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Glutamate Transporters in the Blood-Brain Barrier

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Part of the Advances in Neurobiology book series (NEUROBIOL, volume 16)

Abstract

The amino acid L-glutamate serves a number of roles in the central nervous system, being an excitatory neurotransmitter, metabolite, and building block in protein synthesis. During pathophysiological events, where L-glutamate homeostasis cannot be maintained, the increased brain interstitial fluid concentration of L-glutamate causes excitotoxicity. A tight control of the brain interstitial fluid L-glutamate levels is therefore imperative, in order to maintain optimal neurotransmission and to avoid such excitotoxicity. The blood-brain barrier, i.e., the endothelial lining of the brain capillaries, regulates the exchange of nutrients, gases, and metabolic waste products between plasma and brain interstitial fluid. It has been suggested that brain capillary endothelial cells could play an important role in L-glutamate homeostasis by mediating brain-to-blood L-glutamate efflux. Both in vitro and in vivo studies have demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. A number of studies have shown that brain endothelial cells express excitatory amino acid transporters, which may account for abluminal concentrative uptake of L-glutamate into the capillary endothelial cells. The mechanisms underlying transendothelial L-glutamate transport are however still not well understood. The present chapter summarizes the current knowledge on blood-brain barrier L-glutamate transporters and the suggested pathways for the brain-to-blood L-glutamate efflux.

Keywords

Excitotoxicity EAAT Neurovascular unit Brain glutamate efflux Glutamate metabolism 
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Notes

Conflict of Interest

The author declares no conflicts of interest.

References

  1. Aihara Y, Mashima H, Onda H, Hisano S, Kasuya H, Hori T, et al. Molecular cloning of a novel brain-type Na(+)-dependent inorganic phosphate cotransporter. J Neurochem. 2000;74(6):2622–5.PubMedCrossRefGoogle Scholar
  2. Arriza JL, Eliasof S, Kavanaugh MP, Amara SG. Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci U S A. 1997;94(8):4155–60.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Balcar VJ, Johnston GA. Glutamate uptake by brain slices and its relation to the depolarization of neurones by acidic amino acids. J Neurobiol. 1972;3(4):295–301.PubMedCrossRefGoogle Scholar
  4. Benjamin AM, Quastel JH. Cerebral uptakes and exchange diffusion in vitro of L- and D-glutamates. J Neurochem. 1976;26(3):431–41.PubMedCrossRefGoogle Scholar
  5. Benrabh H, Lefauconnier JM. Glutamate is transported across the rat blood-brain barrier by a sodium-independent system. Neurosci Lett. 1996;210(1):9–12.PubMedCrossRefGoogle Scholar
  6. Blondeau JP. Homologues of amino acid permeases: cloning and tissue expression of XAT1 and XAT2. Gene. 2002;286(2):241–8.PubMedCrossRefGoogle Scholar
  7. Boyko M, Melamed I, Gruenbaum BF, Gruenbaum SE, Ohayon S, Leibowitz A, et al. The effect of blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome in a rat model of subarachnoid hemorrhage. Neurotherapeutics. 2012;9(3):649–57.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Boyko M, Gruenbaum SE, Gruenbaum BF, Shapira Y, Zlotnik A. Brain to blood glutamate scavenging as a novel therapeutic modality: a review. J Neural Transm. 2014;121(8):971–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Campos F, Sobrino T, Ramos-Cabrer P, Argibay B, Agulla J, Perez-Mato M, et al. Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. J Cereb Blood Flow Metab. 2011a;31(6):1378–86.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Campos F, Rodriguez-Yanez M, Castellanos M, Arias S, Perez-Mato M, Sobrino T, et al. Blood levels of glutamate oxaloacetate transaminase are more strongly associated with good outcome in acute ischaemic stroke than glutamate pyruvate transaminase levels. Clin Sci (Lond). 2011b;121(1):11–7.CrossRefGoogle Scholar
