Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement

Abstract

L-Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian CNS and five types of high-affinity Glu transporters (EAAT1-5) have been identified. The transporters EAAT1 and EAAT2 in glial cells are responsible for the majority of Glu uptake while neuronal EAATs appear to have specialized roles at particular types of synapses. Dysfunction of EAATs is specifically implicated in the pathology of neurodegenerative conditions such as amyotrophic lateral sclerosis, epilepsy, Huntington's disease, Alzheimer's disease and ischemic stroke injury, and thus treatments that can modulate EAAT function may prove beneficial in these conditions. Recent advances have been made in our understanding of the regulation of EAATs, including their trafficking, splicing and post-translational modification. This article summarises some recent developments that improve our understanding of the roles and regulation of EAATs.

Figure 1

Mechanisms contributing to short- and long-term regulation of EAAT activity. Cell-surface expression and activity of EAATs is regulated by diverse influences including various receptors, phosphorylation (‘P'), trafficking to and from intracellular pools and interactions with lipid rafts and structural proteins. This figure should be considered as a general schema only, in that it reflects the various processes involved. Whether individual effects occur independently of transcription, via various intracellular pools or purely at the level of the cell surface, has not always been elucidated.

Figure 2

Structure of EAAT ligands. TBOA, L-threo-β-benzyloxyaspartate; TFB-TBOA, (2S,3S)-3-{3-[4-(trifluoromethyl)benzoylamino]benzyloxy}aspartate.