High Affinity Glutamate Transporters: Regulation of Expression and Activity

Abstract

L-Glutamic acid is a major excitatory neurotransmitter in the mammalian central nervous system. The termination of the glutamatergic transmission and the clearance of the excessive, neurotoxic concentrations of glutamate is ensured by a high affinity glutamate uptake system. Four homologous types of Na/K-dependent high affinity glutamate transporters, glutamate/aspartate transporter, glutamate transporter 1, excitatory amino acid carrier 1, and excitatory amino acid transporter 4, have recently been cloned and were assigned to a separate gene family, together with two neutral amino acid carriers, alanine/serine/cysteine transporter 1/serine/alanine/threonine transporter and adipocyte amino acid transporter. The genomic organization of these transporters is still under investigation. Very little is known about the nature of the factors and molecular mechanisms that regulate developmental, regional, and cell type-specific expression of the glutamate transporters and their aberrant functioning in neurodegenerative diseases (e.g., amyotrophic lateral sclerosis and Alzheimer's disease). Some experimental conditions (e.g., ischemia, corticostriatal lesions, hyperosmolarity, culturing conditions) and several naturally occurring and synthetic compounds (e.g., glutamate receptor agonists, dopamine, alpha1- and beta-adrenergic agonists, cAMP, phorbol esters, arachidonic acid, nitric oxide, oxygen free radicals, amyloid beta-peptide, tumor necrosis factor-alpha, glucocorticosteroids, unidentified neuronal factors) affect the molecular expression and activity of glutamate transporters. Further elucidation of the molecular events that link epigenetic signals with transcriptional and post-transcriptional mechanisms (e.g., alternative splicing, translation and post-translational modifications) is crucial for the development of selective pharmacological tools and strategies interfering with the expression of the individual glutamate transporters.

Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis

“…Although, the exact contribution of COX-2 to the epileptogenesis process remains uncertain, the present findings of induction of astrocytic COX-2 in therapy-refractive TLE patients with longstanding and progressive HS may have profound effects on brain function. Activation of the astrocytic metabolism of arachidonic acid leading to increased prostagandin synthesis may promote neuronal damage, either directly through the production of oxygen radicals (Kontos and Povlishock, 1986), or indirectly by modulating glutamate neurotransmitter release and uptake (Gegelashvili and Schousboe, 1997, Manzoni and Mennini, 1997and Bezzi et al, 1998. Accordingly, drugs that inhibit COX activity such as indomethacin, or selective COX-2 inhibitors such as rofecoxib have been found to reduce seizure frequencies and hippocampal cell death in several animal models of epilepsy (Wallenstein, 1987, Wallenstein, 1991, Baran et al, 1994, Paoletti et al, 1998, Kunz and Oliw, 2001and Okada et al, 2001).…”

Insights into glutamate transport regulation in human astrocytes: Cloning of the promoter for excitatory amino acid transporter 2 (EAAT2)

“…1 A). A similar genomic structure is found in the promoter of the ASCT1 gene, which also lacks well-defined cis elements while containing five Sp1 sites and GC-rich repeats (commonly found in early growth response genes, such as those in the EGF family and jun D) (33). Bioinformatic analysis of the promoter region revealed a number of potential regulatory transcription factor-binding elements that may contribute to EAAT2 expression and its regulation, including NFAT, NF-B, and N-myc ( Fig.…”

Activation of ERK/MAPK in the Lateral Amygdala of the Mouse is Required for Acquisition of a Fear-Potentiated Startle response

“…But our analysis was limited to this time point, when the activation is most prominent, as we showed. As far as glia cells are involved in regulating activity of neurons (for a review, see Seifert et al 2006), controlling, for example, their synaptic strength, it is possible that MAPKs still play a role in glia cells, but at different time points after conditioning; the latter serving as, for example, a protective mechanism to restore baseline conditions after a peak of activity, reducing the excess of inter-synaptic glutamate that could result in neurotoxic effects (Gegelashvili and Schousboe, 1997;Kanai, 1997;Nicholls and Attwell, 1990;Rothstein et al, 1996;Tanaka et al, 1997).…”