CoChat
Sign Up
Cited by 146

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond

Magi, Simona, Piccirillo, Silvia, Amoroso, Salvatore, Lariccia, Vincenzo·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20225674PMC PMC6888595
Open this paper in CoChat — free account

Abstract

Na+-dependent excitatory amino acid transporters (EAATs) are the major transport mechanisms for extracellular glutamate removal in the central nervous system (CNS). The primary function assigned to EAATs is the maintenance of low extracellular glutamate levels, thus allowing glutamate to be used as a signaling molecule in the brain and to avoid excitotoxicity. However, glutamate has other recognized functions. For instance, it is a key anaplerotic substrate for the tricarboxylic acid (TCA) cycle, as it can be converted to α-ketoglutarate by transaminases or glutamate dehydrogenase. Furthermore, glutamate is a precursor of the main antioxidant glutathione, which plays a pivotal role in preventing oxidative cell death. Therefore, glutamate signaling/use is at the crossroad of multiple metabolic pathways and accordingly, it can influence a plethora of cell functions, both in health and disease. Here, we provide an overview of the main functions of glutamate and its transport systems, analyzing its role as a neurotransmitter and at the same time, the possible metabolic fates it can undergo in the intracellular milieu. Specifically, the metabolic role of glutamate and the molecular machinery proposed to metabolically support its transport will be further analyzed.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/ijms20225674

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Schematic diagram of the ion-flux coupling stoichiometry for glutamate transporters. The transport of glutamate is coupled with the cotransport of 3 Na+, 1 H+, and 1 K+ ion along their concentration gradient. Additionally, glutamate and Na+ activate an uncoupled chloride conductance through the transporter. The picture was adapted from [26] upon written authorization by the editor.
Figure 1 Schematic diagram of the ion-flux coupling stoichiometry for glutamate transporters. The transport of glutamate is coupled with the cotransport of 3 Na+, 1 H+, and 1 K+ ion along their concentration gradient. Additionally, glutamate and Na+ activate an uncoupled chloride conductance through the transporter. The picture was adapted from [26] upon written authorization by the editor.CC BY · PubMed Central
Figure 2 Schematic representation of the EAATs-including macromolecular complexes. EAATs compartmentalization with Na+/K+-ATPase and NCX1 ensures an efficient glutamate uptake through the maintenance of ion gradients. Compelling evidence supports the concept that the increased Na+ influx generated by the EAAC1 forces NCX1 to work on the reverse mode, thereby activating a virtuous cycle that could induce a slight but significant local increase in Ca2+ levels and stimulate the activity of the Ca2+-sensitive mitochondrial dehydrogenases, fueling ATP synthesis [2]. EAATs local assembly with the “energy producing machinery” further optimizes ATP production, creating a local proteins pool able to quickly support and adjust energy demand. ANT = Adenine Nucleotide Translocator; EAAC1 = Excitatory Amino Acid Carrier1; GLAST = Glutamate Aspartate Transporter; GLT-1 = Glutamate Transporter-1; NCX1 = Na+/Ca2+ exchanger1; UQCRC2 = Ubiquinol Cytochrome c Oxidoreductase Subunit Core 2; VDAC = Voltage-Dependent Anion Channel.
Figure 2 Schematic representation of the EAATs-including macromolecular complexes. EAATs compartmentalization with Na+/K+-ATPase and NCX1 ensures an efficient glutamate uptake through the maintenance of ion gradients. Compelling evidence supports the concept that the increased Na+ influx generated by the EAAC1 forces NCX1 to work on the reverse mode, thereby activating a virtuous cycle that could induce a slight but significant local increase in Ca2+ levels and stimulate the activity of the Ca2+-sensitive mitochondrial dehydrogenases, fueling ATP synthesis [2]. EAATs local assembly with the “energy producing machinery” further optimizes ATP production, creating a local proteins pool able to quickly support and adjust energy demand. ANT = Adenine Nucleotide Translocator; EAAC1 = Excitatory Amino Acid Carrier1; GLAST = Glutamate Aspartate Transporter; GLT-1 = Glutamate Transporter-1; NCX1 = Na+/Ca2+ exchanger1; UQCRC2 = Ubiquinol Cytochrome c Oxidoreductase Subunit Core 2; VDAC = Voltage-Dependent Anion Channel.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 3 references

