Skip to main content

Advertisement

SpringerLink
Log in

The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system. Beyond this function, glutamate also plays a key role in intermediary metabolism in all organs and tissues, linking carbohydrate and amino acid metabolism via the tricarboxylic acid cycle. Under both physiological and pathological conditions, we have recently found that the ability of glutamate to fuel cell metabolism selectively relies on the activity of two main transporters: the sodium–calcium exchanger (NCX) and the sodium-dependent excitatory amino-acid transporters (EAATs). In ischemic settings, when glutamate is administered at the onset of the reoxygenation phase, the coordinate activity of EAAT and NCX allows glutamate to improve cell viability by stimulating ATP production. So far, this phenomenon has been observed in both cardiac and neuronal models. In this review, we focus on the most recent findings exploring the unusual activity of glutamate as a potential survival factor in different settings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

The figure has been entirely reproduced from Magi et al. 2012 [58] in accordance with the journal policy

Fig. 2

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

AGCs:

Aspartate/glutamate carriers

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

DL-TBOA:

DL-Threo-β-benzyloxyaspartic acid

EAAC1:

Excitatory amino acid carrier 1

EAATs:

Excitatory amino-acid transporters

KA:

Kainate

GLAST:

Glutamate–aspartate transporter

GLT1:

Glutamate transporter 1

mGluR:

Metabotropic glutamate receptors

NCX:

Sodium–calcium exchanger

NMDA:

N-Methyl-d-aspartate

SN-6:

2-[[4-[(4-Nitrophenyl)methoxy]phenyl]methyl]-4-thiazolidinecarboxylic acid ethyl ester

References

  1. Watkins JC, Jane DE (2006) The glutamate story. Br J Pharmacol 147(Suppl 1):S100–S108

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Krebs HA (1935) Metabolism of amino-acids: the synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. Biochem J 29:1951–1969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fonnum F (1984) Glutamate: a neurotransmitter in mammalian brain. J Neurochem 42:1–11

    Article  CAS  PubMed  Google Scholar 

  4. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  5. Marmiroli P, Cavaletti G (2012) The glutamatergic neurotransmission in the central nervous system. Curr Med Chem 19:1269–1276

    Article  CAS  PubMed  Google Scholar 

  6. Rose CR, Ziemens D, Untiet V, Fahlke C (2018) Molecular and cellular physiology of sodium-dependent glutamate transporters. Brain Res Bull 136:3–16

    Article  CAS  PubMed  Google Scholar 

  7. O’Shea RD (2002) Roles and regulation of glutamate transporters in the central nervous system. Clin Exp Pharmacol Physiol 29:1018–1023

    Article  PubMed  Google Scholar 

  8. Niciu MJ, Kelmendi B, Sanacora G (2012) Overview of glutamatergic neurotransmission in the nervous system. Pharmacol Biochem Behav 100:656–664

    Article  CAS  PubMed  Google Scholar 

  9. Mennerick S, Dhond RP, Benz A, Xu W, Rothstein JD, Danbolt NC, Isenberg KE, Zorumski CF (1998) Neuronal expression of the glutamate transporter GLT-1 in hippocampal microcultures. J Neurosci 18:4490–4499

    Article  CAS  PubMed  Google Scholar 

  10. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994) Localization of neuronal and glial glutamate transporters. Neuron 13:713–725

    Article  CAS  PubMed  Google Scholar 

  11. Kugler P, Schmitt A (1999) Glutamate transporter EAAC1 is expressed in neurons and glial cells in the rat nervous system. Glia 27:129–142

    Article  CAS  PubMed  Google Scholar 

  12. Domercq M, Sanchez-Gomez MV, Areso P, Matute C (1999) Expression of glutamate transporters in rat optic nerve oligodendrocytes. Eur J Neurosci 11:2226–2236

