excitatory amino acid transporter 4


Summary: A glutamate plasma membrane transporter protein that is primarily expressed in cerebellar PURKINJE CELLS on postsynaptic DENDRITIC SPINES.

Top Publications

  1. Torres Salazar D, Fahlke C. Neuronal glutamate transporters vary in substrate transport rate but not in unitary anion channel conductance. J Biol Chem. 2007;282:34719-26 pubmed
  2. Ward M, Jobling A, Puthussery T, Foster L, Fletcher E. Localization and expression of the glutamate transporter, excitatory amino acid transporter 4, within astrocytes of the rat retina. Cell Tissue Res. 2004;315:305-10 pubmed
    ..characterized to date from neuronal tissue, all of which are expressed within the retina except excitatory amino acid transporter 4 (EAAT4)...
  3. Furuta A, Martin L, Lin C, Dykes Hoberg M, Rothstein J. Cellular and synaptic localization of the neuronal glutamate transporters excitatory amino acid transporter 3 and 4. Neuroscience. 1997;81:1031-42 pubmed
    Glutamate transport is a primary mechanism for the synaptic inactivation of glutamate. Excitatory amino acid transporter 4 (EAAT4) is a novel glutamate transporter with properties of a ligand-gated chloride channel that was recently ..
  4. Wadiche J, Jahr C. Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity. Nat Neurosci. 2005;8:1329-34 pubmed
    ..Regional differences in glutamate transporter expression affect the degree of metabotropic glutamate receptor activation and therefore regulate synaptic plasticity. ..
  5. Yamashita A, Makita K, Kuroiwa T, Tanaka K. 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. Neurosci Res. 2006;55:264-70 pubmed
    ..This result demonstrates that GLAST plays a role in preventing excitotoxic cerebellar damage after ischemia in concert with EAAT4. ..
  6. Melzer N, Biela A, Fahlke C. Glutamate modifies ion conduction and voltage-dependent gating of excitatory amino acid transporter-associated anion channels. J Biol Chem. 2003;278:50112-9 pubmed
    ..These results are incompatible with the notion that glutamate only increases the open probability of the anion pore associated with glutamate transporters and demonstrate unique gating mechanisms of EAAT-associated anion channels. ..
  7. Nikkuni O, Takayasu Y, Iino M, Tanaka K, Ozawa S. Facilitated activation of metabotropic glutamate receptors in cerebellar Purkinje cells in glutamate transporter EAAT4-deficient mice. Neurosci Res. 2007;59:296-303 pubmed
    ..We conclude that EAAT4 is most closely involved in mGluR activation in PCs among the glutamate transporters. ..
  8. Gincel D, Regan M, Jin L, Watkins A, Bergles D, Rothstein J. Analysis of cerebellar Purkinje cells using EAAT4 glutamate transporter promoter reporter in mice generated via bacterial artificial chromosome-mediated transgenesis. Exp Neurol. 2007;203:205-12 pubmed
    ..The correlation of promoter activity to protein expression makes the EAAT4 BAC promoter reporter a valuable tool to study regulation of EAAT4 expression. ..
  9. Williams B, Yaddanapudi K, Hornig M, Lipkin W. Spatiotemporal analysis of purkinje cell degeneration relative to parasagittal expression domains in a model of neonatal viral infection. J Virol. 2007;81:2675-87 pubmed
    ..glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase C and the excitatory amino acid transporter 4 (EAAT4)...

More Information


  1. Fairman W, Vandenberg R, Arriza J, Kavanaugh M, Amara S. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature. 1995;375:599-603 pubmed
    ..Thus EAAT4 combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission. ..
  2. Welsh J, Yuen G, Placantonakis D, Vu T, Haiss F, O HEARN E, et al. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol. 2002;89:331-59 pubmed
    ..Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition. ..
  3. Huang Y, Dykes Hoberg M, Tanaka K, Rothstein J, Bergles D. Climbing fiber activation of EAAT4 transporters and kainate receptors in cerebellar Purkinje cells. J Neurosci. 2004;24:103-11 pubmed
    ..In GluR5 knock-out mice, this current was dramatically reduced, indicating that CF excitation of PCs involves two distinct classes of ionotropic glutamate receptors, AMPA receptors and GluR5-containing kainate receptors. ..
