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Gene Review

SLC1A6  -  solute carrier family 1 (high affinity...

Homo sapiens

Synonyms: EAAT4, Excitatory amino acid transporter 4, Sodium-dependent glutamate/aspartate transporter, Solute carrier family 1 member 6
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Disease relevance of SLC1A6


High impact information on SLC1A6

  • Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane [4].
  • Studies of EAAT4 and EAAC1 indicate an extrasynaptic localization on perisynaptic membranes that are near release sites [5].
  • Here we report the identification and characterization of two proteins, GTRAP41 and GTRAP48 (for glutamate transporter EAAT4 associated protein) that specifically interact with the intracellular carboxy-terminal domain of EAAT4 and modulate its glutamate transport activity [5].
  • Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins [5].
  • The transport activity encoded by EAAT4 has high apparent affinity for L-aspartate and L-glutamate, and has a pharmacological profile consistent with previously described cerebellar transport activities [6].
  • EAAT4 controls activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression [7].
  • Regional differences in EAAT4 expression affect the degree of metabotropic glutamate receptor activation and therefore regulate synaptic plasticity [8]

Chemical compound and disease context of SLC1A6


Biological context of SLC1A6

  • The activation process depends on both membrane potential and extracellular glutamate concentration and causes an accumulation of EAAT4 anion channels in a state favoring cation influx and anion efflux [9].
  • At steady state, EAAT4 was activated by glutamate and Na+ with high affinities of 0.6 microM and 8.4 mM, respectively, and showed kinetics consistent with sequential binding of Na(+)-glutamate-Na+ [10].
  • Finally, we examined whether glutamate signaling mediated by EAAT4 can modulate rod outer segment phagocytosis by the retinal pigment epithelium [11].
  • Neither tamoxifen, known to inhibit both proliferation and glutamate uptake in RPE cells, nor retinoic acid nor insulin, also known to affect cell proliferation rates, were capable of changing the total levels of EAAT4 in APRE-19 cells [12].
  • Facilitated activation of metabotropic glutamate receptors in cerebellar Purkinje cells in glutamate transporter EAAT4-deficient mice [13].
  • The main role of EAAT4 is to remove low concentrations of glutamate that escape from the uptake by glial transporters at late times and thus prevents the transmitter from spilling over to neighboring synapses [14].

Anatomical context of SLC1A6


Associations of SLC1A6 with chemical compounds

  • Thus EAAT4 combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission [6].
  • Thus, enhancement of the substrate-gated currents in EAAT4 does not correlate with the rate of substrate transport and suggests that the niflumic acid-induced currents are not thermodynamically coupled to the transport of substrate [16].
  • 3. Niflumic acid and arachidonic acid co-applied with substrate to EAAT4-expressing oocytes had similar functional consequences [16].
  • In this study we demonstrate that Zn(2+) ions inhibit the uncoupled anion conductance and also reduce the affinity of L-aspartate for EAAT4 [17].
  • Two histidine residues in the extracellular loop between transmembrane domains three and four of EAAT4 appear to confer Zn(2+) inhibition of the anion conductance [17].

Other interactions of SLC1A6


Analytical, diagnostic and therapeutic context of SLC1A6


  1. Glutamate transporters in neonatal cerebellar subarachnoid hemorrhage. Inage, Y.W., Itoh, M., Wada, K., Hoshika, A., Takashima, S. Pediatric neurology. (2000) [Pubmed]
  2. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Welsh, J.P., Yuen, G., Placantonakis, D.G., Vu, T.Q., Haiss, F., O'Hearn, E., Molliver, M.E., Aicher, S.A. Advances in neurology. (2002) [Pubmed]
  3. Glutamate transporters GLAST and EAAT4 regulate postischemic Purkinje cell death: an in vivo study using a cardiac arrest model in mice lacking GLAST or EAAT4. Yamashita, A., Makita, K., Kuroiwa, T., Tanaka, K. Neurosci. Res. (2006) [Pubmed]
  4. Spectrin mutations cause spinocerebellar ataxia type 5. Ikeda, Y., Dick, K.A., Weatherspoon, M.R., Gincel, D., Armbrust, K.R., Dalton, J.C., Stevanin, G., Dürr, A., Zühlke, C., Bürk, K., Clark, H.B., Brice, A., Rothstein, J.D., Schut, L.J., Day, J.W., Ranum, L.P. Nat. Genet. (2006) [Pubmed]
  5. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Jackson, M., Song, W., Liu, M.Y., Jin, L., Dykes-Hoberg, M., Lin, C.I., Bowers, W.J., Federoff, H.J., Sternweis, P.C., Rothstein, J.D. Nature (2001) [Pubmed]
  6. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Fairman, W.A., Vandenberg, R.J., Arriza, J.L., Kavanaugh, M.P., Amara, S.G. Nature (1995) [Pubmed]
  7. Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. Brasnjo, G., Otis, T.S. Neuron. (2001) [Pubmed]
  8. Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity. Wadiche, J.I., Jahr, C.E. Nat. Neurosci. (2005) [Pubmed]
  9. A dynamic switch between inhibitory and excitatory currents in a neuronal glutamate transporter. Melzer, N., Torres-Salazar, D., Fahlke, C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. The glutamate transporter subtypes EAAT4 and EAATs 1-3 transport glutamate with dramatically different kinetics and voltage dependence but share a common uptake mechanism. Mim, C., Balani, P., Rauen, T., Grewer, C. J. Gen. Physiol. (2005) [Pubmed]
  11. Nonsynaptic localization of the excitatory amino acid transporter 4 in photoreceptors. Pignataro, L., Sitaramayya, A., Finnemann, S.C., Sarthy, V.P. Mol. Cell. Neurosci. (2005) [Pubmed]
  12. Expression of glutamate transporter subtypes in cultured retinal pigment epithelial and retinoblastoma cells. Mäenpää, H., Gegelashvili, G., Tähti, H. Curr. Eye Res. (2004) [Pubmed]
  13. Facilitated activation of metabotropic glutamate receptors in cerebellar Purkinje cells in glutamate transporter EAAT4-deficient mice. Nikkuni, O., Takayasu, Y., Iino, M., Tanaka, K., Ozawa, S. Neurosci. Res. (2007) [Pubmed]
  14. 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]
  15. Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlation in development and neonatal hypoxic-ischemic damage. Inage, Y.W., Itoh, M., Wada, K., Takashima, S. J. Neuropathol. Exp. Neurol. (1998) [Pubmed]
  16. Niflumic acid modulates uncoupled substrate-gated conductances in the human glutamate transporter EAAT4. Poulsen, M.V., Vandenberg, R.J. J. Physiol. (Lond.) (2001) [Pubmed]
  17. Zn(2+) inhibits the anion conductance of the glutamate transporter EEAT4. Mitrovic, A.D., Plesko, F., Vandenberg, R.J. J. Biol. Chem. (2001) [Pubmed]
  18. Coexistence and function of different neurotransmitter transporters in the plasma membrane of CNS neurons. Raiteri, L., Raiteri, M., Bonanno, G. Prog. Neurobiol. (2002) [Pubmed]
  19. Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. McCullumsmith, R.E., Meador-Woodruff, J.H. Neuropsychopharmacology (2002) [Pubmed]
  20. Neuronal glutamate transporter EAAT4 is expressed in astrocytes. Hu, W.H., Walters, W.M., Xia, X.M., Karmally, S.A., Bethea, J.R. Glia (2003) [Pubmed]
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