    Article  CAS  PubMed  Google Scholar 

  13. van Landeghem FK, Stover JF, Bechmann I, Bruck W, Unterberg A, Buhrer C, von Deimling A (2001) Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat. Glia 35:167–179

    Article  PubMed  Google Scholar 

  14. Palos TP, Ramachandran B, Boado R, Howard BD (1996) Rat C6 and human astrocytic tumor cells express a neuronal type of glutamate transporter. Brain Res Mol Brain Res 37:297–303

    Article  CAS  PubMed  Google Scholar 

  15. Kanai Y, Clemencon B, Simonin A, Leuenberger M, Lochner M, Weisstanner M, Hediger MA (2013) The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Aspects Med 34:108–120

    Article  CAS  PubMed  Google Scholar 

  16. Whetsell WO Jr, Shapira NA (1993) Neuroexcitation, excitotoxicity and human neurological disease. Lab Investig 68:372–387

    CAS  PubMed  Google Scholar 

  17. Prass K, Dirnagl U (1998) Glutamate antagonists in therapy of stroke. Restor Neurol Neurosci 13:3–10

    CAS  PubMed  Google Scholar 

  18. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531

    Article  CAS  PubMed  Google Scholar 

  19. Rock DM, MacDonald RL (1992) Spermine and related polyamines produce a voltage-dependent reduction of N-methyl-d-aspartate receptor single-channel conductance. Mol Pharmacol 42:157–164

    CAS  PubMed  Google Scholar 

  20. Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263

    Article  CAS  PubMed  Google Scholar 

  21. Palmer CL, Cotton L, Henley JM (2005) The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol Rev 57:253–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sommer B, Kohler M, Sprengel R, Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67:11–19

    Article  CAS  PubMed  Google Scholar 

  23. Henley JM, Wilkinson KA (2016) Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci 17:337–350

    Article  CAS  PubMed  Google Scholar 

  24. Lerma J, Paternain AV, Rodriguez-Moreno A, Lopez-Garcia JC (2001) Molecular physiology of kainate receptors. Physiol Rev 81:971–998

    Article  CAS  PubMed  Google Scholar 

  25. Huettner JE (2003) Kainate receptors and synaptic transmission. Prog Neurobiol 70:387–407

    Article  CAS  PubMed  Google Scholar 

  26. Heuss C, Scanziani M, Gahwiler BH, Gerber U (1999) G-protein-independent signaling mediated by metabotropic glutamate receptors. Nat Neurosci 2:1070–1077

    Article  CAS  PubMed  Google Scholar 

  27. Chavis P, Shinozaki H, Bockaert J, Fagni L (1994) The metabotropic glutamate receptor types 2/3 inhibit L-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells. J Neurosci 14:7067–7076

    Article  CAS  PubMed  Google Scholar 

  28. Tanabe Y, Nomura A, Masu M, Shigemoto R, Mizuno N, Nakanishi S (1993) Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J Neurosci 13:1372–1378

    Article  CAS  PubMed  Google Scholar 

  29. Mercier MS, Lodge D (2014) Group III metabotropic glutamate receptors: pharmacology, physiology and therapeutic potential. Neurochem Res 39:1876–1894

    Article  CAS  PubMed  Google Scholar 

  30. Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460:525–542

    Article  CAS  PubMed  Google Scholar 

  31. Maragakis NJ, Rothstein JD (2001) Glutamate transporters in neurologic disease. Arch Neurol 58:365–370

    Article  CAS  PubMed  Google Scholar 

  32. Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171–182

    Article  CAS  PubMed  Google Scholar 

  33. Beal MF (1992) Mechanisms of excitotoxicity in neurologic diseases. FASEB J 6:3338–3344

    Article  CAS  PubMed  Google Scholar 

  34. Piccirillo S, Castaldo P, Macri ML, Amoroso S, Magi S (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Manev H, Favaron M, Guidotti A, Costa E (1989) Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol 36:106–112

