Disease relevance of Slc1a1

• In spite of this selective degeneration of motor neurons (resulting in strong decrease in the neuronal glutamate transporter EAAC1) and reactive gliosis in the cervical spinal cord, the levels of the glial glutamate transporter proteins GLT-1 and GLAST were similar in wobbler and control mice [1].
• Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) but not the glial glutamate transporters may be of therapeutic interest, allowing blockage of glutamate exit from neurons due to "reversed glutamate transport" of EAAC1, which will occur during pathological conditions, such as during ischemia after a stroke [2].
• In the present study, PDGF increased the level of Akt phosphorylation (Ser 473) in C6 glioma cells, a cell line that has been used to study regulated trafficking of endogenous EAAC1 [3].

High impact information on Slc1a1

• Neurons also express a glutamate transporter, termed excitatory amino acid carrier-1 (EAAC1), but the physiological function of this transporter remains uncertain [4].
• Neurons in the hippocampal slices of EAAC1(-/-) mice were found to have reduced glutathione content, increased oxidant levels and increased susceptibility to oxidant injury [4].
• EAAC1 can also rapidly transport cysteine, an obligate precursor for neuronal glutathione synthesis [4].
• These changes were reversed by treating the EAAC1(-/-) mice with N-acetylcysteine, a membrane-permeable cysteine precursor [4].
• These findings suggest that EAAC1 is the primary route for neuronal cysteine uptake and that EAAC1 deficiency thereby leads to impaired neuronal glutathione metabolism, oxidative stress and age-dependent neurodegeneration [4].

Biological context of Slc1a1

• Here, we screened a cDNA library derived from mouse cerebellum and isolated the two glutamate transporters, termed MGLT1 and MEAAC1 [5].
• Because glutamate is used as an osmolyte in somatic cells, the lack of EAAC1 reported here may disturb normal osmolyte balance in the proximal epididymal lumen and compromise sperm maturation, in particular the development of sperm volume regulatory mechanisms [6].
• These results indicate that EAAC2 is transcribed from an independent promoter but not an alternative splicing event [7].
• Functional analysis of glutamate transporters in excitatory synaptic transmission of GLAST1 and GLAST1/EAAC1 deficient mice [8].
• Glutamate transporter EAAC1 removes excitatory neurotransmitter in central nervous system, and also absorbs glutamate in epithelia of intestine, kidney, liver and heart for normal cell growth [7].

Anatomical context of Slc1a1

• MEAAC1 mRNA was expressed in brain, lung, kidney and skeletal muscle, whereas expression of MGLT1 was restricted to brain [5].
• A comparison of responses recorded from wild-type and transporter knock-out mice revealed that the astroglial glutamate transporters GLT-1 and GLAST, but not the neuronal transporter EAAC1, restrict activation of mGluRs in O-LM interneurons [9].
• To investigate the specific physiological and pathophysiological role of the neuronal EAAC-1, which is also expressed in kidney and small intestine, we have generated two independent mouse lines lacking EAAC-1. eaac-1(-/-) mice develop dicarboxylic aminoaciduria [10].
• Lack of glutamate transporter EAAC1 in the epididymis of infertile c-ros receptor tyrosine-kinase deficient mice [6].
• Immunohistochemical staining for EAAC1 confirmed regional mRNA expression and demonstrated an adluminal location on stereocilia/microvilli of principal cells [6].

Associations of Slc1a1 with chemical compounds

• Our evidence suggests that addicsin mRNA is chiefly expressed in the excitatory and inhibitory neurons, and that addicsin may participate in the functional expression of the somatic sensory system by modulation of EAAC1-mediated glutamate transport [11].
• The non-selective EAAT inhibitor threo-beta-hydroxyaspartate had a significantly greater maximal inhibitory effect than did the EAAT2-selective inhibitor, dihydrokainate, indicating uptake by both EAAT2 and EAAT3 [12].
• Structure activity studies on a series of beta-substituted aspartate analogues identify L-beta-benzyl-aspartate (L-beta-BA) as among the first blockers that potently and preferentially inhibits the neuronal EAAT3 subtype [13].
• The increase in luminal fluid pH in the KO mice could also be contributed to by other epithelial regulating factors including the Na(+)-dependent glutamate transporter EAAC1 formerly reported to be down regulated in the KO [14].
• Administration of dihydrotestosterone (DHT) to the castrates maintained the proximal and distal caput epithelia and induced a proximal epithelium, which resembled the initial segment in its prominent staining for Golgi, EAAC1 and beta-Gal activity, although it was short and exhibited no MEP17 expression [15].

Other interactions of Slc1a1

• Immunohistochemical analysis demonstrated a region-specific modification of neuronal glutamate transporter, EAAT3 trafficking in the GFAP null phenotype [16].
• The glutamate transporters EAAC1 (EAAT3) and EAAT5 were downregulated and upregulated, respectively [17].
• Electron-microscopically, EAAC1 immunoreactivity was predominantly localized in the striated border of enterocytes [18].
• Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1 [3].
• Functional significance of N- and C-terminus of the amino acid transporters EAAC1 and ASCT1: characterization of chimeric transporters [19].

Analytical, diagnostic and therapeutic context of Slc1a1

• Reverse-transcriptase PCR identified the expression of EAAT1, EAAT2, EAAT3 and EAAT4 mRNAs in primary cultures of mouse cortical or striatal neurones [20].
• Sequence analysis shows that EAAC2 has it's own start code and unique 5'UTR that is different from that of EAAC1 [7].
• We performed immunoelectron microscopy by preembedding peroxidase and immunogold methods and by postembedding immunogold to detect expression of the glutamate transporters GLAST, GLT-1, and EAAC1 in the mouse cochlear nucleus [21].

References