Cell surface turnover of the glutamate transporter GLT‐1 is mediated by ubiquitination/deubiquitination

Villarreal, Jaime Martínez de; Tardón, Noemí García; Ibáñez, Ignacio; Giménez, Cecilio; Zafra, Francisco

doi:10.1002/glia.22354

Cited by 52 publications

(70 citation statements)

References 45 publications

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“…3B) in the primary astrocytes from LD mice in comparison to healthy animals. Since GLT-1 is a protein mainly located at the plasma membrane of the astrocytes, being its localization regulated by ubiquitin-dependent endocytosis [15],[16],[17],[30], we decided to study whether the localization of this transporter was affected in primary astrocytes from LD mouse models. With this aim, we stained them with anti-EAAT2 antibodies and analyzed them by flow cytometry under native conditions, to label only the protein that was present at the outer surface of the plasma membrane.…”

Section: - Resultsmentioning

confidence: 99%

“…GLT-1 (EAAT2) transporter is responsible of up to 90% of glutamate uptake, and it is expressed mainly in perisynaptic astrocytes [10],[11],[12],[13]. This transporter is incorporated into the astrocytic plasma membrane by exocytosis in a Ca 2+ dependent manner [14], and recycled by endocytosis upon PKC activation and Nedd4.2-mediated ubiquitination [15],[16],[17]. Other groups have also described the sumoylation at the C-terminal tail as a mechanism of regulation of EAAT2 localization, since EAAT2 sumoylation retains the transporter in intracellular compartments [18].…”

Section: - Introductionmentioning

confidence: 99%

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Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Muñoz‐Ballester¹,

Berthier²,

Viana³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Lafora disease (LD, OMIM 254780) is a fatal rare disorder characterized by epilepsy and neurodegeneration. Although in recent years a lot of information has been gained on the molecular basis of the neurodegeneration that accompanies LD, the molecular basis of epilepsy is poorly understood. Here, we present evidence indicating that the homeostasis of glutamate transporter GLT-1 (EAAT2) is compromised in mouse models of LD. Our results indicate that primary astrocytes from LD mice have reduced capacity of glutamate transport, probably because they present a reduction in the levels of the glutamate transporter at the plasma membrane. On the other hand, the overexpression in cellular models of laforin and malin, the two proteins related to LD, results in an accumulation of GLT-1 (EAAT2) at the plasma membrane and in a severe reduction of the ubiquitination of the transporter. All these results suggest that the laforin/malin complex slows down the endocytic recycling of the GLT-1 (EAAT2) transporter. Since, defects in the function of this transporter lead to excitotoxicity and epilepsy, we suggest that the epilepsy that accompanies LD could be due, at least in part, to deficiencies in the function of the GLT-1 (EAAT2) transporter.

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Section: - Resultsmentioning

confidence: 99%

Section: - Introductionmentioning

confidence: 99%

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Muñoz‐Ballester¹,

Berthier²,

Viana³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…These pathways regulate genes involved in cell cycle, cell survival and cytokine secretion (Paramanik and Thakur, 2013). Downstream activation of PKA and PKC leads to the modulation of regulatory units on the EAAT-2 promoter, translational and post-translational modifications and ubiquitination (Casado et al, 1993; Kalandadze et al, 2002; Martinez-Villarreal et al, 2012; Schlag et al, 1998; Tan et al, 1999). Analysis of the EAAT-2 promoter showed that NF-κB is an important regulator of EAAT-2 transcription in astrocytes (Aida et al, 2011) and the rate of NF-κB translocation into the nucleus is regulated by the activation of PKA, downstream of cAMP (King et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes

Cisneros¹,

Ghorpade²

2014

Neuropharmacology

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Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10–15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH +/− HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.

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“…Accordingly, inhibition of the ubiquitin-activating enzyme E1 promotes the retention of GLT-1 at the plasma membrane. The translocation of EAAT2 (GLT-1) from the recycling endosomes to the plasma membrane is blocked by inhibition of the deubiquitinating enzyme (DUB) ubiquitin C-terminal hydrolase-L1, suggesting the existence of specific ubiquitination/deubiquitination cycles in regulating optimal concentrations of GLT-1 at the cell surface [85]. …”

Section: Post Translational Deregulation Of Eaat2mentioning

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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Cell surface turnover of the glutamate transporter GLT‐1 is mediated by ubiquitination/deubiquitination

Cited by 52 publications

References 45 publications

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes

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

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