    CAS  PubMed  Google Scholar 

  36. Marini AM, Spiga G, Mocchetti I (1997) Toward the development of strategies to prevent ischemic neuronal injury. In vitro studies. Ann N Y Acad Sci 825:209–219

    Article  CAS  PubMed  Google Scholar 

  37. Qin Z (1998) A review of therapeutic potentials in ischemic stroke. Eur Neurol 39(Suppl 1):21–25

    Article  PubMed  Google Scholar 

  38. Ikonomidou C, Turski L (2002) Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 1:383–386

    Article  CAS  PubMed  Google Scholar 

  39. Birmingham K (2002) Future of neuroprotective drugs in doubt. Nat Med 8:5

    Article  CAS  PubMed  Google Scholar 

  40. Sacco RL et al (2001) Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 285:1719–1728

    Article  CAS  PubMed  Google Scholar 

  41. Albers GW, Goldstein LB, Hall D, Lesko LM (2001) Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286:2673–2682

    Article  CAS  PubMed  Google Scholar 

  42. Khanna S, Briggs Z, Rink C (2015) Inducible glutamate oxaloacetate transaminase as a therapeutic target against ischemic stroke. Antioxid Redox Signal 22:175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. McKenna MC, Tildon JT, Stevenson JH, Huang X (1996) New insights into the compartmentation of glutamate and glutamine in cultured rat brain astrocytes. Dev Neurosci 18:380–390

    Article  CAS  PubMed  Google Scholar 

  44. Sonnewald U, Westergaard N, Schousboe A (1997) Glutamate transport and metabolism in astrocytes. Glia 21:56–63

    Article  CAS  PubMed  Google Scholar 

  45. Bing RJ (1965) Cardiac metabolism. Physiol Rev 45:171–213

    Article  CAS  PubMed  Google Scholar 

  46. Kodde IF, van der Stok J, Smolenski RT, de Jong JW (2007) Metabolic and genetic regulation of cardiac energy substrate preference. Comp Biochem Physiol A Mol Integr Physiol 146:26–39

    Article  CAS  PubMed  Google Scholar 

  47. Palmieri L et al (2001) Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 20:5060–5069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fiermonte G, Palmieri L, Todisco S, Agrimi G, Palmieri F, Walker JE (2002) Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. J Biol Chem 277:19289–19294

    Article  CAS  PubMed  Google Scholar 

  49. Ralphe JC, Segar JL, Schutte BC, Scholz TD (2004) Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria. J Mol Cell Cardiol 37:33–41

    Article  CAS  PubMed  Google Scholar 

  50. Ralphe JC, Bedell K, Segar JL, Scholz TD (2005) Correlation between myocardial malate/aspartate shuttle activity and EAAT1 protein expression in hyper- and hypothyroidism. Am J Physiol Heart Circ Physiol 288:H2521–H2526

    Article  CAS  PubMed  Google Scholar 

  51. Annunziato L, Pignataro G, Di Renzo GF (2004) Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev 56:633–654

    Article  CAS  PubMed  Google Scholar 

  52. Blaustein MP, Lederer WJ (1999) Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763–854

    Article  CAS  PubMed  Google Scholar 

  53. Philipson KD, Nicoll DA (2000) Sodium–calcium exchange: a molecular perspective. Annu Rev Physiol 62:111–133

    Article  CAS  PubMed  Google Scholar 

  54. Shigekawa M, Iwamoto T (2001) Cardiac Na+–Ca2+ exchange: molecular and pharmacological aspects. Circ Res 88:864–876

    Article  CAS  PubMed  Google Scholar 

  55. Gobbi P, Castaldo P, Minelli A, Salucci S, Magi S, Corcione E, Amoroso S (2007) Mitochondrial localization of Na+/Ca2+ exchangers NCX1-3 in neurons and astrocytes of adult rat brain in situ. Pharmacol Res 56:556–565