  4. Mim C, Balani P, Rauen T, Grewer C. The glutamate transporter subtypes EAAT4 and EAATs 1-3 transport glutamate with dramatically different kinetics and voltage dependence but share a common uptake mechanism. J Gen Physiol. 2005;126:571-89 pubmed
    ..Therefore, we propose that EAAT4 is a high-affinity/low-capacity transport system, supplementing low-affinity/high-capacity synaptic glutamate uptake by the other subtypes. ..
  5. Rajamanickam J, Palmada M, Lang F, Boehmer C. EAAT4 phosphorylation at the SGK1 consensus site is required for transport modulation by the kinase. J Neurochem. 2007;102:858-66 pubmed
    ..In conclusion, maximal glutamate transport modulation by SGK1 is accomplished by direct EAAT4 stimulation and to a lesser extent by inhibition of intrinsic Nedd4-2. ..
  6. Mim C, Tao Z, Grewer C. Two conformational changes are associated with glutamate translocation by the glutamate transporter EAAC1. Biochemistry. 2007;46:9007-18 pubmed
  7. Slemmer J, Haasdijk E, Engel D, Plesnila N, Weber J. Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity. Eur J Neurosci. 2007;26:649-56 pubmed
    ..The results from the present study indicate that aldolase C provides marked neuroprotection to PCs after trauma and excitotoxicity. ..
  8. de Vivo L, Melone M, Bucci G, Rothstein J, Conti F. Quantitative analysis of EAAT4 promoter activity in neurons and astrocytes of mouse somatic sensory cortex. Neurosci Lett. 2010;474:42-5 pubmed publisher
    ..These results extend our knowledge on EAAT4 expression in the cerebral cortex of adult mice, and suggest that the role of EAAT4 in cortical glutamatergic transmission may be more important than previously thought. ..
  9. Kovermann P, Machtens J, Ewers D, Fahlke C. A conserved aspartate determines pore properties of anion channels associated with excitatory amino acid transporter 4 (EAAT4). J Biol Chem. 2010;285:23676-86 pubmed publisher
    ..The finding that mutating a pore-forming residue modifies gating illustrates the close linkage between pore conformation and voltage- and substrate-dependent gating in EAAT4 anion channels. ..
  10. Poulsen M, Vandenberg R. Niflumic acid modulates uncoupled substrate-gated conductances in the human glutamate transporter EAAT4. J Physiol. 2001;534:159-67 pubmed
  11. Win Shwe T, Fujimaki H, Fujitani Y, Hirano S. Novel object recognition ability in female mice following exposure to nanoparticle-rich diesel exhaust. Toxicol Appl Pharmacol. 2012;262:355-62 pubmed publisher
    ..The present study suggests that genes related to glutamate metabolism may be involved in the NRDE-induced neurotoxicity observed in the present mouse model. ..
  12. Nothmann D, Leinenweber A, Torres Salazar D, Kovermann P, Hotzy J, Gameiro A, et al. Hetero-oligomerization of neuronal glutamate transporters. J Biol Chem. 2011;286:3935-43 pubmed publisher
    ..Our results demonstrate the existence of heterotrimeric glutamate transporters and provide novel information about the physiological impact of EAAT oligomerization. ..
  13. Sopjani M, Alesutan I, Dërmaku Sopjani M, Fraser S, Kemp B, Foller M, et al. Down-regulation of Na+-coupled glutamate transporter EAAT3 and EAAT4 by AMP-activated protein kinase. J Neurochem. 2010;113:1426-35 pubmed publisher
    ..The observations show that AMPK down-regulates Na(+)-coupled glutamate transport. ..
  14. Beaudin S, Welsh J. 1,25-Dihydroxyvitamin D induces the glutamate transporter SLC1A1 and alters glutamate handling in non-transformed mammary cells. Mol Cell Endocrinol. 2016;424:34-41 pubmed publisher
    ..Taken together, these data identify 1,25D as a physiological regulator of multiple membrane glutamate transporters that impacts on overall cellular glutamate handling. ..
