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

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Abstract

Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 (glutamate transporter 1 and glutamate aspartate transporter 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 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 nuclear factor κB and cAMP response element binding protein 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 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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Acknowledgments

The present study was supported in part by NIH Grants, NIGMS SC1089630 (EL) and R01ES10563 and R01ES10563S1 (MA).

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Authors and Affiliations

  1. Department of Physiology, Meharry Medical College, 1005 DB Todd Jr Blvd, Nashville, TN, 37208, USA

    Pratap Karki, Keisha Smith, James Johnson Jr. & Eunsook Y. Lee

  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Michael Aschner

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  1. Pratap Karki
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  2. Keisha Smith
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  3. James Johnson Jr.
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  4. Michael Aschner
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  5. Eunsook Y. Lee
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Correspondence to Eunsook Y. Lee.

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Special Issue: In honor of Michael Norenberg.

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Karki, P., Smith, K., Johnson, J. et al. Genetic Dys-regulation of Astrocytic Glutamate Transporter EAAT2 and its Implications in Neurological Disorders and Manganese Toxicity. Neurochem Res 40, 380–388 (2015). https://doi.org/10.1007/s11064-014-1391-2

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  • DOI: https://doi.org/10.1007/s11064-014-1391-2

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