    Article  CAS  PubMed  Google Scholar 

  56. Scorziello A et al (2013) NCX3 regulates mitochondrial Ca2+ handling through the AKAP121-anchored signaling complex and prevents hypoxia-induced neuronal death. J Cell Sci 126:5566–5577

    Article  CAS  PubMed  Google Scholar 

  57. Secondo A et al (2018) Na+/Ca2+ exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca2+ regulation during neuronal differentiation. Cell Death Discov 4:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Magi S, Lariccia V, Castaldo P, Arcangeli S, Nasti AA, Giordano A, Amoroso S (2012) Physical and functional interaction of NCX1 and EAAC1 transporters leading to glutamate-enhanced ATP production in brain mitochondria. PLoS One 7:e34015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rothman DL, Behar KL, Hyder F, Shulman RG (2003) In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu Rev Physiol 65:401–427

    Article  CAS  PubMed  Google Scholar 

  60. Panov A, Schonfeld P, Dikalov S, Hemendinger R, Bonkovsky HL, Brooks BR (2009) The neuromediator glutamate, through specific substrate interactions, enhances mitochondrial ATP production and reactive oxygen species generation in nonsynaptic brain mitochondria. J Biol Chem 284:14448–14456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hertz L, Hertz E (2003) Cataplerotic TCA cycle flux determined as glutamate-sustained oxygen consumption in primary cultures of astrocytes. Neurochem Int 43:355–361

    Article  CAS  PubMed  Google Scholar 

  62. McKenna MC (2013) Glutamate pays its own way in astrocytes. Front Endocrinol (Lausanne) 4:191

    Article  Google Scholar 

  63. McKenna MC (2007) The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85:3347–3358

    Article  CAS  PubMed  Google Scholar 

  64. McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S (1993) Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 15:320–329

    Article  CAS  PubMed  Google Scholar 

  65. Tildon JT, Roeder LM, Stevenson JH (1985) Substrate oxidation by isolated rat brain mitochondria and synaptosomes. J Neurosci Res 14:207–215

    Article  CAS  PubMed  Google Scholar 

  66. Olstad E, Qu H, Sonnewald U (2007) Glutamate is preferred over glutamine for intermediary metabolism in cultured cerebellar neurons. J Cereb Blood Flow Metab 27:811–820

    Article  CAS  PubMed  Google Scholar 

  67. Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (1998) DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. Mol Pharmacol 53:195–201

    Article  CAS  PubMed  Google Scholar 

  68. Cox DA, Conforti L, Sperelakis N, Matlib MA (1993) Selectivity of inhibition of Na(+)–Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157. J Cardiovasc Pharmacol 21:595–599

    Article  CAS  PubMed  Google Scholar 

  69. Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787:1309–1316

    Article  CAS  PubMed  Google Scholar 

  70. Magi S et al (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 84:603–614

    Article  CAS  PubMed  Google Scholar 

  71. Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR (2009) Glutamate transporter coupling to Na, K-ATPase. J Neurosci 29:8143–8155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Johansen L, Roberg B, Kvamme E (1987) Uptake and release for glutamine and glutamate in a crude synaptosomal fraction from rat brain. Neurochem Res 12:135–140

    Article  CAS  PubMed  Google Scholar 

  73. Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14:2924–2932

    Article  CAS  PubMed  Google Scholar 

  74. Iwamoto T, Inoue Y, Ito K, Sakaue T, Kita S, Katsuragi T (2004) The exchanger inhibitory peptide region-dependent inhibition of Na+/Ca2+ exchange by SN-6 [2-[4-(4-nitrobenzyloxy)benzyl]thiazolidine-4-carboxylic acid ethyl ester], a novel benzyloxyphenyl derivative. Mol Pharmacol 66:45–55

    Article  CAS  PubMed  Google Scholar 

  75. Rojas H, Colina C, Ramos M, Benaim G, Jaffe E, Caputo C, Di Polo R (2013) Sodium–calcium exchanger modulates the l-glutamate Ca 2+i signalling in type-1 cerebellar astrocytes. Adv Exp Med Biol 961:267–274

