GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

Abstract

Synaptically released L-glutamate, the most important excitatory neurotransmitter in the CNS, is removed from extracellular space by fast and efficient transport mediated by several transporters; the most abundant ones are EAAT1/GLAST and EAAT2/GLT1. The review first summarizes their location, functions and basic characteristics. We then look at genetics and epigenetics of EAAT1/GLAST and EAAT2/GLT1 and perform in silico analyses of their promoter regions. There is one CpG island in SLC1A2 (EAAT2/GLT1) gene and none in SLC1A3 (EAAT1/GLAST) suggesting that DNA methylation is not the most important epigenetic mechanism regulating EAAT1/GLAST levels in brain. There are targets for specific miRNA in SLC1A2 (EAAT2/GLT1) gene. We also note that while defects in EAAT2/GLT1 have been associated with various pathological states including chronic neurodegenerative diseases, very little is known on possible contributions of defective or dysfunctional EAAT1/GLAST to any specific brain disease. Finally, we review evidence of EAAT1/GLAST involvement in mechanisms of brain response to alcoholism and present some preliminary data showing that ethanol, at concentrations which may be reached following heavy drinking, can have an effect on the distribution of EAAT1/GLAST in cultured astrocytes; the effect is blocked by baclofen, a GABA-B receptor agonist and a drug potentially useful in the treatment of alcoholism. We argue that more research effort should be focused on EAAT1/GLAST, particularly in relation to alcoholism and drug addiction.

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

“…Baclofen, which has anticraving effects in patients with alcohol dependence [82], also affects glutamate transporter expression, as it prevented changes in subcellular localization of GLAST in cultured alcohol-treated astrocytes. This indicates a possible link between astrocytic glutamate transport and baclofen's anticraving effects [76]. However, other non-glutamatergic responses in astrocytes could also be modulated by long-term alcohol exposure and play a role in alcohol dependence.…”

“…Upregulation of glutamate transporters in postmortem alcoholic brain could be a sign of compensation for increased levels of extracellular glutamate. In cultured astrocytes, ethanol exposure alters the distribution of the glutamate transporter GLAST, shifting GLAST expression from the cytoplasm to the plasma membrane [76]. Ethanol-treated rats display lower levels of the astrocyte glutamate transporter GLT-1 [77].…”

Could ethanol-induced alterations in the expression of glutamate transporters in testes contribute to the effect of paternal drinking on the risk of abnormalities in the offspring?

“…There are five genes coding for the transporters (reviews: [15,16]) but protein products of two of them predominate: GLAST transporter encoded by SLC1A3 and GLT1 transporter encoded by SLC1A2. GLT1 and GLAST are also referred to as EAAT1 and EAAT2, respectively, particularly when discussing human brains.…”

“…GLT1 and GLAST are also referred to as EAAT1 and EAAT2, respectively, particularly when discussing human brains. Both transporters require Na + and K + transmembrane gradients as the driving force to transport L-glutamate from the extracellular space (reviews: [15,16]). In addition, GLAST acts as a chloride-selective ligand-(L-glutamate-) gated channel and thus has a capability to hyperpolarise GLAST-expressing cells in the presence of L-glutamate [review : 16].…”

Astrocytes, Metabolism, Signaling and Brain Drains: Introduction to the Special Issue in Honor of Gerald Dienel

“…This work also provides an historical and theoretical overview of the synapse concept, nicely illustrating the role of the malate-aspartate shuttle and 2-oxoglutarate in generation of synaptic glutamate. Epigenetic modification of glutamate uptake mechanisms in conditions such as alcoholism is then explored in an original research paper showing how distribution of GLAST in astrocytes can be altered by heavy drinking [3].…”