Research works printed but not linked: 73

  1. Gonzalez, 2013, In silico insights of L-glutamate: Structural features in vacuum and in complex with its receptor, J. Amino Acids, 2013, 872058, 10.1155/2013/872058 · DOI
  2. Magi, 2019, The dual face of glutamate: From a neurotoxin to a potential survival factor-metabolic implications in health and disease, Cell. Mol. Life Sci., 76, 1473, 10.1007/s00018-018-3002-x · DOI
  3. Reiner, 2018, Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert, Neuron, 98, 1080, 10.1016/j.neuron.2018.05.018 · DOI
  4. Whetsell, 1993, Neuroexcitation, excitotoxicity and human neurological disease, Lab. Investig., 68, 372
  5. Ribeiro, 2017, Metabotropic glutamate receptors and neurodegenerative diseases, Pharmacol. Res., 115, 179, 10.1016/j.phrs.2016.11.013 · DOI
  6. Crupi, 2019, Role of Metabotropic Glutamate Receptors in Neurological Disorders, Front. Mol. Neurosci., 12, 20, 10.3389/fnmol.2019.00020 · DOI
  7. Olloquequi, 2018, Excitotoxicity in the pathogenesis of neurological and psychiatric disorders: Therapeutic implications, J. Psychopharmacol., 32, 265, 10.1177/0269881118754680 · DOI
  8. Zhou, 2014, Glutamate as a neurotransmitter in the healthy brain, J. Neural Transm., 121, 799, 10.1007/s00702-014-1180-8 · DOI
  9. Grewer, 2014, SLC1 glutamate transporters, Pflug. Arch. Eur. J. Physiol., 466, 3, 10.1007/s00424-013-1397-7 · DOI
  10. Vandenberg, 2013, Mechanisms of glutamate transport, Physiol. Rev., 93, 1621, 10.1152/physrev.00007.2013 · DOI
  11. Fremeau, 2004, VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate, Trends Neurosci., 27, 98, 10.1016/j.tins.2003.11.005 · DOI · Paper page
  12. Danbolt, 1990, Purification and reconstitution of the sodium- and potassium-coupled glutamate transport glycoprotein from rat brain, Biochemistry, 29, 6734, 10.1021/bi00480a025 · DOI
  13. Pines, 1992, Cloning and expression of a rat brain L-glutamate transporter, Nature, 360, 464, 10.1038/360464a0 · DOI
  14. Storck, 1992, Structure, expression, and functional analysis of a Na+-dependent glutamate/aspartate transporter from rat brain, Proc. Natl. Acad. Sci. USA, 89, 10955, 10.1073/pnas.89.22.10955 · DOI
  15. Kanai, 1993, The elusive transporters with a high affinity for glutamate, Trends Neurosci., 16, 365, 10.1016/0166-2236(93)90094-3 · DOI
  16. Fairman, 1995, An excitatory amino-acid transporter with properties of a ligand-gated chloride channel, Nature, 375, 599, 10.1038/375599a0 · DOI
  17. Arriza, 1997, Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance, Proc. Natl. Acad. Sci. USA, 94, 4155, 10.1073/pnas.94.8.4155 · DOI
  18. Rothstein, 1994, Localization of neuronal and glial glutamate transporters, Neuron, 13, 713, 10.1016/0896-6273(94)90038-8 · DOI
  19. Mennerick, 1998, Neuronal expression of the glutamate transporter GLT-1 in hippocampal microcultures, J. Neurosci., 18, 4490, 10.1523/JNEUROSCI.18-12-04490.1998 · DOI
  20. Kugler, 1999, Glutamate transporter EAAC1 is expressed in neurons and glial cells in the rat nervous system, Glia, 27, 129, 10.1002/(SICI)1098-1136(199908)27:2<129::AID-GLIA3>3.0.CO;2-Y · DOI
  21. Domercq, 1999, Expression of glutamate transporters in rat optic nerve oligodendrocytes, Eur. J. Neurosci., 11, 2226, 10.1046/j.1460-9568.1999.00639.x · DOI
  22. Stover, 2001, Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat, Glia, 35, 167, 10.1002/glia.1082 · DOI
  23. Palos, 1996, Rat C6 and human astrocytic tumor cells express a neuronal type of glutamate transporter, Mol. Brain Res., 37, 297, 10.1016/0169-328X(95)00331-L · DOI
  24. Danbolt, 2001, Glutamate uptake, Prog. Neurobiol., 65, 1, 10.1016/S0301-0082(00)00067-8 · DOI · Paper page
  25. Ryan, 2005, A channel in a transporter, Clin. Exp. Pharmacol. Physiol., 32, 1, 10.1111/j.1440-1681.2005.04164.x · DOI
  26. Owe, 2006, The ionic stoichiometry of the GLAST glutamate transporter in salamander retinal glia, J. Physiol., 577, 591, 10.1113/jphysiol.2006.116830 · DOI
  27. Zerangue, 1996, Flux coupling in a neuronal glutamate transporter, Nature, 383, 634, 10.1038/383634a0 · DOI