    Article  CAS  PubMed  Google Scholar 

  76. Magi S, Nasti AA, Gratteri S, Castaldo P, Bompadre S, Amoroso S, Lariccia V (2015) Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: detrimental role of Na+–Ca2+ exchanger. Eur J Pharmacol 746:31–40

    Article  CAS  PubMed  Google Scholar 

  77. Secondo A, Bagetta G, Amantea D (2018) On the role of store-operated calcium entry in acute and chronic neurodegenerative diseases. Front Mol Neurosci 11:87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sisalli MJ, Secondo A, Esposito A, Valsecchi V, Savoia C, Di Renzo GF, Annunziato L, Scorziello A (2014) Endoplasmic reticulum refilling and mitochondrial calcium extrusion promoted in neurons by NCX1 and NCX3 in ischemic preconditioning are determinant for neuroprotection. Cell Death Differ 21:1142–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Maiolino M, Castaldo P, Lariccia V, Piccirillo S, Amoroso S, Magi S (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Drake KJ, Sidorov VY, McGuinness OP, Wasserman DH, Wikswo JP (2012) Amino acids as metabolic substrates during cardiac ischemia. Exp Biol Med (Maywood) 237:1369–1378

    Article  CAS  Google Scholar 

  81. Pisarenko OI, Lepilin MG, Ivanov VE (1986) Cardiac metabolism and performance during l-glutamic acid infusion in postoperative cardiac failure. Clin Sci (Lond) 70:7–12

    Article  CAS  Google Scholar 

  82. Svedjeholm R, Vanhanen I, Hakanson E, Joachimsson PO, Jorfeldt L, Nilsson L (1996) Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations. J Thorac Cardiovasc Surg 112:1468–1477

    Article  CAS  PubMed  Google Scholar 

  83. Thomassen A, Botker HE, Nielsen TT, Thygesen K, Henningsen P (1990) Effects of glutamate on exercise tolerance and circulating substrate levels in stable angina pectoris. Am J Cardiol 65:173–178

    Article  CAS  PubMed  Google Scholar 

  84. Kristiansen SB, Lofgren B, Stottrup NB, Kimose HH, Nielsen-Kudsk JE, Botker HE, Nielsen TT (2008) Cardioprotection by l-glutamate during postischaemic reperfusion: reduced infarct size and enhanced glycogen resynthesis in a rat insulin-free heart model. Clin Exp Pharmacol Physiol 35:884–888

    Article  CAS  PubMed  Google Scholar 

  85. Williams H, King N, Griffiths EJ, Suleiman MS (2001) Glutamate-loading stimulates metabolic flux and improves cell recovery following chemical hypoxia in isolated cardiomyocytes. J Mol Cell Cardiol 33:2109–2119

    Article  CAS  PubMed  Google Scholar 

  86. Suleiman MS, Dihmis WC, Caputo M, Angelini GD, Bryan AJ (1997) Changes in myocardial concentration of glutamate and aspartate during coronary artery surgery. Am J Physiol 272:H1063–H1069

    CAS  PubMed  Google Scholar 

  87. Kristiansen SB, Nielsen-Kudsk JE, Botker HE, Nielsen TT (2005) Effects of KATP channel modulation on myocardial glycogen content, lactate, and amino acids in nonischemic and ischemic rat hearts. J Cardiovasc Pharmacol 45:456–461

    Article  CAS  PubMed  Google Scholar 

  88. Vincent A et al (2017) Cardiac mGluR1 metabotropic receptors in cardioprotection. Cardiovasc Res 113:644–655

    Article  CAS  PubMed  Google Scholar 

  89. Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta 1830:3143–3153

    Article  CAS  PubMed  Google Scholar 

  90. Chen S, Li S (2012) The Na+/Ca2+ exchanger in cardiac ischemia/reperfusion injury. Med Sci Monit 18:RA161-5

    PubMed  Google Scholar 

  91. Namekata I, Shimada H, Kawanishi T, Tanaka H, Shigenobu K (2006) Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca2+ overload. Eur J Pharmacol 543:108–115