  11. Cardelli-Cangiano P, Cangiano C, James JH, Jeppsson B, Brenner W, Fischer JE. Uptake of amino acids by brain microvessels isolated from rats after portacaval anastomosis. J Neurochem. 1981;36(2):627–32.PubMedCrossRefGoogle Scholar
  12. Castillo J, Loza MI, Mirelman D, Brea J, Blanco M, Sobrino T, et al. A novel mechanism of neuroprotection: blood glutamate grabber. J Cereb Blood Flow Metab. 2016;36(2):292–301.PubMedCrossRefGoogle Scholar
  13. Cederberg HH, Uhd NC, Brodin B. Glutamate efflux at the blood-brain barrier: cellular mechanisms and potential clinical relevance. Arch Med Res. 2014;45(8):639–45.PubMedCrossRefGoogle Scholar
  14. Chaudhry FA, Lehre KP, van Lookeren Campagne M, Ottersen OP, Danbolt NC, Storm-Mathisen J. Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron. 1995;15(3):711–20.PubMedCrossRefGoogle Scholar
  15. Chodobski A, Zink BJ, Szmydynger-Chodobska J. Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res. 2011;2(4):492–516.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Christensen HN. Organic ion transport during seven decades. The amino acids. Biochim Biophys Acta. 1984;779(3):255–69.PubMedCrossRefGoogle Scholar
  17. Chun HB, Scott M, Niessen S, Hoover H, Baird A, Yates J 3rd, et al. The proteome of mouse brain microvessel membranes and basal lamina. J Cereb Blood Flow Metab. 2011;31(12):2267–81.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cohen-Kashi-Malina K, Cooper I, Teichberg VI. Mechanisms of glutamate efflux at the blood-brain barrier: involvement of glial cells. J Cereb Blood Flow Metab. 2012;32(1):177–89.PubMedCrossRefGoogle Scholar
  19. Contreras L, Urbieta A, Kobayashi K, Saheki T, Satrustegui J. Low levels of citrin (SLC25A13) expression in adult mouse brain restricted to neuronal clusters. J Neurosci Res. 2010;88(5):1009–16.PubMedCrossRefGoogle Scholar
  20. Cox DW, Headley MH, Watkins JC. Actions of L- and D-homocysteate in rat CNS: a correlation between low-affinity uptake and the time courses of excitation by microelectrophoretically applied L-glutamate analogues. J Neurochem. 1977;29(3):579–88.PubMedCrossRefGoogle Scholar
  21. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65(1):1–105.PubMedCrossRefGoogle Scholar
  22. Danbolt NC, Storm-Mathisen J, Kanner BI. An [Na+ + K+]coupled L-glutamate transporter purified from rat brain is located in glial cell processes. Neuroscience. 1992;51(2):295–310.PubMedCrossRefGoogle Scholar
  23. Danbolt NC, Storm-Mathisen J, Ottersen OP. Sodium/potassium-coupled glutamate transporters, a “new” family of eukaryotic proteins: do they have “new” physiological roles and could they be new targets for pharmacological intervention? Prog Brain Res. 1994;100:53–60.PubMedCrossRefGoogle Scholar
  24. Danbolt NC, Furness DN, Zhou Y. Neuronal vs glial glutamate uptake: resolving the conundrum. Neurochem Int. 2016;98:29–45.PubMedCrossRefGoogle Scholar
  25. Daneman R, Zhou L, Agalliu D, Cahoy JD, Kaushal A, Barres BA. The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One. 2010;5(10):e13741.PubMedPubMedCentralCrossRefGoogle Scholar
