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Glutamate Neurotoxicity, Transport and Alternate Splicing of Transporters

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Handbook of Neurotoxicity

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Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system and its levels in the synaptic cleft are tightly controlled by high affinity glutamate transporters (also known as Excitatory Amino Acid Transporters or EAATs). The EAAT family is comprised of five members (EAAT1-5), and these transporters are subject to alternative splicing. Alternative splicing of the EAAT genes is a fundamental mechanism that can give rise to multiple distinct mRNA transcripts, producing protein isoforms with potentially altered functions. Numerous splice variants of EAATs have been identified in humans, rodents, and other mammalian species. All splice variants of EAATs cloned to date are either exon-skipping and/or intron-retaining types. These modifications may impact upon protein structure, posttranslational modification, function, cellular localization, and trafficking. Message and protein for these splice variants are detectable in the normal brain and, in many instances, have been shown to be induced by pathophysiological insults such as hypoxia. In addition, aberrant expression of EAAT splice variants has been reported in neurodegenerative conditions such as amyotrophic lateral sclerosis, Alzheimer’s disease, ischemic stroke, and age-related macular degeneration. These EAAT variants may represent therapeutic targets and thus require an improved understanding of their regulation. This chapter describes recent developments in investigating the molecular heterogeneity, localization, function, structure, and regulation of the EAATs and their splice variants.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

AMD:

Age-related macular degeneration

CNS:

Central nervous system

EAAC1:

Excitatory amino acid carrier 1

EAAT:

Excitatory amino acid transporter

GABA:

Gamma-aminobutyric acid

GLAST:

Glutamate aspartate transporter

GLT-1:

Glutamate transporter-1

GTRAP:

Glutamate transporter associated protein

hnRNP:

heterogeneous nuclear ribonucleoproteins

HSP70:

70 kDa heat shock proteins

MAP2:

Microtubule-associated protein 2

MLO-Y4:

Murine long bone osteocyte Y4

mRNA:

messenger ribonucleic acid

PDZ:

Postsynaptic density (PSD), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (ZO-1)

SLC:

Solute carrier

SOD:

Superoxide dismutase

SR protein:

Serine/arginine-rich protein

SRPK:

Serine/arginine-rich protein kinase

UTR:

Untranslated region

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Authors and Affiliations

  1. UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4029, Australia

    Aven Lee & Shannon Beasley

  2. School of Medical Sciences and Health Innovations Research Institute, RMIT University, Melbourne, VIC, 3083, Australia

    David V. Pow

Authors
  1. Aven Lee
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  2. Shannon Beasley
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  3. David V. Pow
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Correspondence to Aven Lee .

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Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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Lee, A., Beasley, S., Pow, D.V. (2014). Glutamate Neurotoxicity, Transport and Alternate Splicing of Transporters. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_129

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