    Article  CAS  PubMed  Google Scholar 

  92. Seki S, Taniguchi M, Takeda H, Nagai M, Taniguchi I, Mochizuki S (2002) Inhibition by KB-r7943 of the reverse mode of the Na+/Ca2+ exchanger reduces Ca2+ overload in ischemic-reperfused rat hearts. Circ J 66:390–396

    Article  CAS  PubMed  Google Scholar 

  93. Castaldo P, Macri ML, Lariccia V, Matteucci A, Maiolino M, Gratteri S, Amoroso S, Magi S (2017) Na+/Ca2+ exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models. Eur J Pharmacol 794:246–256

    Article  CAS  PubMed  Google Scholar 

  94. Lariccia V, Fine M, Magi S, Lin MJ, Yaradanakul A, Llaguno MC, Hilgemann DW (2011) Massive calcium-activated endocytosis without involvement of classical endocytic proteins. J Gen Physiol 137:111–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Molinaro P et al (2008) Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage. J Neurosci 28:1179–1184

    Article  CAS  PubMed  Google Scholar 

  96. Molinaro P et al (2016) Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt. J Cereb Blood Flow Metab 36:1790–1803

    Article  CAS  PubMed  Google Scholar 

  97. Pignataro G et al (2004) Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats. Neuropharmacology 46:439–448

    Article  CAS  PubMed  Google Scholar 

  98. Divakaruni AS et al (2017) Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. J Cell Biol 216:1091–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Fendt SM, Verstreken P (2017) Neurons eat glutamate to stay alive. J Cell Biol 216:863–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kristian T, Siesjo BK (1998) Calcium in ischemic cell death. Stroke 29:705–718

    Article  CAS  PubMed  Google Scholar 

  101. Tortiglione A et al (2002) Na+/Ca2+ exchanger in Na+ efflux–Ca2+ influx mode of operation exerts a neuroprotective role in cellular models of in vitro anoxia and in vivo cerebral ischemia. Ann N Y Acad Sci 976:408–412

    Article  CAS  PubMed  Google Scholar 

  102. Pascual JM, Carceller F, Roda JM, Cerdan S (1998) Glutamate, glutamine, and GABA as substrates for the neuronal and glial compartments after focal cerebral ischemia in rats. Stroke 29:1048–1056 (discussion 1056–7)

    Article  CAS  PubMed  Google Scholar 

  103. Rink C, Gnyawali S, Peterson L, Khanna S (2011) Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke. Antioxid Redox Signal 14:1777–1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rink C, Roy S, Khan M, Ananth P, Kuppusamy P, Sen CK, Khanna S (2010) Oxygen-sensitive outcomes and gene expression in acute ischemic stroke. J Cereb Blood Flow Metab 30:1275–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rink C, Gnyawali S, Stewart R, Teplitsky S, Harris H, Roy S, Sen CK, Khanna S (2017) Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain. FASEB J 31:1709–1718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kim AY, Jeong KH, Lee JH, Kang Y, Lee SH, Baik EJ (2017) Glutamate dehydrogenase as a neuroprotective target against brain ischemia and reperfusion. Neuroscience 340:487–500

    Article  CAS  PubMed  Google Scholar 

  107. Dhawan J, Benveniste H, Luo Z, Nawrocky M, Smith SD, Biegon A (2011) A new look at glutamate and ischemia: NMDA agonist improves long-term functional outcome in a rat model of stroke. Future Neurol 6:823–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Magi S et al (2016) Intracellular calcium dysregulation: implications for Alzheimer’s disease. Biomed Res Int 2016:6701324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pannaccione A et al (2012) A new concept: Abeta1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death. J Neurosci 32:10609–10617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mark RJ, Hensley K, Butterfield DA, Mattson MP (1995) Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J Neurosci 15:6239–6249

