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Gene Review

Slc1a3  -  solute carrier family 1 (glial high...

Mus musculus

Synonyms: AI504299, B430115D02Rik, Eaat1, Excitatory amino acid transporter 1, GLAST, ...
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Disease relevance of Slc1a3

  • Our findings are indicative of a relationship between astrocytic phenotype and the level of EAAT activity that may be a vital component of astrocytic homeostatic responses in brain injury [1].
  • In GLAST-deficient mice, the electroretinogram b-wave and oscillatory potentials are reduced and retinal damage after ischemia is exacerbated, whereas GLT-1-deficient mice show almost normal electroretinograms and mild increased retinal damage after ischemia [2].
  • In addition, although no significant differences were seen in kindled seizure development, the generalized seizure duration of AM-kindled seizures in GLAST(-/-) mice was significantly prolonged (approximately 35%) compared with that of C57 mice [3].
  • Exacerbation of noise-induced hearing loss in mice lacking the glutamate transporter GLAST [4].
  • Here we show that after acoustic overstimulation, GLAST-deficient mice show increased accumulation of glutamate in perilymphs, resulting in exacerbation of hearing loss [4].

Psychiatry related information on Slc1a3


High impact information on Slc1a3

  • Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes [6].
  • In knockout mice, for either glial glutamate transporters, GLAST or GLT-1, a classical metabolic response to synaptic activation (i.e., enhancement of glucose utilization) is decreased at an early functional stage in the somatosensory barrel cortex following activation of whiskers [7].
  • From the Cover: Indispensability of the glutamate transporters GLAST and GLT1 to brain development [8].
  • Here, we report abnormal formation of the neocortex in GLAST/GLT1 mutants [8].
  • These results provide direct in vivo evidence that GLAST and GLT1 are necessary for brain development through regulation of extracellular glutamate concentration and show that an important mechanism is likely to be maintenance of glutamate-mediated synaptic transmission [8].

Chemical compound and disease context of Slc1a3

  • We have previously shown that exposure of Clone 9 cells to hypoxia, cyanide, or azide results in an acute stimulation of glucose transport that is largely mediated by "activation" of glucose transporter (Glut1) sites preexisting in the plasma membrane [9].

Biological context of Slc1a3

  • EAAT dysfunction during the excitotoxicity and oxidative stress of neurological insults may involve homoeostatic mechanisms associated with astrocytic function [1].
  • In both culture systems, prominent changes were noted in EAAT function and localization in conjunction with altered astrocytic phenotype [1].
  • To clarify the functional significance of the coexistence of these transporters, we analyzed the kinetics of EPSCs in Purkinje cells of mice lacking either GLAST or EAAT4 [10].
  • Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST [11].
  • The divergent temporal and spatial expression of EAAT subtypes and their persistence in mature fiber tracts and radial glia layers reveal that specific EAATs are likely to play multiple distinct roles in the developing and adult CNS, including the regulation of cell proliferation, axon-glia interactions, and neuronal survival [12].

Anatomical context of Slc1a3


Associations of Slc1a3 with chemical compounds

  • The excitatory amino acid transporters (EAAT) removes neurotransmitters glutamate and aspartate from the synaptic cleft [14].
  • However, the induction of chondroitin sulfate proteoglycans, tenascin, S-100B as well as glutamate transporter proteins, GLAST and GLT-1, and glutamine synthetase are independent of IL-1RI signaling [17].
  • Moreover, dihydrokainic acid, a selective inhibitor of glutamate transporter 1 (GLT1), does not block the effect of HMGB1, indicating a role for the glial glutamate-aspartate transporter (GLAST) subtype in this response [18].
  • Furthermore, although HMGB1 can physically interact with GLAST and the receptor for advanced glycation end products (RAGE), only its binding with RAGE is promoted by Ca(2+) [18].
  • The astrocytic glutamate transporters, EAAT1 and EAAT2, remove released L-glutamate from the synaptic milieu thereby maintaining normal excitatory transmission [1].

Physical interactions of Slc1a3

  • Biochemical analyses demonstrated that Sept2 bound directly to the carboxy-terminal region of GLAST in a GDP-form dependent manner [19].

Co-localisations of Slc1a3

  • The present study revealed that Sept2 co-localizes with the astrocyte glutamate transporter GLAST in the Bergmann glial processes facing axons and synapses [19].

Regulatory relationships of Slc1a3


Other interactions of Slc1a3

  • Selective inhibition of GLT-1 [for glutamate transporter; EAAT2 (for excitatory amino acid transporter)] with dihydrokainate increased the amplitude of these responses approximately threefold, indicating that these transporters compete with mGluRs for synaptically released glutamate [23].
  • 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 [23].
  • In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice [10].
  • Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression [24].
  • Expression of constitutive GDP-form Sept2 mutant reduced the glutamate uptake activity of GLAST via internalization of GLAST from cell surface [19].

