Disease relevance of Slc1a3

• Our findings are indicative of a relationship between astrocytic phenotype and the level of EAAT activity that may be a vital component of astrocytic homeostatic responses in brain injury [1].
• In GLAST-deficient mice, the electroretinogram b-wave and oscillatory potentials are reduced and retinal damage after ischemia is exacerbated, whereas GLT-1-deficient mice show almost normal electroretinograms and mild increased retinal damage after ischemia [2].
• In addition, although no significant differences were seen in kindled seizure development, the generalized seizure duration of AM-kindled seizures in GLAST(-/-) mice was significantly prolonged (approximately 35%) compared with that of C57 mice [3].
• Exacerbation of noise-induced hearing loss in mice lacking the glutamate transporter GLAST [4].
• Here we show that after acoustic overstimulation, GLAST-deficient mice show increased accumulation of glutamate in perilymphs, resulting in exacerbation of hearing loss [4].

Psychiatry related information on Slc1a3

• The EAAT1 locus is located in a region of 5p deletions that have been associated with mental retardation and microcephaly [5].

High impact information on Slc1a3

• Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes [6].
• In knockout mice, for either glial glutamate transporters, GLAST or GLT-1, a classical metabolic response to synaptic activation (i.e., enhancement of glucose utilization) is decreased at an early functional stage in the somatosensory barrel cortex following activation of whiskers [7].
• From the Cover: Indispensability of the glutamate transporters GLAST and GLT1 to brain development [8].
• Here, we report abnormal formation of the neocortex in GLAST/GLT1 mutants [8].
• These results provide direct in vivo evidence that GLAST and GLT1 are necessary for brain development through regulation of extracellular glutamate concentration and show that an important mechanism is likely to be maintenance of glutamate-mediated synaptic transmission [8].

Chemical compound and disease context of Slc1a3

• We have previously shown that exposure of Clone 9 cells to hypoxia, cyanide, or azide results in an acute stimulation of glucose transport that is largely mediated by "activation" of glucose transporter (Glut1) sites preexisting in the plasma membrane [9].

Biological context of Slc1a3

• EAAT dysfunction during the excitotoxicity and oxidative stress of neurological insults may involve homoeostatic mechanisms associated with astrocytic function [1].
• In both culture systems, prominent changes were noted in EAAT function and localization in conjunction with altered astrocytic phenotype [1].
• To clarify the functional significance of the coexistence of these transporters, we analyzed the kinetics of EPSCs in Purkinje cells of mice lacking either GLAST or EAAT4 [10].
• Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST [11].
• The divergent temporal and spatial expression of EAAT subtypes and their persistence in mature fiber tracts and radial glia layers reveal that specific EAATs are likely to play multiple distinct roles in the developing and adult CNS, including the regulation of cell proliferation, axon-glia interactions, and neuronal survival [12].

Anatomical context of Slc1a3

• In addition, RC2, GLAST, and BLBP antisera label precursor cells with different morphologies and thereby cover almost the entire progenitor pool in the developing cerebral cortex [13].
• In contrast, an enriched population of multipotential cells, neurosphere cultures derived from the adult or embryonic telencephalon, is immunoreactive for RC2, GLAST, and BLBP [13].
• Uptake of [3H]D-aspartate or [3H]L-glutamate into these preparations revealed sodium-dependent uptake in GPV and synaptosomes which was inhibited by a range of EAAT blockers: dihydrokainate, serine-o-sulfate, l-trans-2,4-pyrrolidine dicarboxylate (PDC) (+/-)-threo-3-methylglutamate and (2S,4R )-4-methylglutamate [14].
• Immunohistochemical analysis revealed distribution profiles different from each other with GLAST, GLT-1 and EAAT4 isoforms in sections of cultured metatarsals and isolated tibiae [15].
• TGF-beta induced CysC and GFAP expression in AP-16 cells, an astrocyte progenitor-like cell line expressing GLAST (a glutamate transporter subtype specifically expressed in immature astrocytes) [16].