    Article  CAS  PubMed  Google Scholar 

  112. Hattori N et al (1998) CI-ATPase and Na+/K+-ATPase activities in Alzheimer’s disease brains. Neurosci Lett 254:141–144

    Article  CAS  PubMed  Google Scholar 

  113. Chauhan NB, Lee JM, Siegel GJ (1997) Na, K-ATPase mRNA levels and plaque load in Alzheimer’s disease. J Mol Neurosci 9:151–166

    Article  CAS  PubMed  Google Scholar 

  114. Mukhamedyarov MA, Grishin SN, Yusupova ER, Zefirov AL, Palotas A (2009) Alzheimer’s beta-amyloid-induced depolarization of skeletal muscle fibers: implications for motor dysfunctions in dementia. Cell Physiol Biochem 23:109–114

    Article  CAS  PubMed  Google Scholar 

  115. Hynd MR, Scott HL, Dodd PR (2004) Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int 45:583–595

    Article  CAS  PubMed  Google Scholar 

  116. Gerardo-Nava J, Mayorenko II, Grehl T, Steinbusch HW, Weis J, Brook GA (2013) Differential pattern of neuroprotection in lumbar, cervical and thoracic spinal cord segments in an organotypic rat model of glutamate-induced excitotoxicity. J Chem Neuroanat 53:11–17

    Article  CAS  PubMed  Google Scholar 

  117. Jacob CP et al (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11:97–116

    Article  CAS  PubMed  Google Scholar 

  118. Ribeiro FM, Paquet M, Cregan SP, Ferguson SS (2010) Group I metabotropic glutamate receptor signalling and its implication in neurological disease. CNS Neurol Disord Drug Targets 9:574–595

    Article  CAS  PubMed  Google Scholar 

  119. Baglietto-Vargas D et al. (2018) Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer’s disease. Aging Cell 17:e12791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hettinger JC, Lee H, Bu G, Holtzman DM, Cirrito JR (2018) AMPA-ergic regulation of amyloid-beta levels in an Alzheimer’s disease mouse model. Mol Neurodegener 13:22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40:759–766

    Article  CAS  PubMed  Google Scholar 

  122. Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D (2009) Soluble oligomers of amyloid beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62:788–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Burbaeva G, Boksha IS, Tereshkina EB, Savushkina OK, Starodubtseva LI, Turishcheva MS (2005) Glutamate metabolizing enzymes in prefrontal cortex of Alzheimer’s disease patients. Neurochem Res 30:1443–1451

    Article  CAS  PubMed  Google Scholar 

  124. Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842:1240–1247

    Article  CAS  PubMed  Google Scholar 

  125. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta 1802:2–10

    Article  CAS  PubMed  Google Scholar 

  126. Zhang C, Rissman RA, Feng J (2015) Characterization of ATP alternations in an Alzheimer’s disease transgenic mouse model. J Alzheimers Dis 44:375–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cassano T et al (2012) Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease. Neurobiol Aging 33(1121):e1–e12

    Google Scholar 

  128. Quintanilla RA, Dolan PJ, Jin YN, Johnson GV (2012) Truncated tau and Abeta cooperatively impair mitochondria in primary neurons. Neurobiol Aging 33(619):e25–e35

    Google Scholar 

  129. Rhein V et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 106:20057–20062

    Article  PubMed  Google Scholar 

  130. Procter AW, Palmer AM, Francis PT, Lowe SL, Neary D, Murphy E, Doshi R, Bowen DM (1988) Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer’s disease. J Neurochem 50:790–802

    Article  CAS  PubMed  Google Scholar 

  131. Riederer P, Hoyer S (2006) From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain. J Neural Transm (Vienna) 113:1671–1677