  15. Yi J, Herrero R, Chen G, Hazell A. Glutamate transporter EAAT4 is increased in hippocampal astrocytes following lateral fluid-percussion injury in the rat. Brain Res. 2007;1154:200-5 pubmed
    ..Given the reported novel characteristics of chloride conductance displayed by this transporter, our findings of increased EAAT4 levels suggest this protein may play an important role in the pathophysiology of TBI. ..
  16. Abrahamsen B, Schneider N, Erichsen M, Huynh T, Fahlke C, Bunch L, et al. Allosteric modulation of an excitatory amino acid transporter: the subtype-selective inhibitor UCPH-101 exerts sustained inhibition of EAAT1 through an intramonomeric site in the trimerization domain. J Neurosci. 2013;33:1068-87 pubmed publisher
    ..quot; ..
  17. Machtens J, Kovermann P, Fahlke C. Substrate-dependent gating of anion channels associated with excitatory amino acid transporter 4. J Biol Chem. 2011;286:23780-8 pubmed publisher
    ..We conclude that all voltage- and substrate-dependent conformational changes of the EAAT4 anion channel are linked to transitions within the transport cycle. ..
  18. Ikeda Y, Dick K, Weatherspoon M, Gincel D, Armbrust K, Dalton J, et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet. 2006;38:184-90 pubmed
    ..Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling. ..
  19. Wadiche J, Tzingounis A, Jahr C. Intrinsic kinetics determine the time course of neuronal synaptic transporter currents. Proc Natl Acad Sci U S A. 2006;103:1083-7 pubmed
    ..monitored by recording the synaptic transport current (STC) mediated by the PC-specific transporter excitatory amino acid transporter 4 (EAAT4)...
  20. Otis T, Brasnjo G, Dzubay J, Pratap M. Interactions between glutamate transporters and metabotropic glutamate receptors at excitatory synapses in the cerebellar cortex. Neurochem Int. 2004;45:537-44 pubmed
    ..g. selective serotonin reuptake inhibitors) and drugs of abuse (amphetamine, cocaine), little is known about how they operate at a molecular level or contribute to synaptic transmission. ..
  21. Butchbach M, Tian G, Guo H, Lin C. Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function. J Biol Chem. 2004;279:34388-96 pubmed
  22. Su L, Shen Y. Blockade of glutamate transporters facilitates cerebellar synaptic long-term depression. Neuroreport. 2009;20:502-7 pubmed publisher
    ..Our results suggest that neuronal glutamate transporters strongly influence mGluR1-dependent cerebellar LTD. ..
  23. Satake S, Song S, Konishi S, Imoto K. Glutamate transporter EAAT4 in Purkinje cells controls intersynaptic diffusion of climbing fiber transmitter mediating inhibition of GABA release from interneurons. Eur J Neurosci. 2010;32:1843-53 pubmed publisher
  24. Wilmsdorff M, Blaich C, Zink M, Treutlein J, Bauer M, Schulze T, et al. Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment. World J Biol Psychiatry. 2013;14:490-9 pubmed publisher
    ..Decreased SLC1A6 expression in NRG1 risk variant may be an adaptive effect to restore glutamate signalling, but treatment effects cannot be excluded. ..
  25. Dalet A, Bonsacquet J, Gaboyard Niay S, Calin Jageman I, Chidavaenzi R, Venteo S, et al. Glutamate transporters EAAT4 and EAAT5 are expressed in vestibular hair cells and calyx endings. PLoS ONE. 2012;7:e46261 pubmed publisher
    ..Our results show that these two transporters have a wider distribution in mice. This is the first demonstration of the presence of transporters in hair cells and provides one of the few examples of EAATs in presynaptic elements. ..
  26. Yoo S, Kim J, Do S, Zuo Z. Inhibition of the activity of excitatory amino acid transporter 4 expressed in Xenopus oocytes after chronic exposure to ethanol. Alcohol Clin Exp Res. 2008;32:1292-8 pubmed publisher
    ..These effects of ethanol on EAAT4 may cause an increase in peri-Purkinje cellular glutamate concentration, and may be involved in cerebellar dysfunction and motor impairment after chronic ethanol ingestion. ..
