Compartmentation of Brain Glutamate Metabolism in Neurons and Glia

Daikhin, Yevgeny; Yudkoff, Marc

doi:10.1093/jn/130.4.1026s

Cited by 315 publications

(262 citation statements)

References 41 publications

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“…Basal synaptic concentrations of GLU are estimated to be in the 2-5 mmol/l range, and rise to 50-100 mmol/l following release (Daikhin and Yudkoff, 2000;Meldrum, 2000). Plasma GLU concentrations are typically 50-100 mmol/l under normal conditions (Tsai and Huang, 1999;Fernstrom et al, 1996) and do not rise significantly even in the presence of sizable oral doses of MSG (Tsai and Huang, 1999).…”

Section: Central Nervous Systemmentioning

confidence: 99%

Consensus meeting: monosodium glutamate – an update

et al. 2006

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Objective: Update of the Hohenheim consensus on monosodium glutamate from 1997: Summary and evaluation of recent knowledge with respect to physiology and safety of monosodium glutamate. Design: Experts from a range of relevant disciplines received and considered a series of questions related to aspects of the topic. Setting: University of Hohenheim, Stuttgart, Germany. Method: The experts met and discussed the questions and arrived at a consensus. Conclusion: Total intake of glutamate from food in European countries is generally stable and ranged from 5 to 12 g/day (free: ca. 1 g, protein-bound: ca. 10 g, added as flavor: ca. 0.4 g). L-Glutamate (GLU) from all sources is mainly used as energy fuel in enterocytes. A maximum intake of 16.000 mg/kg body weight is regarded as safe. The general use of glutamate salts (monosodium-L-glutamate and others) as food additive can, thus, be regarded as harmless for the whole population. Even in unphysiologically high doses GLU will not trespass into fetal circulation. Further research work should, however, be done concerning the effects of high doses of a bolus supply at presence of an impaired blood brain barrier function. In situations with decreased appetite (e.g., elderly persons) palatability can be improved by low dose use of monosodium-L-glutamate.

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Section: Central Nervous Systemmentioning

confidence: 99%

Consensus meeting: monosodium glutamate – an update

et al. 2006

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“…The metabolic consequences, however, could be analogous to those observed in HI/HA syndrome, in which enhanced glutamate oxidation (by the overactive hGDH1 mutants) increases ATP production and reduces the glutamate pool involved in urea synthesis. 33 In brain, glutamate is distributed in multiple pools, 34 the maintenance of which requires the operation of transport systems and metabolizing enzymes, including GDH. Whereas glutamate oxidation in brain proceeds mainly through transamination, 35 the GDH-catalyzed reaction assumes importance under conditions of intense excitatory transmission.…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

et al. 2009

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Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens. INTRODUCTIONParkinson's disease (PD) affects about 1.8% of people over the age of 65 years. 1 It is clinically characterized by tremor, rigidity and bradykinesia, which often occur along with disturbances of posture and gait. 2 About 80% of PD cases are sporadic, with males being more frequently affected than females (ratio¼1.5:1).The etiology of PD remains largely unknown, although interplay of environmental toxins with genetic susceptibility may be operational. The genetic hypothesis is supported by community-based studies showing that a substantial number of PD patients have similarly affected relatives. 3,4 This was also revealed by a PD study conducted by us on Crete, 5 an island of about 0.6 million people sharing the same genetic and cultural background and a common environment. Moreover, this study suggested an oligogenic model for PD, according to which disease-predisposing alleles from two or more genes need to be present in the same individual for the disorder to be expressed.With regard to the pathophysiology of PD, several hypotheses have been proposed in an attempt to explain the degeneration of dopaminergic neurons in this disorder. One of these suggests that mitochondrial dysfunction is involved, 6 a contention supported by the recent discovery of monogenetic forms of PD resulting from mutations of

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“…In vivo, ex vivo and in vitro 13 C-NMR spectroscopy has been widely used to follow up the metabolism of glucose in human and animal brain as well as primary brain cell cultures. The most commonly used glucose isotopomers are [1][2][3][4][5][6][7][8][9][10][11][12][13] C 1 ]-, [2][3][4][5][6][7][8][9][10][11][12][13] C 1 ]-and [U- 13 C 6 ]glucose, which lead to differently labelled metabolic isotopomers, such as pyruvate and TCA cycle intermediates, depending on the enzymatic pathways involved (Table 1).…”

Section: Substrate Selection [ 13 C]glucose Metabolismmentioning

confidence: 99%

“…However, the brain contains metabolically different compartments [5][6][7][8][9][10][11] with at least two kinetically different TCA cycles, i.e. neuronal and glial compartments, which are connected by the exchange of metabolites.…”

Section: Introductionmentioning

confidence: 99%

Regulation of glial metabolism studied by ¹³C‐NMR

Zwingmann¹,

Leibfritz²

2003

NMR in Biomedicine

106

107

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Glial metabolism and their metabolic trafficking with neurons are essential parts of neuronal function, as they modulate, by this means, neuronal activity. Ex vivo and in vitro 13 C-NMR spectroscopy have been used to monitor neural cellular and tissue metabolism. Special emphasis has been given to the metabolic specialization of astrocytes and its enzymatic regulation. For this purpose primary cell cultures are useful tools to study neuronal-glial metabolic relationships as the extracellular fluid can be investigated and manipulated by various stimuli. In astrocytes, glucose is utilized predominantly anaerobically. Glycolysis is interrelated to the astrocytic TCA cycle via bi-directional signals and metabolic exchange processes between astrocytes and neurons. Besides glucose oxidation, neuronally released glutamate is metabolized through the glial TCA cycle. The flexibility of glutamate metabolism, depending on ammonia and energy homeostasis, and the discovered pyruvate recycling pathway in astrocytes, modulates the glutamine-glutamate cycle. 13 C-NMR studies have extended the concept of the 'non-stoichiometric' glutamate-glutamine cycle between neurons and astrocytes. An alanine-lactate shuttle between neurons and astrocytes contributes to nitrogen transfer from neurons to astrocytes, recycles energy substrates for neurons, and in return promotes intercellular glutamine-glutamate cycling. The conversion of alanine to lactate in astrocytes is regulated by intracytosolic pyruvate compartmentation. In essence, the metabolic flexibility and compartmentalized enzymatic specialization of astrocytes buffers the brain tissue against metabolic impairments and excitotoxicity in response to extracellular stimuli, some of them being released by neurons. These in vitro studies using 13 C-NMR spectroscopy provide important knowledge regarding physiological and pathophysiological regulation of neural metabolism to improve our understanding of general brain function.

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Compartmentation of Brain Glutamate Metabolism in Neurons and Glia

Cited by 315 publications

References 41 publications

Consensus meeting: monosodium glutamate – an update

Consensus meeting: monosodium glutamate – an update

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

Regulation of glial metabolism studied by ¹³C‐NMR

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Compartmentation of Brain Glutamate Metabolism in Neurons and Glia

Cited by 315 publications

References 41 publications

Consensus meeting: monosodium glutamate – an update

Consensus meeting: monosodium glutamate – an update

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

Regulation of glial metabolism studied by 13C‐NMR

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Regulation of glial metabolism studied by ¹³C‐NMR