Disease relevance of Slc1a1

• The neuronal glutamate transporter, EAAC1 (excitatory amino acid carrier 1), undergoes rapid regulation after treatment with platelet-derived growth factor (PDGF) or phorbol ester in C6 glioma cells and neurons [1].
• The results indicate the presence of EAAC1 in the dorsal root ganglion neurons and their central terminals [2].
• The presence of EAAT3, glutaminase and VGLUT1-3 was examined in mouse, rat and rabbit species at mRNA and protein levels in hypothalamic neurons which are involved in the regulation of body weight using in situ hybridization and immunohistochemistry [3].

High impact information on Slc1a1

• Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18 [4].
• Excitatory amino-acid carrier 1 (EAAC1) is a high-affinity Na+-dependent L-glutamate/D,L-aspartate cell-membrane transport protein [4].
• The expression of GTRAP3-18 can be upregulated by retinoic acid, which results in a specific reduction of EAAC1-mediated glutamate transport [4].
• However, the possible functional role of EAAC1 in preventing neuron death has not been resolved as compared with glial glutamate transporters such as GLT-1 [5].
• Unique anti-apoptotic activity of EAAC1 in injured motor neurons [5].

Chemical compound and disease context of Slc1a1

• The purpose of the current investigation was to determine whether the pharmacological properties of EAAC1 parallel those observed in cortical or cerebellar synaptosomes, C6 glioma, or primary astrocyte-enriched cultures [6].

Biological context of Slc1a1

• Thus, we suggest a new transport mechanism, in which Glu-373 forms part of the binding site of EAAC1 for the cotransported proton [7].
• In line with these findings the transport kinetics of the mutant EAAC1 show no deuterium isotope effect [7].
• DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier) [8].
• Reverse transcription polymerase chain reaction revealed constitutive expression of mRNA for the neuronal GluT subtype excitatory amino acid carrier-1, in addition to glial subtypes such as glutamate aspartate transporter and glutamate transporter-1, in rat calvarial osteoblasts cultured for 7-21 days in vitro (DIV) [9].
• These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA [10].

Anatomical context of Slc1a1

• It localizes to the cell membrane and cytoplasm, and specifically interacts with carboxy-terminal intracellular domain of EAAC1 [4].
• This unique anti-apoptotic mechanism of EAAC1 functions in rescuing PC12 cells and motor neurons from NGF deprivation and nerve injury, respectively [5].
• Immunoelectron microscopic study revealed that the perinuclear EAAC1 immunoreactivity corresponded to the translocation to the Golgi complex [11].
• As an early alteration, perinuclear deposits of EAAC1 protein were found mainly in the large pyramidal neurons at the hippocampus, neocortex, piriform cortex, and amygdala with the reduction of neuropil staining 6 hours after KA injection [11].
• In previous studies, we have shown that activation of protein kinase C (PKC) rapidly (within minutes) increases the activity and cell surface expression of the glutamate transporter EAAC1 in two systems that endogenously express this transporter (C6 glioma cells and cocultures of neurons and astrocytes) [12].

Associations of Slc1a1 with chemical compounds

• In brain, EAAC1 is the primary neuronal glutamate transporter [4].
• One candidate for this binding site, the highly conserved glutamic acid residue Glu-373 of EAAC1, was mutated to glutamine [7].
• However, it was also speculated that the cotransported proton is shared in a H(+)-binding network, possibly involving the conserved histidine 295 in the sixth transmembrane domain of EAAC1 [13].
• Together, these results suggest that histidine 295 is not protonated in EAAC1 at physiological pH and, thus, does not contribute to H(+) cotransport [13].
• Our results show that replacement of H295 with glutamine, an amino acid residue that cannot be protonated, generates a fully functional transporter with transport kinetics that are close to those of the wild-type EAAC1 [13].
• In hippocampal cultures, brief (5 min), robust (100 microM NMDA, 10 microM glycine) activation of the NMDA receptor decreased biotinylated EAAC1 to approximately 50% of control levels [14].

Other interactions of Slc1a1

• The results revealed a decrease in glutamate receptor 2 (GluR2) mRNA expression and protein levels as well as an increase in protein levels for the excitatory amino acid carrier 1 (EAAC1) in P10 SE rats compared to controls [15].
• Genes associated with the glutamatergic system were up-regulated (N-methyl-d-aspartate receptor, NMDAR-2A and NMDAR-2B and excitatory amino acid carrier 1, EAAC1), while genes related to the gamma-aminobutyric acid (GABA) system were down-regulated (GABAA receptor, glutamate decarboxylase GAD65) [16].

Analytical, diagnostic and therapeutic context of Slc1a1

• Here, we used site-directed mutagenesis together with pre-steady-state electrophysiological analysis of the mutant transporters to test the protonation state of H295 and to determine its involvement in proton transport by EAAC1 [13].
• Immunocytochemistry reveals that approximately 46.6% of the dorsal root ganglion neurons are EAAC1-positive [2].
• Immunoblotting analysis further confirms existence of EAAC1 protein in this region [2].
• Unilateral dorsal rhizotomy experiments further show that EAAC1 immunoreactivity is less intense in superficial dorsal horn on the side ipsilateral to the dorsal rhizotomy than on the contralateral side [2].
• Reverse transcriptase-polymerase chain reaction shows expression of EAAC1 mRNA in the dorsal root ganglion [2].

References