  27. Koch H, Brown R, Larsson H. The glutamate-activated anion conductance in excitatory amino acid transporters is gated independently by the individual subunits. J Neurosci. 2007;27:2943-7 pubmed
  28. Dirson G, Desjardins P, Tannenberg T, Dodd P, Butterworth R. Selective loss of expression of glutamate GluR2/R3 receptor subunits in cerebellar tissue from a patient with olivopontocerebellar atrophy. Metab Brain Dis. 2002;17:77-82 pubmed
  29. Hu W, Walters W, Xia X, Karmally S, Bethea J. Neuronal glutamate transporter EAAT4 is expressed in astrocytes. Glia. 2003;44:13-25 pubmed
    ..These results demonstrate that EAAT4 is expressed in astrocytes. This astrocytic localization of neuronal EAAT4 may reveal a new function of EAAT4 in the central nervous system. ..
  30. Pignataro L, Sitaramayya A, Finnemann S, Sarthy V. Nonsynaptic localization of the excitatory amino acid transporter 4 in photoreceptors. Mol Cell Neurosci. 2005;28:440-51 pubmed
  31. Ward M, Jobling A, Kalloniatis M, Fletcher E. Glutamate uptake in retinal glial cells during diabetes. Diabetologia. 2005;48:351-60 pubmed
    ..These results suggest that although Muller cells undergo gliosis at an early stage of diabetes, one of the most important functions for maintaining normal retinal function is preserved within the retina. ..
  32. Böhmer C, Philippin M, Rajamanickam J, Mack A, Broer S, Palmada M, et al. Stimulation of the EAAT4 glutamate transporter by SGK protein kinase isoforms and PKB. Biochem Biophys Res Commun. 2004;324:1242-8 pubmed
    ..In conclusion, SGK1 expression is upregulated by ischemia, excitation, and dehydration in cerebellar Purkinje cells. The upregulation of SGK1 may serve to stimulate EAAT4 and thus to reduce neuroexcitotoxicity. ..
  33. Hamamura M, Watanabe S, Fukumaki Y. Selective changes in the shapes of parasagittal bands of Aldoc (Zebrin) mRNA in the rat vermis of the cerebellum after repeated methamphetamine injections. Cerebellum. 2004;3:236-47 pubmed
  34. Maragakis N, Dietrich J, Wong V, Xue H, Mayer Proschel M, Rao M, et al. Glutamate transporter expression and function in human glial progenitors. Glia. 2004;45:133-43 pubmed
  35. Perkins E, Suminaite D, Clarkson Y, Lee S, Lyndon A, Rothstein J, et al. Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST. Hum Mol Genet. 2016;25:4448-4461 pubmed publisher
  36. Jackson M, Song W, Liu M, Jin L, Dykes Hoberg M, Lin C, et al. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature. 2001;410:89-93 pubmed
  37. McCullumsmith R, Meador Woodruff J. Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology. 2002;26:368-75 pubmed
    ..These results suggest that changes in striatal transporter mRNA expression are restricted to neuronal EAATs and extend the body of evidence implicating abnormal glutamatergic neurotransmission in schizophrenia and mood disorders. ..
  38. Suchak S, Baloyianni N, Perkinton M, Williams R, Meldrum B, Rattray M. The 'glial' glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. J Neurochem. 2003;84:522-32 pubmed
    ..The data presented in this study indicate that EAAT2 is the predominant nerve terminal glutamate transporter in the adult rodent CNS. ..
  39. Machtens J, Fahlke C, Kovermann P. Noise analysis to study unitary properties of transporter-associated ion channels. Channels (Austin). 2011;5:468-74 pubmed publisher
  40. Paukert M, Huang Y, Tanaka K, Rothstein J, Bergles D. Zones of enhanced glutamate release from climbing fibers in the mammalian cerebellum. J Neurosci. 2010;30:7290-9 pubmed publisher
    ..The enhanced release of glutamate from CFs in Z(+) zones may alter the threshold for synaptic plasticity and prolong inhibition of cerebellar output neurons in deep cerebellar nuclei. ..
  41. Alesutan I, Ureche O, Laufer J, Klaus F, Zurn A, Lindner R, et al. Regulation of the glutamate transporter EAAT4 by PIKfyve. Cell Physiol Biochem. 2010;25:187-94 pubmed publisher
    ..Furthermore, coexpression of (S318A)PIKfyve significantly blunted the stimulating effect of SGK1 on EAAT4 activity. The observations disclose that PIKfyve indeed participates in the regulation of EAAT4. ..