    Article  CAS  Google Scholar 

  132. Wenk GL (2006) Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J Clin Psychiatry 67(Suppl 3):3–7 (quiz 23)

    CAS  PubMed  Google Scholar 

  133. Dupuis L, Pradat PF, Ludolph AC, Loeffler JP (2011) Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol 10:75–82

    Article  CAS  PubMed  Google Scholar 

  134. Smith EF, Shaw PJ, De Vos KJ (2017) The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. https://doi.org/10.1016/j.neulet.2017.06.052

    Article  PubMed  PubMed Central  Google Scholar 

  135. Tefera TW, Borges K (2016) Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Front Neurosci 10:611

    PubMed  Google Scholar 

  136. Dorst J, Ludolph AC, Huebers A (2018) Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis. Ther Adv Neurol Disord 11:1756285617734734

    Article  PubMed  Google Scholar 

  137. Sirabella R et al (2018) Ionic homeostasis maintenance in ALS: focus on new therapeutic targets. Front Neurosci 12:510

    Article  PubMed  PubMed Central  Google Scholar 

  138. Vandoorne T, De Bock K, Van Den Bosch L (2018) Energy metabolism in ALS: an underappreciated opportunity? Acta Neuropathol 135:489–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Battaglia G, Bruno V (2018) Metabotropic glutamate receptor involvement in the pathophysiology of amyotrophic lateral sclerosis: new potential drug targets for therapeutic applications. Curr Opin Pharmacol 38:65–71

    Article  CAS  PubMed  Google Scholar 

  140. Andreadou E et al (2008) Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis. In Vivo 22:137–141

    CAS  PubMed  Google Scholar 

  141. Foran E, Trotti D (2009) Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxid Redox Signal 11:1587–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Van Den Bosch L, Robberecht W (2000) Different receptors mediate motor neuron death induced by short and long exposures to excitotoxicity. Brain Res Bull 53:383–388

    Article  Google Scholar 

  143. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468

    Article  CAS  PubMed  Google Scholar 

  144. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84

    Article  CAS  PubMed  Google Scholar 

  145. Schultz J (2018) Disease-modifying treatment of amyotrophic lateral sclerosis. Am J Manag Care 24:S327–S335

    PubMed  Google Scholar 

  146. Petrov D, Mansfield C, Moussy A, Hermine O (2017) ALS clinical trials review: 20 years of failure. Are we any closer to registering a new treatment? Front Aging Neurosci 9:68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Koh JY, Kim DK, Hwang JY, Kim YH, Seo JH (1999) Antioxidative and proapoptotic effects of riluzole on cultured cortical neurons. J Neurochem 72:716–723

    Article  CAS  PubMed  Google Scholar 

  148. Ahmed RM, Dupuis L, Kiernan MC (2018) Paradox of amyotrophic lateral sclerosis and energy metabolism. J Neurol Neurosurg Psychiatry 89:1013–1014

    Article  PubMed  Google Scholar 

  149. Lau CG, Zukin RS (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8:413–426

    Article  CAS  PubMed  Google Scholar 

  150. Shepherd JD, Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23:613–643

    Article  CAS  PubMed  Google Scholar 

  151. Grosenbaugh DK, Ross BM, Wagley P, Zanelli SA (2018) The role of kainate receptors in the pathophysiology of hypoxia-induced seizures in the neonatal mouse. Sci Rep 8:7035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  CAS  PubMed  Google Scholar 

  153. Kim CH, Lee J, Lee JY, Roche KW (2008) Metabotropic glutamate receptors: phosphorylation and receptor signaling. J Neurosci Res 86:1–10

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126, Ancona, Italy

    Simona Magi, Silvia Piccirillo & Salvatore Amoroso

Authors
  1. Simona Magi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Piccirillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Salvatore Amoroso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simona Magi.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Magi, S., Piccirillo, S. & Amoroso, S. The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease. Cell. Mol. Life Sci. 76, 1473–1488 (2019). https://doi.org/10.1007/s00018-018-3002-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-3002-x

Keywords

Search

Navigation