Metabolism and role of glutamate in mammalian brain

Erecińska, Maria; Silver, Ian A.

doi:10.1016/0301-0082(90)90013-7

Cited by 640 publications

(507 citation statements)

References 430 publications

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“…6 Based on extensive data from isotopic labeling studies, immunohistochemical staining of cortical cells for specific enzymes, isolated cells and tissue fractionation studies it has been proposed that 66 GABAergic neurons Energy metabolism Inhibitory neurotransmission Glucose 47,50 Neurons/glia Glucose transport Glutamine 13,42 Glia Glutamate neurotransmitter cycling Ammonia detoxification Osmotic regulation Glial pH Homocarnosine 67 Subclass of GABAergic neurons pH, inhibitory neuromodulation NAA 68 Neurons Volume Mitochondrial function Myoinositol 69 Glia Osmotic regulation glutamate (as well as GABA) taken up by the glia from the synaptic cleft may be returned to the neuron in the form of glutamine. [7][8][9][10] Figure 1 shows the currently accepted model of the glutamine/glutamate cycle. As shown in Fig.…”

Section: Mrs Studies Of Neuronal Glial Gluta-mate Traffickingmentioning

confidence: 99%

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Rothman

2001

NMR in Biomedicine

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Organs consist of several types of cells with specialized functions. This cellular localization of function is often referred to as compartmentation. Due to the intrinsic low sensitivity of MR methods it is generally not possible in vivo to obtain images or spectra of single cells. Instead the MRS signal is the sum of the signal from millions of cells and multiple cell types. A major challenge in using MRS to study biological processes such as metabolism and transport is to devise measurements that provide cell-specific information from this mix. Fortunately nature has helped the MR scientist by in several cases nearly completely localizing metabolic pathways and their associated metabolites in specific cell types. The chemical specificity of MRS allows the concentrations and synthesis rates of these metabolites to be measured, providing information about the compartmentation of metabolism and function. In this review examples are presented from MRS studies of metabolic trafficking between neurons and astrocytes in the brain, brain glucose transport, and the role of muscle glucose transport in insulin resistance and diabetes. The concepts and approaches used in these studies are generally applicable for studying cellular metabolic compartmentation in a wide range of systems.

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Section: Mrs Studies Of Neuronal Glial Gluta-mate Traffickingmentioning

confidence: 99%

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Rothman

2001

NMR in Biomedicine

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“…native possibility, that glutamate has been con sumed by metabolic processes, seems remote, since the rate of glutamate turnover cannot account for such a dramatic reduction in glutamate concentra tion over a 30-min interval (Erecinska and Silver, 1990). The membrane depolarization and rise in ex ternal [K +] seen during prolonged ischemia may cause a release of glutamate through reversal of the high-affinity glutamate uptake (Hansen, 1985;Rader and Lanthorn, 1989;Nicholls and Attwell, 1990).…”

Section: Redistribution Of Glutamatementioning

confidence: 99%

“…Also, the biochemical reaction catalyzed by glutamate dehydrogenase will be affected during ischemia. Thus, during energy failure, the increased [NADH]I[NAD] ratio would favor a reductive am ination of 2-oxoglutarate, i.e., production of gluta mate (Erecinska and Silver, 1990).…”

Section: Redistribution Of Glutamatementioning

confidence: 99%

Redistribution of Glutamate and Glutamine in Slices of Human Neocortex Exposed to Combined Hypoxia and Glucose Deprivation in vitro