  26. del Arco A, Satrustegui J. Molecular cloning of Aralar, a new member of the mitochondrial carrier superfamily that binds calcium and is present in human muscle and brain. J Biol Chem. 1998;273(36):23327–34.PubMedCrossRefGoogle Scholar
  27. Del Arco A, Agudo M, Satrustegui J. Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues. Biochem J. 2000;345(Pt 3):725–32.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Divino Filho JC, Barany P, Stehle P, Furst P, Bergstrom J. Free amino-acid levels simultaneously collected in plasma, muscle, and erythrocytes of uraemic patients. Nephrol Dial Transplant. 1997;12(11):2339–48.PubMedCrossRefGoogle Scholar
  29. Doczi T, Joo F, Adam G, Bozoky B, Szerdahelyi P. Blood-brain barrier damage during the acute stage of subarachnoid hemorrhage, as exemplified by a new animal model. Neurosurgery. 1986;18(6):733–9.PubMedCrossRefGoogle Scholar
  30. Drewes LR, Conway WP, Gilboe DD. Net amino acid transport between plasma and erythrocytes and perfused dog brain. Am J Phys. 1977;233(4):E320–5.Google Scholar
  31. Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature. 1995;375(6532):599–603.PubMedCrossRefGoogle Scholar
  32. Fiermonte G, Palmieri L, Todisco S, Agrimi G, Palmieri F, Walker JE. Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. J Biol Chem. 2002;277(22):19289–94.PubMedCrossRefGoogle Scholar
  33. Fogal B, Li J, Lobner D, McCullough LD, Hewett SJ. System x(c)- activity and astrocytes are necessary for interleukin-1 beta-mediated hypoxic neuronal injury. J Neurosci. 2007;27(38):10094–105.PubMedCrossRefGoogle Scholar
  34. Fotiadis D, Kanai Y, Palacin M. The SLC3 and SLC7 families of amino acid transporters. Mol Asp Med. 2013;34(2–3):139–58.CrossRefGoogle Scholar
  35. Fredriksson K, Kalimo H, Westergren I, Kahrstrom J, Johansson BB. Blood-brain barrier leakage and brain edema in stroke-prone spontaneously hypertensive rats. Effect of chronic sympathectomy and low protein/high salt diet. Acta Neuropathol. 1987;74(3):259–68.PubMedCrossRefGoogle Scholar
  36. Gillessen T, Budd SL, Lipton SA. Excitatory amino acid neurotoxicity. Adv Exp Med Biol. 2002;513:3–40.PubMedCrossRefGoogle Scholar
  37. Gottlieb M, Wang Y, Teichberg VI. Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem. 2003;87(1):119–26.PubMedCrossRefGoogle Scholar
  38. Graham TE, Turcotte LP, Kiens B, Richter EA. Training and muscle ammonia and amino acid metabolism in humans during prolonged exercise. J Appl Physiol (1985). 1995;78(2):725–35.Google Scholar
  39. Guo S, Zhou Y, Xing C, Lok J, Som AT, Ning M, et al. The vasculome of the mouse brain. PLoS One. 2012;7(12):e52665.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Hagenfeldt L, Arvidsson A. The distribution of amino acids between plasma and erythrocytes. Clin Chim Acta. 1980;100(2):133–41.PubMedCrossRefGoogle Scholar
  41. Hawkins RA. The blood-brain barrier and glutamate. Am J Clin Nutr. 2009;90(3):867S–74S.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hegedus T, Taale M. SLC tables: bioparadigms.org. 2013 [cited 2016 03-10-2016]. Available from: http://slc.bioparadigms.org/.
  43. Helms HC, Madelung R, Waagepetersen HS, Nielsen CU, Brodin B. In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate. Glia. 2012;60(6):882–93.PubMedCrossRefGoogle Scholar
  44. Helms HC, Aldana BI, Groth S, Jensen MM, Waagepetersen HS, Nielsen CU, et al. Characterization of the L-glutamate clearance pathways across the blood-brain barrier and the effect of astrocytes in an in vitro blood-brain barrier model. J Cereb Blood Flow Metab. 2017; doi: 10.1177/271678X17690760.