Associations of Slc1a3 with chemical compounds

• The excitatory amino acid transporters (EAAT) removes neurotransmitters glutamate and aspartate from the synaptic cleft [14].
• However, the induction of chondroitin sulfate proteoglycans, tenascin, S-100B as well as glutamate transporter proteins, GLAST and GLT-1, and glutamine synthetase are independent of IL-1RI signaling [17].
• Moreover, dihydrokainic acid, a selective inhibitor of glutamate transporter 1 (GLT1), does not block the effect of HMGB1, indicating a role for the glial glutamate-aspartate transporter (GLAST) subtype in this response [18].
• Furthermore, although HMGB1 can physically interact with GLAST and the receptor for advanced glycation end products (RAGE), only its binding with RAGE is promoted by Ca(2+) [18].
• The astrocytic glutamate transporters, EAAT1 and EAAT2, remove released L-glutamate from the synaptic milieu thereby maintaining normal excitatory transmission [1].

Physical interactions of Slc1a3

• Biochemical analyses demonstrated that Sept2 bound directly to the carboxy-terminal region of GLAST in a GDP-form dependent manner [19].

Co-localisations of Slc1a3

• The present study revealed that Sept2 co-localizes with the astrocyte glutamate transporter GLAST in the Bergmann glial processes facing axons and synapses [19].

Regulatory relationships of Slc1a3

• Thus Sept2 may regulate GLAST-mediated glutamate uptake by astrocytes, which is important for appropriate transmitter signalling in the cerebellum [19].
• At P7, GLAST-expressing cells were immunopositive for glial fibrillary acidic protein, an intermediate filament specific to astrocytes [20].
• However when trains of stimuli were applied, even to a small number of parallel fibres, knocking out GLAST or blocking GLT-1 in the absence of GLAST greatly prolonged and enhanced the AMPA receptor-mediated current [21].
• The glutamate transporter GLAST is localized on the cell membrane of mature astrocytes and is also expressed in the ventricular zone of developing brains [20].
• Electrophysiological analyses revealed that TBOA analogs block the transport-associated currents in all five EAAT subtypes and also block leak currents in EAAT5 [22].

Other interactions of Slc1a3

• Selective inhibition of GLT-1 [for glutamate transporter; EAAT2 (for excitatory amino acid transporter)] with dihydrokainate increased the amplitude of these responses approximately threefold, indicating that these transporters compete with mGluRs for synaptically released glutamate [23].
• A comparison of responses recorded from wild-type and transporter knock-out mice revealed that the astroglial glutamate transporters GLT-1 and GLAST, but not the neuronal transporter EAAC1, restrict activation of mGluRs in O-LM interneurons [23].
• In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice [10].
• Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression [24].
• Expression of constitutive GDP-form Sept2 mutant reduced the glutamate uptake activity of GLAST via internalization of GLAST from cell surface [19].

Analytical, diagnostic and therapeutic context of Slc1a3

• Western blotting showed detectable levels of the transporters EAAT1 (GLAST) and EAAT2 (Glt-1) in both synaptosomes and GPVs [14].
• Reverse-transcriptase PCR identified the expression of EAAT1, EAAT2, EAAT3 and EAAT4 mRNAs in primary cultures of mouse cortical or striatal neurones [14].
• We have used in situ hybridization analysis with subtype-specific antisense-oligonucleotides to study the distribution of glia-specific excitatory amino acid transporter (mEAAT1 and mEAAT2) mRNAs during the later stages of embryogenesis and postnatal CNS development [12].
• By P12, and despite an increased global expression as observed by immunoblotting, the barrel pattern of GLAST and GLT-1 staining is no longer evident [25].
• In the present study, we investigated the morphodifferentiation of BG by immunohistochemistry for glutamate transporter GLAST and electron microscopy [26].

References