Aas

Berg-Johnsen

Hegstad

et al. 1993

J Cereb Blood Flow Metab

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Summary: This study was undertaken to elucidate the roles of neurons and glial cells in the handling of gluta mate and glutamine, a glutamate precursor, during cere bral ischemia. Slices (400--6 00 fLm) from human neocortex obtained during surgery for epilepsy or brain tumors were incubated in artificial cerebrospinal fluid and subjected to 30 min of combined hypoxia and glucose deprivation (an in vitro model of brain ischemia). These slices, and con trol slices that had not been subjected to "ischemic" con ditions, were then fixed and embedded. Ultrathin sec tions were processed according to a postembedding im munocytochemical method with polyclonal antibodies raised against glutamate or glutamine, followed by colloi dal gold-labeled secondary antibodies. The gold particle densities over various tissue profiles were calculated from electron micrographs using a specially designed computer program. Combined hypoxia and glucose dep rivation caused a reduced glutamate immunolabeling in neuronal somata, while that of glial processes increased. Following 1 h of recovery, the glutamate labeling of neu ronal somata declined further to very low values, com pared to control slices. The glutamate labeling of glial cells returned to normal levels following recovery. InThe pathogenesis of ischemic brain damage is not fully understood, and a number of neurotoxic sub stances has been implicated (Krause et aI. , 1988; Siesjo, 1988;Ginsberg, 1990; Siesjo et aI. , 1990 503axon terminals, no consistent change in the level of glu tamate immunolabeling was observed. Immunolabeling of glutamine was low in both nerve terminals and neuronal somata in normal slices and was reduced to nondetectable levels in nerve terminals upon hypoxia and glucose dep rivation. This treatment was also associated with a re duced glutamine immunolabeling in glial cells. Reversed glutamate uptake due to perturbations of the transmem brane ion concentrations and membrane potential proba bly contributes to the loss of neuronal glutamate under "ischemic" conditions. The increased glutamate labeling of glial cells under the same conditions can best be ex plained by assuming that glial cells resist a reversal of glutamate uptake, and that their ability to convert gluta mate into glutamine is compromised due to the energy failure. The persistence of a nerve terminal pool of glu tamate is compatible with recent biochemical data indi cating that the exocytotic glutamate release is contingent on an adequate energy supply and therefore impeded dur ing ischemia.

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“…The metabolic pool of GLU is small in glia (estimated to be $1-2 lmol/g) and much larger in neurons ($10 lmol/g) (Erecińska and Silver 1990;Chapa et al 2000). Glutamatergic neurons contain, in addition, the neurotransmitter GLU pool in presynaptic vesicles (reviewed by Danbolt 2001;Erecińska and Silver 1990).…”

mentioning

confidence: 99%

“…This estimate was based on the reasonable assumptions (i) that the rate-limiting step in the loss of 13 C from the glial GLU C5 as 13 CO 2 / H 13 CO 3 -is the glial TCA-cycle rate, for which the minimum reported rate in normal rodent brain was 0.4 lmol/g/min (Cruz and Cerdán 1999); (ii) that GLU pools are 1-2 lmol/g in glia and 10 lmol/g in neurons (Erecińska and Silver 1990;Chapa et al 2000); and (iii) our experimental observation that after 0.35 hours of chase, $30% of whole-brain [5-13 C]GLU was replaced by 12 C in vivo (Kanamori and Ross 2001, and Fig. 2 of this manuscript).…”

mentioning

confidence: 99%

Glial uptake of neurotransmitter glutamate from the extracellular fluid studiedin vivoby microdialysis and¹³C NMR

Kanamori

Ross

Kondrat

2002

Journal of Neurochemistry

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Glial uptake of neurotransmitter glutamate (GLU) from the extracellular fluid was studied in vivo in rat brain by 13 C NMR and microdialysis combined with gas-chromatography/massspectrometry. Brain GLU C5 was 13 C enriched by intravenous [2,5-13 C]glucose infusion, followed by [ 12 C]glucose infusion to chase 13 C from the small glial GLU pool. This leaves [5-13 C]GLU mainly in the large neuronal metabolic pool and the vesicular neurotransmitter pool. During the chase, the 13 C enrichment of whole-brain GLU C5 was significantly lower than that of extracellular GLU (GLU ECF ) derived from exocytosis of vesicular GLU. Glial uptake of neurotransmitter N enrichment of precursor NH 3 (0.87 ± 0.014), the rate of synthesis of GLN (V¢ GLN ), derived from neurotransmitter GLU ECF , was determined to be 6.4 ± 0.44 lmol/g/h. Comparison with V GLN measured previously by an independent method showed that the neurotransmitter provides 80-90% of the substrate GLU pool for GLN synthesis. Hence, under our experimental conditions, the rate of 6.4 ± 0.44 lmol/g/h also represents a reasonable estimate for the rate of glial uptake of GLU ECF , a process that is crucial for protecting the brain from GLU excitotoxicity.

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Metabolism and role of glutamate in mammalian brain

Cited by 640 publications

References 430 publications

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Redistribution of Glutamate and Glutamine in Slices of Human Neocortex Exposed to Combined Hypoxia and Glucose Deprivation in vitro

Glial uptake of neurotransmitter glutamate from the extracellular fluid studiedin vivoby microdialysis and¹³C NMR

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Metabolism and role of glutamate in mammalian brain

Cited by 640 publications

References 430 publications

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Redistribution of Glutamate and Glutamine in Slices of Human Neocortex Exposed to Combined Hypoxia and Glucose Deprivation in vitro

Glial uptake of neurotransmitter glutamate from the extracellular fluid studiedin vivoby microdialysis and13C NMR

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Glial uptake of neurotransmitter glutamate from the extracellular fluid studiedin vivoby microdialysis and¹³C NMR