  45. Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T. Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci. 2013;102(9):3343–55.Google Scholar
  46. Hosoya K, Sugawara M, Asaba H, Terasaki T. Blood-brain barrier produces significant efflux of L-aspartic acid but not D-aspartic acid: in vivo evidence using the brain efflux index method. J Neurochem. 1999;73(3):1206–11.PubMedCrossRefGoogle Scholar
  47. Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Saeki S, Kanai Y, et al. Enhancement of L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment. J Pharmacol Exp Ther. 2002;302(1):225–31.PubMedCrossRefGoogle Scholar
  48. Hutchison HT, Eisenberg HM, Haber B. High-affinity transport of glutamate in rat brain microvessels. Exp Neurol. 1985;87(2):260–9.PubMedCrossRefGoogle Scholar
  49. Iijima K, Takase S, Tsumuraya K, Endo M, Itahara K. Changes in free amino acids of cerebrospinal fluid and plasma in various neurological diseases. Tohoku J Exp Med. 1978;126(2):133–50.PubMedCrossRefGoogle Scholar
  50. Jackman NA, Uliasz TF, Hewett JA, Hewett SJ. Regulation of system x(c)(-)activity and expression in astrocytes by interleukin-1beta: implications for hypoxic neuronal injury. Glia. 2010;58(15):1806–15.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kanai Y, Hediger MA. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature. 1992;360(6403):467–71.PubMedCrossRefGoogle Scholar
  52. Kanai Y, Stelzner M, Nussberger S, Khawaja S, Hebert SC, Smith CP, et al. The neuronal and epithelial human high affinity glutamate transporter. Insights into structure and mechanism of transport. J Biol Chem. 1994;269(32):20599–606.PubMedGoogle Scholar
  53. Kanai Y, Clemencon B, Simonin A, Leuenberger M, Lochner M, Weisstanner M, et al. The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Asp Med. 2013;34(2–3):108–20.CrossRefGoogle Scholar
  54. Kim JY, Kanai Y, Chairoungdua A, Cha SH, Matsuo H, Kim DK, et al. Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. Biochim Biophys Acta. 2001;1512(2):335–44.PubMedCrossRefGoogle Scholar
  55. Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet. 1999;22(2):159–63.PubMedCrossRefGoogle Scholar
  56. Krueger M, Hartig W, Reichenbach A, Bechmann I, Michalski D. Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS One. 2013;8(2):e56419.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Lecointre M, Hauchecorne M, Chaussivert A, Marret S, Leroux P, Jegou S, et al. The efficiency of glutamate uptake differs between neonatal and adult cortical microvascular endothelial cells. J Cereb Blood Flow Metab. 2014;34(5):764–7.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Lee WJ, Hawkins RA, Vina JR, Peterson DR. Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal. Am J Phys. 1998;274(4 Pt 1):C1101–7.Google Scholar
  59. Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci. 1995;15(3 Pt 1):1835–53.PubMedGoogle Scholar
  60. Leibowitz A, Boyko M, Shapira Y, Zlotnik A. Blood glutamate scavenging: insight into neuroprotection. Int J Mol Sci. 2012;13(8):10041–66.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Levy LM, Warr O, Attwell D. Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. J Neurosci. 1998;18(23):9620–8.PubMedGoogle Scholar
  62. Lin CL, Tzingounis AV, Jin L, Furuta A, Kavanaugh MP, Rothstein JD. Molecular cloning and expression of the rat EAAT4 glutamate transporter subtype. Brain Res Mol Brain Res. 1998;63(1):174–9.PubMedCrossRefGoogle Scholar
  63. Lyck R, Ruderisch N, Moll AG, Steiner O, Cohen CD, Engelhardt B, et al. Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. J Cereb Blood Flow Metab. 2009;29(9):1491–502.PubMedCrossRefGoogle Scholar
  64. Malet M, Vieytes CA, Lundgren KH, Seal RP, Tomasella E, Seroogy KB, et al. Transcript expression of vesicular glutamate transporters in lumbar dorsal root ganglia and the spinal cord of mice – effects of peripheral axotomy or hindpaw inflammation. Neuroscience. 2013;248:95–111.Google Scholar
  65. Mann GE, Yudilevich DL, Sobrevia L. Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev. 2003;83(1):183–252.PubMedCrossRefGoogle Scholar
