Disease relevance of Slc1a2

• It is easily conceivable that expression alterations of 5' splice variants of EAAT2 are related to glutamate transporter malfunction after chemical hypoxia [1].
• Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1 [2].
• 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 [3].
• We conclude that alternative splicing of 5'-sequences may contribute to the regional expression of the EAAT2 RNA and was altered in the pre-symptomatic stage of the SOD1G93A-mouse model for amyotrophic lateral sclerosis [4].
• However, GLT1 is severely down-regulated in amyotrophic lateral sclerosis, a progressive neurodegenerative disease [5].
• Our results suggest that GLT1 (+/-) mice may serve as a potentially useful model to study neurodegenerative disease conditions with mild hyperglutamatergic activity [6].

High impact information on Slc1a2

• 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].
• However, the possible functional role of EAAC1 in preventing neuron death has not been resolved as compared with glial glutamate transporters such as GLT-1 [8].
• These results demonstrate that GLAST is required for normal signal transmission between photoreceptors and bipolar cells and that both GLAST and GLT-1 play a neuroprotective role during ischemia in the retina [3].
• Glutamate transporter GLT-1 is transiently localized on growing axons of the mouse spinal cord before establishing astrocytic expression [9].
• Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes [10].

Chemical compound and disease context of Slc1a2

• In this study, we investigated alternative splicing of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3-nitropropionic acid (3-NP) [1].
• At the distal end of C6 glioma cell processes, GLT-1 clusters undergo rapid morphological changes in both shape and size, and these changes are inhibited by cytochalasin D treatment, suggesting that the morphogenesis of GLT-1 clusters is highly dependent on the actin network [11].
• Moreover, intraperitoneal injection of dihydrokainate (10 mg/kg), a specific inhibitor of GLT-1, augmented brain swelling [12].

Biological context of Slc1a2

• Here, we screened a cDNA library derived from mouse cerebellum and isolated the two glutamate transporters, termed MGLT1 and MEAAC1 [13].
• In the murine CNS we found a region-specific expression pattern of the novel 5'-variants of EAAT2 as shown by in situ hybridization, dot blotting and competitive reverse transcription polymerase chain reaction [4].
• Here, using knockout mice lacking GLT-1, that is the most abundant glial subtype of glutamate transporters, we showed that long-term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region [14].
• Although GLAST is expressed six-fold more abundantly than GLT-1, no change is detected in the kinetics of climbing fiber (CF)-mediated excitatory postsynaptic currents (CF-EPSCs) in PCs in GLAST(-/-) mice compared to the wild-type mice (WT) [15].
• Abeta(1-42) addition to synaptosomes also results in HNE binding to Glt-1, thereby coupling increased Abeta(1-42) in AD brain to increased lipid peroxidation and its sequelae and possibly explaining the mechanism of glutamate transport inhibition known in AD brain [16].

Anatomical context of Slc1a2

• Western blotting showed detectable levels of the transporters EAAT1 (GLAST) and EAAT2 (Glt-1) in both synaptosomes and GPVs [17].
• The 'glial' glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings [17].
• Spinal cord GLT-1 glutamate transporter and blood glutamic acid alterations in motor neuron degeneration (Mnd) mice [18].
• This function of the astrocyte is dependent on its positioning around the synapse, as well as on the level of expression of its high-affinity glutamate transporters, GLT1 and GLAST [19].
• MEAAC1 mRNA was expressed in brain, lung, kidney and skeletal muscle, whereas expression of MGLT1 was restricted to brain [13].

Associations of Slc1a2 with chemical compounds

• 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 [20].
• 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 [21].
• However, at P9-10, the functional response to whisker stimulation, measured by deoxyglucose uptake, is markedly decreased in GLT-1 -/- and GLAST -/- mice [22].
• The administration of estrogen significantly increased the expression of GLT-1 and GLAST on the mRNA and protein level [23].
• The high affinity, Na(+)-dependent, electrogenic glial L-glutamate transporters GLAST1 and GLT1, and two neuronal EAAC1 and EAAT4, regulate the neurotransmitter concentration in excitatory synapses of the central nervous system [24].

Regulatory relationships of Slc1a2

• 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 [25].

Other interactions of Slc1a2

• Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression [26].
• Here we show that the glial glutamate transporters GLAST and GLT-1 limit the activation of Purkinje cell AMPA receptors produced by glutamate diffusion between parallel fibre synapses in the cerebellar cortex of juvenile mice [25].
• These findings suggest that GLT-1 plays critical roles in LTP induction, as well as in short-term potentiation, through regulation of extracellular levels of glutamate, which enables appropriate NMDA receptor activation [14].
• More than 95% of these cells expressed the astrocyte markers glial fibrillary acidic protein and GLT-1 glutamate transporter, and the morphological characteristics of these cells were typical of astrocytes [27].
• The generalized decrease in GLT-1, decreased excitatory amino acid receptor levels, and increased GABAA receptor levels may reflect an early glutamate-mediated excitotoxicity following cycad exposure [28].

Analytical, diagnostic and therapeutic context of Slc1a2

• Here we report an expression analysis of five known (mEAAT2/5UT1-5) and two novel (mEAAT2/5UT6, -7) 5' splice variants of EAAT2 using semiquantitative PCR [1].
• By in situ hybridization, 35S-labeled antisense oligonucleotide probes for GLT-1 mRNA consistently labeled the mantle zone/gray matter from embryonic day 11 through the adult stage [9].
• By electron microscopy, GLT-1 immunoreactivity was detected in axons forming frequent enlargements and was focally localized on a small portion of the axolemma, particularly that facing adjacent axons [9].
• 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 [22].
• Both of the two 3'-ends have been demonstrated by RT-PCR to be present not only in liver but also in brain, indicating both brain and liver GLT-1 possess two types of 3'-ends [29].

References