  28. Kanai, 1995, Electrogenic properties of the epithelial and neuronal high affinity glutamate transporter, J. Biol. Chem., 270, 16561, 10.1074/jbc.270.28.16561 · DOI
  29. Wadiche, 1995, Ion fluxes associated with excitatory amino acid transport, Neuron, 15, 721, 10.1016/0896-6273(95)90159-0 · DOI
  30. Vandenberg, 1995, Constitutive ion fluxes and substrate binding domains of human glutamate transporters, J. Biol. Chem., 270, 17668, 10.1074/jbc.270.30.17668 · DOI
  31. Billups, 1996, Anion conductance behavior of the glutamate uptake carrier in salamander retinal glial cells, J. Neurosci., 16, 6722, 10.1523/JNEUROSCI.16-21-06722.1996 · DOI
  32. Sonders, 1996, Channels in transporters, Curr. Opin. Neurobiol., 6, 294, 10.1016/S0959-4388(96)80111-5 · DOI
  33. Vandenberg, 2008, Slips, leaks and channels in glutamate transporters, Channels, 2, 51, 10.4161/chan.2.1.6047 · DOI
  34. Veruki, 2006, Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling, Nat. Neurosci., 9, 1388, 10.1038/nn1793 · DOI
  35. Wersinger, 2006, The glutamate transporter EAAT5 works as a presynaptic receptor in mouse rod bipolar cells, J. Physiol., 577, 221, 10.1113/jphysiol.2006.118281 · DOI
  36. Gameiro, 2011, The discovery of slowness: Low-capacity transport and slow anion channel gating by the glutamate transporter EAAT5, Biophys. J., 100, 2623, 10.1016/j.bpj.2011.04.034 · DOI
  37. 2012, Toward a new role for plasma membrane sodium-dependent glutamate transporters of astrocytes: Maintenance of antioxidant defenses beyond extracellular glutamate clearance, Amino Acids, 42, 181, 10.1007/s00726-011-0863-9 · DOI
  38. Chen, 2003, The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures, J. Neurochem., 84, 1332, 10.1046/j.1471-4159.2003.01630.x · DOI
  39. Cho, 1990, Uptake of glutamate and cysteine in C-6 glioma cells and in cultured astrocytes, J. Neurochem., 55, 2091, 10.1111/j.1471-4159.1990.tb05800.x · DOI
  40. Shanker, 2001, Methylmercury inhibits cysteine uptake in cultured primary astrocytes, but not in neurons, Brain Res., 914, 159, 10.1016/S0006-8993(01)02791-3 · DOI
  41. Bender, 2000, Characterization of cystine uptake in cultured astrocytes, Neurochem. Int., 37, 269, 10.1016/S0197-0186(00)00035-8 · DOI
  42. Hayes, 2005, Transport of L-[14C]cystine and L-[14C]cysteine by subtypes of high affinity glutamate transporters over-expressed in HEK cells, Neurochem. Int., 46, 585, 10.1016/j.neuint.2005.03.001 · DOI
  43. Zerangue, 1996, Interaction of L-cysteine with a human excitatory amino acid transporter, J. Physiol., 493, 419, 10.1113/jphysiol.1996.sp021393 · DOI
  44. Himi, 2003, Role of neuronal glutamate transporter in the cysteine uptake and intracellular glutathione levels in cultured cortical neurons, J. Neural Transm., 110, 1337, 10.1007/s00702-003-0049-z · DOI
  45. Harada, 2007, The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma, J. Clin. Investig., 117, 1763, 10.1172/JCI30178 · DOI
  46. Berman, 2011, N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/- mouse, Ann. Neurol., 69, 509, 10.1002/ana.22162 · DOI
  47. Li, 2011, Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice, J. Cereb. Blood Flow Metab., 31, 1283, 10.1038/jcbfm.2010.222 · DOI
  48. McKenna, 2007, The glutamate-glutamine cycle is not stoichiometric: Fates of glutamate in brain, J. Neurosci. Res., 85, 3347, 10.1002/jnr.21444 · DOI
  49. Panov, 2009, The neuromediator glutamate, through specific substrate interactions, enhances mitochondrial ATP production and reactive oxygen species generation in nonsynaptic brain mitochondria, J. Biol. Chem., 284, 14448, 10.1074/jbc.M900985200 · DOI
  50. Hertz, 2003, Cataplerotic TCA cycle flux determined as glutamate-sustained oxygen consumption in primary cultures of astrocytes, Neurochem. Int., 43, 355, 10.1016/S0197-0186(03)00022-6 · DOI
  51. McKenna, 2013, Glutamate pays its own way in astrocytes, Front. Endocrinol., 4, 191, 10.3389/fendo.2013.00191 · DOI
  52. McKenna, 1993, Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: Differences revealed using aminooxyacetate, Dev. Neurosci., 15, 320, 10.1159/000111351 · DOI