  66. Matsuo H, Kanai Y, Kim JY, Chairoungdua A, Kim DK, Inatomi J, et al. Identification of a novel Na+-independent acidic amino acid transporter with structural similarity to the member of a heterodimeric amino acid transporter family associated with unknown heavy chains. J Biol Chem. 2002;277(23):21017–26.PubMedCrossRefGoogle Scholar
  67. Molinari F, Raas-Rothschild A, Rio M, Fiermonte G, Encha-Razavi F, Palmieri L, et al. Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet. 2005;76(2):334–9.PubMedCrossRefGoogle Scholar
  68. Montiel T, Camacho A, Estrada-Sanchez AM, Massieu L. Differential effects of the substrate inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC) and the non-substrate inhibitor DL-threo-beta-benzyloxyaspartate (DL-TBOA) of glutamate transporters on neuronal damage and extracellular amino acid levels in rat brain in vivo. Neuroscience. 2005;133(3):667–78.Google Scholar
  69. Nagamori S, Wiriyasermkul P, Guarch ME, Okuyama H, Nakagomi S, Tadagaki K, et al. Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1. Proc Natl Acad Sci U S A. 2016;113(3):775–80.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science. 1992;258(5082):597–603.PubMedCrossRefGoogle Scholar
  71. Ni B, Rosteck PR Jr, Nadi NS, Paul SM. Cloning and expression of a cDNA encoding a brain-specific Na(+)-dependent inorganic phosphate cotransporter. Proc Natl Acad Sci U S A. 1994;91(12):5607–11.PubMedPubMedCentralCrossRefGoogle Scholar
  72. O’Kane RL, Martinez-Lopez I, DeJoseph MR, Vina JR, Hawkins RA. Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem. 1999;274(45):31891–5.PubMedCrossRefGoogle Scholar
  73. Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Phys. 1971;221(6):1629–39.Google Scholar
  74. Oldendorf WH, Szabo J. Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Phys. 1976;230(1):94–8.Google Scholar
  75. Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol. 1977;1(5):409–17.PubMedCrossRefGoogle Scholar
  76. Olsen GM, Sonnewald U. Glutamate: where does it come from and where does it go? Neurochem Int. 2015;88:47–52.PubMedCrossRefGoogle Scholar
  77. Pajecka K, Nissen JD, Stridh MH, Skytt DM, Schousboe A, Waagepetersen HS. Glucose replaces glutamate as energy substrate to fuel glutamate uptake in glutamate dehydrogenase-deficient astrocytes. J Neurosci Res. 2015;93(7):1093–100.PubMedCrossRefGoogle Scholar
  78. Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Asp Med. 2013;34(2–3):465–84.CrossRefGoogle Scholar
  79. Pardridge W. Regulation of amino acid availability to brain: selective control mechanisms for glutamate. In: Filer Jr L, editor. Glutamic acid: advances in biochemistry and physiology. New York: Raven Press; 1979. p. 125–36.Google Scholar
  80. Perez-Mato M, Ramos-Cabrer P, Sobrino T, Blanco M, Ruban A, Mirelman D, et al. Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia. Cell Death Dis. 2014;5:e992.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Persson L, Hillered L. Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg. 1992;76(1):72–80.PubMedCrossRefGoogle Scholar
  82. Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, et al. Cloning and expression of a rat brain L-glutamate transporter. Nature. 1992;360(6403):464–7.PubMedCrossRefGoogle Scholar
  83. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch. 2000;440(5):653–66.PubMedCrossRefGoogle Scholar
  84. Ramos M, del Arco A, Pardo B, Martinez-Serrano A, Martinez-Morales JR, Kobayashi K, et al. Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Brain Res Dev Brain Res. 2003;143(1):33–46.Google Scholar
  85. Reimer RJ. SLC17: a functionally diverse family of organic anion transporters. Mol Asp Med. 2013;34(2–3):350–9.CrossRefGoogle Scholar
  86. Roberts RC, Roche JK, McCullumsmith RE. Localization of excitatory amino acid transporters EAAT1 and EAAT2 in human postmortem cortex: a light and electron microscopic study. Neuroscience. 2014;277C:522–40.CrossRefGoogle Scholar
  87. Robinson MB, Jackson JG. Astroglial glutamate transporters coordinate excitatory signaling and brain energetics. Neurochem Int. 2016;98:56–71.PubMedCrossRefGoogle Scholar
  88. Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR. Glutamate transporter coupling to Na,K-ATPase. J Neurosci. 2009;29(25):8143–55.PubMedCrossRefGoogle Scholar
  89. Rothman S. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci. 1984;4(7):1884–91.PubMedGoogle Scholar
