Glutamate Neurotoxicity, Transport and Alternate Splicing of Transporters

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 exonskipping 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.