  53. Tildon, 1985, Substrate oxidation by isolated rat brain mitochondria and synaptosomes, J. Neurosci. Res., 14, 207, 10.1002/jnr.490140206 · DOI
  54. Olstad, 2007, Glutamate is preferred over glutamine for intermediary metabolism in cultured cerebellar neurons, J. Cereb. Blood Flow Metab., 27, 811, 10.1038/sj.jcbfm.9600400 · DOI
  55. Divakaruni, 2017, Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death, J. Cell. Biol., 216, 1091, 10.1083/jcb.201612067 · DOI
  56. Fendt, 2017, Neurons eat glutamate to stay alive, J. Cell. Biol., 216, 863, 10.1083/jcb.201702003 · DOI
  57. Magi, S., Lariccia, V., Castaldo, P., Arcangeli, S., Nasti, A.A., Giordano, A., and Amoroso, S. (2012). Physical and functional interaction of NCX1 and EAAC1 transporters leading to glutamate-enhanced ATP production in brain mitochondria. PLoS ONE, 7. · DOI
  58. Palmieri, 2001, Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria, EMBO J., 20, 5060, 10.1093/emboj/20.18.5060 · DOI
  59. Fiermonte, 2002, Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms, J. Biol. Chem., 277, 19289, 10.1074/jbc.M201572200 · DOI · Paper page
  60. Ortega, 2017, Glial Glutamate Transporters as Signaling Molecules, Adv. Neurobiol., 16, 185, 10.1007/978-3-319-55769-4_9 · DOI
  61. Ralphe, 2004, Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria, J. Mol. Cell. Cardiol., 37, 33, 10.1016/j.yjmcc.2004.04.008 · DOI
  62. Ralphe, 2005, Correlation between myocardial malate/aspartate shuttle activity and EAAT1 protein expression in hyper- and hypothyroidism, Am. J. Physiol. Heart. Circ. Physiol., 288, H2521, 10.1152/ajpheart.00991.2004 · DOI
  63. Annunziato, 2004, Pharmacology of brain Na+/Ca2+ exchanger: From molecular biology to therapeutic perspectives, Pharmacol. Rev., 56, 633, 10.1124/pr.56.4.5 · DOI
  64. Blaustein, 1999, Sodium/calcium exchange: Its physiological implications, Physiol. Rev., 79, 763, 10.1152/physrev.1999.79.3.763 · DOI
  65. Philipson, 2000, Sodium-calcium exchange: A molecular perspective, Annu. Rev. Physiol., 62, 111, 10.1146/annurev.physiol.62.1.111 · DOI
  66. Quednau, 1997, Tissue specificity and alternative splicing of the Na+/Ca2+ exchanger isoforms NCX1, NCX2, and NCX3 in rat, Am. J. Physiol., 272, C1250, 10.1152/ajpcell.1997.272.4.C1250 · DOI
  67. Giladi, 2017, Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms, Sci. Rep., 7, 993, 10.1038/s41598-017-01102-x · DOI
  68. Magi, 2013, Glutamate-induced ATP synthesis: Relationship between plasma membrane Na+/Ca2+ exchanger and excitatory amino acid transporters in brain and heart cell models, Mol. Pharmacol., 84, 603, 10.1124/mol.113.087775 · DOI
  69. Maiolino, 2017, Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation, Sci. Rep., 7, 13073, 10.1038/s41598-017-13478-x · DOI
  70. Piccirillo, 2018, Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: Leading role of the Na+/Ca2+ exchanger, Cell. Death Dis., 9, 731, 10.1038/s41419-018-0784-6 · DOI
  71. Gegelashvili, 2019, Glutamate transport system as a key constituent of glutamosome: Molecular pathology and pharmacological modulation in chronic pain, Neuropharmacology, 153, 53
  72. Genda, 2011, Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria, J. Neurosci., 31, 18275, 10.1523/JNEUROSCI.3305-11.2011 · DOI
  73. Bauer, 2012, The glutamate transporter, GLAST, participates in a macromolecular complex that supports glutamate metabolism, Neurochem. Int., 61, 566, 10.1016/j.neuint.2012.01.013 · DOI

Cited by

Sorted by citations

See all 146

Metadata

Authors
Magi, S., Piccirillo, S., Amoroso, S., & Lariccia, V.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-11-13
Volume
20
Issue
22
Pages
5674
ISSN
1422-0067
DOI
10.3390/ijms20225674
PMC
PMC6888595
Cited by
146
References
3
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond. https://app.cochat.ai/papers/10.3390/ijms20225674
The paper
Magi, S., Piccirillo, S., Amoroso, S., & Lariccia, V. (2019). Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms20225674