  90. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, et al. Localization of neuronal and glial glutamate transporters. Neuron. 1994;13(3):713–25.PubMedCrossRefGoogle Scholar
  91. Ruban A, Mohar B, Jona G, Teichberg VI. Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. J Cereb Blood Flow Metab. 2014;34(2):221–7.PubMedCrossRefGoogle Scholar
  92. Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC. Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol. 2014;11:13–30.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Sershen H, Lajtha A. Capillary transport of amino acids in the developing brain. Exp Neurol. 1976;53(2):465–74.PubMedCrossRefGoogle Scholar
  94. Shashidharan P, Huntley GW, Meyer T, Morrison JH, Plaitakis A. Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain. Brain Res. 1994;662(1–2):245–50.PubMedCrossRefGoogle Scholar
  95. Shawahna R, Uchida Y, Decleves X, Ohtsuki S, Yousif S, Dauchy S, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8(4):1332–41.PubMedCrossRefGoogle Scholar
  96. Skytt DM, Klawonn AM, Stridh MH, Pajecka K, Patruss Y, Quintana-Cabrera R, et al. siRNA knock down of glutamate dehydrogenase in astrocytes affects glutamate metabolism leading to extensive accumulation of the neuroactive amino acids glutamate and aspartate. Neurochem Int. 2012;61(4):490–7.PubMedCrossRefGoogle Scholar
  97. Spink DC, Swann JW, Snead OC, Waniewski RA, Martin DL. Analysis of aspartate and glutamate in human cerebrospinal fluid by high-performance liquid chromatography with automated precolumn derivatization. Anal Biochem. 1986;158(1):79–86.PubMedCrossRefGoogle Scholar
  98. Storck T, Schulte S, Hofmann K, Stoffel W. Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci U S A. 1992;89(22):10955–9.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Takamori S, Malherbe P, Broger C, Jahn R. Molecular cloning and functional characterization of human vesicular glutamate transporter 3. EMBO Rep. 2002;3(8):798–803.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Teichberg VI, Cohen-Kashi-Malina K, Cooper I, Zlotnik A. Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience. 2009;158(1):301–8.PubMedCrossRefGoogle Scholar
  101. Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117(2):333–45.PubMedCrossRefGoogle Scholar
  102. Waagepetersen HS, Qu H, Sonnewald U, Shimamoto K, Schousboe A. Role of glutamine and neuronal glutamate uptake in glutamate homeostasis and synthesis during vesicular release in cultured glutamatergic neurons. Neurochem Int. 2005;47(1–2):92–102.PubMedCrossRefGoogle Scholar
  103. Westergaard N, Sonnewald U, Unsgard G, Peng L, Hertz L, Schousboe A. Uptake, release, and metabolism of citrate in neurons and astrocytes in primary cultures. J Neurochem. 1994;62(5):1727–33.PubMedCrossRefGoogle Scholar
  104. Zerangue N, Kavanaugh MP. Flux coupling in a neuronal glutamate transporter. Nature. 1996;383(6601):634–7.PubMedCrossRefGoogle Scholar
  105. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929–47.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Zhang D, Mably AJ, Walsh DM, Rowan MJ. Peripheral interventions enhancing brain glutamate homeostasis relieve amyloid beta- and TNFalpha- mediated synaptic plasticity disruption in the rat hippocampus. Cereb Cortex 2016:1–12. doi:  10.1093/cercor/bhw193.
  107. Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm. 2014;121(8):799–817.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Zlotnik A, Gruenbaum SE, Artru AA, Rozet I, Dubilet M, Tkachov S, et al. The neuroprotective effects of oxaloacetate in closed head injury in rats is mediated by its blood glutamate scavenging activity: evidence from the use of maleate. J Neurosurg Anesthesiol. 2009;21(3):235–41.PubMedCrossRefGoogle Scholar
  109. Zlotnik A, Sinelnikov I, Gruenbaum BF, Gruenbaum SE, Dubilet M, Dubilet E, et al. Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats. Anesthesiology. 2012;116(1):73–83.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pharmacy, The Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of Physics, Chemistry and PharmacyUniversity of Southern DenmarkOdenseDenmark
  3. 3.Department of Drug Design and Pharmacology, The Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

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