Splicing of the glutamate transporter EAAT2: a candidate gene of amyotrophic lateral sclerosis

Meyer, Thomas; Münch, Christoph; Liebau, Stefan; Fromm, Andrea; Schwalenstöcker, Birgit; Völkel, Helge; Ludolph, Albert C.

doi:10.1136/jnnp.65.6.954

Cited by 28 publications

(12 citation statements)

References 5 publications

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“…Nevertheless, this was a possibility considering that there are multiple EAAT2 splice variants (e.g. Meyer et al, 1998a;Meyer et al, 1998b;Meyer et al, 1998c;Honig et al, 2000;Flowers et al, 2001;Berger et al, 2005;Sullivan et al, 2004;Rauen et al, 2004;Peacey et al, 2009). One of these variants might be selective for the axon-terminals.…”

Section: Eaat2 Protein In Axon-terminalsmentioning

confidence: 99%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

186

152

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Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However, the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox. ABBREVIATIONSCre, Cyclization recombinase (Le and Sauer, 2000); EAAC1, glutamate transporter (EAAT3; slc1a1; Kanai and Hediger, 1992; Bjørås et al., 1996); EAAT, excitatory amino acid transporter (synonym to glutamate transporter); GABA, γ-aminobutyric acid; GLAST, rat glutamate transporter (EAAT1; slc1a3; Storck et al., 1992;Tanaka, 1993a); GLT-1, rat glutamate transporter (EAAT2; slc1a2; Pines et al., 1992); GLUL, glutamine synthetase; TBOA, DL-threo-β-benzyloxyaspartate AbstractNeither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that astrocytes and neurons express glutamate transporters. The relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) an hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

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Section: Eaat2 Protein In Axon-terminalsmentioning

confidence: 99%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

186

152

View full text Add to dashboard Cite

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“…transmembrane domains and is a homotrimer, and three splice variants were described (Hediger et al 1995;Kirschner et al 1994;Meyer et al 1997Meyer et al , 1998Mukainaka et al 1995;Peacey et al 2009;Raunser et al 2005;Suchak et al 2003;Sutherland et al 1995;Williams et al 2005). Posttranslational modifications include phosphorylations at S21, Y493, Y537, S562 (UniProtKB P43006) (Ballif et al 2008;Gonzalez et al 2005;Munton et al 2007), and GlcNAC at N205 and N215.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal glutamate transporter 1 (GLT-1) complex levels are paralleling memory training in the Multiple T-Maze in C57BL/6J mice

et al. 2011

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The glutamate transporter 1 (GLT-1) is essential for glutamate uptake in the brain and associated with various psychiatric and neurological disorders. Pharmacological inhibition of GLT-1 results in memory deficits, but no study linking native GLT-1 complexes was published so far. It was therefore the aim of the study to associate this highly hydrophobic, eight transmembrane spanning domains containing transporter to memory training in the Multiple T-maze (MTM). C57BL/6J mice were used for the spatial memory training experiments, and trained mice were compared to untrained (yoked) animals. Mouse hippocampi were dissected out 6 h after training on day 4, and a total enriched membrane fraction was prepared by ultracentrifugation. Membrane proteins were separated by blue native polyacrylamide gel electrophoresis (BN-PAGE) with subsequent Western blotting against GLT-1 on these native gels. Moreover, GLT-1 complexes were identified by mass spectrometry (nano-LC-ESI-MS/MS). Animals learned the MTM task and multiple GLT-1 complexes were detected at apparent molecular weights of 242, 480 and 720 kDa on BN-PAGE Western blotting. GLT-1 complex levels were significantly higher in the trained group as compared to yoked controls, and antibody specificity was verified by immunoblotting on multidimensional gels. Hippocampal GLT-1 was unambiguously identified by mass spectrometry with high sequence coverage, and glycosylation was observed. It is revealed that increased GLT-1 complex levels are paralleling and are linked to spatial memory training. We provide evidence that signal termination, represented by the excitatory amino acid transporter GLT-1 complexes, is involved in spatial memory mechanisms.

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“…Genetic dysregulation of EAAT2, such as single nucleotide polymorphisms (SNPs) and aberrant mRNA splicing of EAAT2 are known to impair EAAT2 expression and function, and are linked to several neurological diseases [18, 19]. Several pharmacological agents, such as ceftriaxone [20], estrogen [21], tamoxifen [21, 22] and riluzole [23] increase EAAT1 and EAAT2 expression at the transcription level via activation of nuclear factor κB (NF-κB) [22, 24].…”

Section: Introductionmentioning

confidence: 99%

Genetic Dys-regulation of Astrocytic Glutamate Transporter EAAT2 and its Implications in Neurological Disorders and Manganese Toxicity

et al. 2014

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Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 [glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) in rodents, respectively], are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms (SNPs) and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via NF-κB and CREB at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 (YY1) plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics, and translational regulation of EAAT2.

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Splicing of the glutamate transporter EAAT2: a candidate gene of amyotrophic lateral sclerosis

Cited by 28 publications

References 5 publications

Neuronal vs glial glutamate uptake: Resolving the conundrum

Neuronal vs glial glutamate uptake: Resolving the conundrum

Hippocampal glutamate transporter 1 (GLT-1) complex levels are paralleling memory training in the Multiple T-Maze in C57BL/6J mice

Genetic Dys-regulation of Astrocytic Glutamate Transporter EAAT2 and its Implications in Neurological Disorders and Manganese Toxicity

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