  42. Lim S, Han H, Kim K, Park S. Both B1R and B2R act as intermediate signaling molecules in high glucose-induced stimulation of glutamate uptake in ARPE cells. J Cell Physiol. 2009;221:677-87 pubmed publisher
  43. Hinoi E, Wang L, Takemori A, Yoneda Y. Functional expression of particular isoforms of excitatory amino acid transporters by rodent cartilage. Biochem Pharmacol. 2005;70:70-81 pubmed
    ..These results suggest that extracellular Glu could be cleared up into intracellular locations through particular glial and/or neuronal EAAT isoforms functionally expressed by the rodent cartilage. ..
  44. Takayasu Y, Iino M, Kakegawa W, Maeno H, Watase K, Wada K, et al. Differential roles of glial and neuronal glutamate transporters in Purkinje cell synapses. J Neurosci. 2005;25:8788-93 pubmed
    ..Two distinct glutamate transporters, glutamate-aspartate transporter (GLAST) and excitatory amino acid transporter 4 (EAAT4), are expressed most abundantly in the molecular layer of the cerebellar cortex...
  45. Torres Salazar D, Fahlke C. Intersubunit interactions in EAAT4 glutamate transporters. J Neurosci. 2006;26:7513-22 pubmed
    ..Our results demonstrate that glutamate carriers cooperatively interact during anion channel activation. ..
  46. Lee A, Anderson A, Barnett A, Chan A, Pow D. Expression of multiple glutamate transporter splice variants in the rodent testis. Asian J Androl. 2011;13:254-65 pubmed publisher
    ..transporter (GLAST), glutamate transporter 1 (GLT1), excitatory amino acid carrier 1 (EAAC1), excitatory amino acid transporter 4 (EAAT4) and EAAT5...
  47. Yukitake M, Satoh J, Katamine S, Kuroda Y. EAAT4 mRNA expression is preserved in the cerebellum of prion protein-deficient mice. Neurosci Lett. 2003;352:171-4 pubmed
  48. Stankewich M, Gwynn B, Ardito T, Ji L, Kim J, Robledo R, et al. Targeted deletion of betaIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. Proc Natl Acad Sci U S A. 2010;107:6022-7 pubmed publisher
    ..The mislocalization of these proteins secondarily disrupts glutamate transport dynamics, leading to seizures, neuronal damage, and compensatory changes in EAAT3 and neuropeptide Y...
  49. Gao Y, Perkins E, Clarkson Y, Tobia S, Lyndon A, Jackson M, et al. ?-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis. J Neurosci. 2011;31:16581-90 pubmed publisher
  50. Hosseinzadeh Z, Bhavsar S, Sopjani M, Alesutan I, Saxena A, Dërmaku Sopjani M, et al. Regulation of the glutamate transporters by JAK2. Cell Physiol Biochem. 2011;28:693-702 pubmed publisher
    ..In conclusion, JAK2 is a novel powerful regulator of glutamate transporters and thus participates in the protection against excitotoxicity. ..
  51. Tsai M, Tanaka K, Overstreet Wadiche L, Wadiche J. Neuronal glutamate transporters regulate glial excitatory transmission. J Neurosci. 2012;32:1528-35 pubmed publisher
    ..These results demonstrate that physiological regulation of neuronal transporter expression can alter extrasynaptic neuroglial signaling. ..
  52. Sachs A, David S, Haider N, Nystuen A. Patterned neuroprotection in the Inpp4a(wbl) mutant mouse cerebellum correlates with the expression of Eaat4. PLoS ONE. 2009;4:e8270 pubmed publisher
    ..Our data suggest that Purkinje cell loss in the Inpp4a(wbl) mutant is due to glutamate excitotoxicity initiated by the climbing fiber, and that Eaat4 may exert a protective effect...
  53. Lauriat T, Dracheva S, Chin B, Schmeidler J, McInnes L, Haroutunian V. Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain. Neuroscience. 2006;137:843-51 pubmed
    ..However, because most of the schizophrenic subjects in the cohort had been treated with antipsychotics for many years, it is still possible that changes in transporter expression were masked by medication effects. ..