Analytical, diagnostic and therapeutic context of Slc1a3


  1. Regulation of glutamate transporters in astrocytes: evidence for a relationship between transporter expression and astrocytic phenotype. Zagami, C.J., O'Shea, R.D., Lau, C.L., Cheema, S.S., Beart, P.M. Neurotoxicity research. (2005) [Pubmed]
  2. Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K., Tanaka, K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  3. Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. Watanabe, T., Morimoto, K., Hirao, T., Suwaki, H., Watase, K., Tanaka, K. Brain Res. (1999) [Pubmed]
  4. Exacerbation of noise-induced hearing loss in mice lacking the glutamate transporter GLAST. Hakuba, N., Koga, K., Gyo, K., Usami, S.I., Tanaka, K. J. Neurosci. (2000) [Pubmed]
  5. The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5. Kirschner, M.A., Arriza, J.L., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Magenis, E., Amara, S.G. Genomics (1994) [Pubmed]
  6. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Spanagel, R., Pendyala, G., Abarca, C., Zghoul, T., Sanchis-Segura, C., Magnone, M.C., Lascorz, J., Depner, M., Holzberg, D., Soyka, M., Schreiber, S., Matsuda, F., Lathrop, M., Schumann, G., Albrecht, U. Nat. Med. (2005) [Pubmed]
  7. Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Voutsinos-Porche, B., Bonvento, G., Tanaka, K., Steiner, P., Welker, E., Chatton, J.Y., Magistretti, P.J., Pellerin, L. Neuron (2003) [Pubmed]
  8. From the Cover: Indispensability of the glutamate transporters GLAST and GLT1 to brain development. Matsugami, T.R., Tanemura, K., Mieda, M., Nakatomi, R., Yamada, K., Kondo, T., Ogawa, M., Obata, K., Watanabe, M., Hashikawa, T., Tanaka, K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Activation of Glut1 glucose transporter in response to inhibition of oxidative phosphorylation. Hamrahian, A.H., Zhang, J.Z., Elkhairi, F.S., Prasad, R., Ismail-Beigi, F. Arch. Biochem. Biophys. (1999) [Pubmed]
  10. Differential roles of glial and neuronal glutamate transporters in Purkinje cell synapses. Takayasu, Y., Iino, M., Kakegawa, W., Maeno, H., Watase, K., Wada, K., Yanagihara, D., Miyazaki, T., Komine, O., Watanabe, M., Tanaka, K., Ozawa, S. J. Neurosci. (2005) [Pubmed]
  11. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. Duan, S., Anderson, C.M., Stein, B.A., Swanson, R.A. J. Neurosci. (1999) [Pubmed]
  12. Glutamate transporter mRNA expression in proliferative zones of the developing and adult murine CNS. Sutherland, M.L., Delaney, T.A., Noebels, J.L. J. Neurosci. (1996) [Pubmed]
  13. Characterization of CNS precursor subtypes and radial glia. Hartfuss, E., Galli, R., Heins, N., Götz, M. Dev. Biol. (2001) [Pubmed]
  14. The 'glial' glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Suchak, S.K., Baloyianni, N.V., Perkinton, M.S., Williams, R.J., Meldrum, B.S., Rattray, M. J. Neurochem. (2003) [Pubmed]
  15. Functional expression of particular isoforms of excitatory amino acid transporters by rodent cartilage. Hinoi, E., Wang, L., Takemori, A., Yoneda, Y. Biochem. Pharmacol. (2005) [Pubmed]
  16. Isolation of cystatin C via functional cloning of astrocyte differentiation factors. Kumada, T., Hasegawa, A., Iwasaki, Y., Baba, H., Ikenaka, K. Dev. Neurosci. (2004) [Pubmed]
  17. Astrogliosis is delayed in type 1 interleukin-1 receptor-null mice following a penetrating brain injury. Lin, H.W., Basu, A., Druckman, C., Cicchese, M., Krady, J.K., Levison, S.W. Journal of neuroinflammation [electronic resource]. (2006) [Pubmed]
  18. Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein. Pedrazzi, M., Raiteri, L., Bonanno, G., Patrone, M., Ledda, S., Passalacqua, M., Milanese, M., Melloni, E., Raiteri, M., Pontremoli, S., Sparatore, B. J. Neurochem. (2006) [Pubmed]
  19. Mammalian septin Sept2 modulates the activity of GLAST, a glutamate transporter in astrocytes. Kinoshita, N., Kimura, K., Matsumoto, N., Watanabe, M., Fukaya, M., Ide, C. Genes Cells (2004) [Pubmed]
  20. Glutamate transporter GLAST is expressed in the radial glia-astrocyte lineage of developing mouse spinal cord. Shibata, T., Yamada, K., Watanabe, M., Ikenaka, K., Wada, K., Tanaka, K., Inoue, Y. J. Neurosci. (1997) [Pubmed]
  21. The role of glial glutamate transporters in maintaining the independent operation of juvenile mouse cerebellar parallel fibre synapses. Marcaggi, P., Billups, D., Attwell, D. J. Physiol. (Lond.) (2003) [Pubmed]
  22. Characterization of novel L-threo-beta-benzyloxyaspartate derivatives, potent blockers of the glutamate transporters. Shimamoto, K., Sakai, R., Takaoka, K., Yumoto, N., Nakajima, T., Amara, S.G., Shigeri, Y. Mol. Pharmacol. (2004) [Pubmed]
  23. Astrocyte glutamate transporters regulate metabotropic glutamate receptor-mediated excitation of hippocampal interneurons. Huang, Y.H., Sinha, S.R., Tanaka, K., Rothstein, J.D., Bergles, D.E. J. Neurosci. (2004) [Pubmed]
  24. Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Wong, M., Ess, K.C., Uhlmann, E.J., Jansen, L.A., Li, W., Crino, P.B., Mennerick, S., Yamada, K.A., Gutmann, D.H. Ann. Neurol. (2003) [Pubmed]
  25. Glial glutamate transporters and maturation of the mouse somatosensory cortex. Voutsinos-Porche, B., Knott, G., Tanaka, K., Quairiaux, C., Welker, E., Bonvento, G. Cereb. Cortex (2003) [Pubmed]
  26. Dynamic transformation of Bergmann glial fibers proceeds in correlation with dendritic outgrowth and synapse formation of cerebellar Purkinje cells. Yamada, K., Fukaya, M., Shibata, T., Kurihara, H., Tanaka, K., Inoue, Y., Watanabe, M. J. Comp. Neurol. (2000) [Pubmed]
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