues [12].

Chemical compound and disease context of SLC1A3

• In retinal amacrine and ganglion cells, EAAT5 is colocalized with the serum and glucocorticoid inducible kinase SGK1, a serine/threonine kinase known to regulate transport [13].
• L-glutamate per se was gliotoxic only at concentrations much higher than the maximum reached with the potent EAAT substrate inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC), and toxicity was lower [14].

Biological context of SLC1A3

• CONCLUSIONS: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD [4].
• SLC1A3 was mapped to chromosome 5p13 [15].
• Glutamate uptake inhibitors were used to compare the pharmacologies of the EAAT subtypes [16].
• 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 [17].
• 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].

Anatomical context of SLC1A3

• EAAC1 is selective for neurons, while GLT-1 and GLAST are selective for astroglia [2].
• The kinetic parameters and pharmacological characteristics of transport mediated by each EAAT subtype were determined in transfected mammalian cells by radio-label uptake and in microinjected oocytes by voltage-clamp measurements [16].
• By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST [2].
• In this study, the distribution of protein and mRNA of EAAT subtypes was examined in the hippocampus of TLE patients with hippocampal sclerosis (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls without neurological disorders [18].
• Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia [19].

Associations of SLC1A3 with chemical compounds

• Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization [15].
• The affinities of the EAAT subtypes for L-glutamate were similar, with Km determinations varying from 48 to 97 microM in the mammalian cell assay and from 18 to 28 microM in oocytes [16].
• 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) [16].
• Interaction of L-cysteine with a human excitatory amino acid transporter [20].
• More recent data show that astrocyte-secreted factors such as cholesterol could also influence rapid changes in the location of EAAC1/EAAT3 between the plasma membrane and the cytoplasmic compartment [21].

Regulatory relationships of SLC1A3

• 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 [22].
• High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamine/neutral amino acid transporter ASCT2 in human fetal astrocytes [23].

Other interactions of SLC1A3

• Glutamate induces a current in Xenopus oocytes expressing EAAT1, but not in water-injected oocytes, which is decreased by co-expression of Nedd4-2, an effect reversed by additional co-expression of S422DSGK1, SGK3 and T308D,S473DPKB, but not K127NSGK1 [24].
• In order to investigate this hypothesis further, the expression of several 'glutamatergic' markers, the metabotropic glutamate receptors (mGluRs; mGluR3, 5) and the human excitatory amino acid transporter (EAAT2) were compared in the PFC of normal individuals and schizophrenics [25].
• Here, we cloned and characterized a 2.1-kb promoter region of human EAAT1 and investigated its function in the transcriptional regulation of the EAAT1 gene in human primary astrocytes [26].
• In a case with "burnt out" HIVE following highly active antiretroviral therapy (HAART), EAAT-1 expression was mild, identical to that of HLA-DR and CD68 in the white matter and cortex and involved perineuronal microglial cells [27].
• Occasional EAAT-1 expressing AMM were found in patients with short survival, whereas diffuse EAAT-1 expression by AMM was observed in cases with long survival (24 to 33 months) that most often were heterozygous for Met/Val at codon 129 of the PRNP gene [28].

Analytical, diagnostic and therapeutic context of SLC1A3

• Chromosomal location of the human glutamate transporter, hGluT-1, gene (SLC1A3) was determined by fluorescence in situ hybridization [15].
• Such a highly regulated process of EAAC1/EAAT3 activity/expression may have implications in the physiopathology of major diseases affecting EAA brain signalling, which is further supported by data obtained in animal models of hypoxia-anoxia, for example [21].
• 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].
• Using immunohistochemistry, EAAT1 expression was found in the syncytiotrophoblast layer, while EAAT2 was detected in the syncytiotrophoblast layer and in endothelial cells of about 5 per cent of all fetal blood vessels [29].
• By Northern blot analysis, the expression of glial glutamate transporter GLT-1, but not GLAST, mRNA was decreased in the striatum/nucleus accumbens (NAc) and thalamus of morphine-dependent rats [7].

References