The Glutamine–Glutamate/GABA Cycle: Function, Regional Differences in Glutamate and GABA Production and Effects of Interference with GABA Metabolism (original) (raw)
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Journal of Neurochemistry, 2007
GABA synthesis is necessary to maintain synaptic vesicle filling, and key proteins in its biosynthetic pathways may play a role in regulating inhibitory synaptic stability and strength. GABAergic neurons require a source of precursor glutamate, possibly from glutamine, although it is controversial whether glutamine contributes to the synaptic pool of GABA. Here we report that inhibition of System A glutamine transporters with a-(methyl-amino) isobutyric acid rapidly reduced the amplitude of inhibitory post-synaptic currents and miniature inhibitory post-synaptic currents (mIPSCs) recorded in rat hippocampal area cornu ammonis 1 (CA1) pyramidal neurons, indicating that synaptic vesicle content of GABA was reduced. After inhibiting astrocytic glutamine synthesis by either blocking glutamate transporters or the glutamine synthetic enzyme, the effect of a-(methyl-amino) isobutyric acid on mIPSC amplitudes was abolished. Exogenous glutamine did not affect mIPSC amplitudes, suggesting that the neuronal transporters are normally saturated. Our findings demonstrate that a constitutive supply of glutamine is provided by astrocytes to inhibitory neurons to maintain vesicle filling. Therefore, glutamine transporters, like those for glutamate, are potential regulators of inhibitory synaptic strength. However, in contrast to glutamate, extracellular glutamine levels are normally high. Therefore, we propose a supportive role for glutamine, even under resting conditions, to maintain GABA vesicle filling.
Neuronal Glutamine Utilization: Pathways of Nitrogen Transfer tudied with [15N]Glutamine
Journal of Neurochemistry, 1989
Gas chromatography-mass spectrometry was used to evaluate the metabolism of [15N]glutamine in isolated rat brain synaptosomes. In the presence of 0.5 mM glutamine, synaptosomes accumulated this amino acid to a level of 25-35 nmol/mg protein at an initial rate >Y nmol/min/mg of protein. The metabolism of [ "N]glutamine generated "Nlabelled glutamate, aspartate, and y-aminobutyric acid (GABA). An efflux of both ['5N)glutamate and ["N]aspartate from synaptosomes to the medium was observed. Enrichment of I5N in alanine could not be detected because of a limited pool size. Elimination of glucose from the incubation medium substantially increased the rate and amount of [ "Nlaspartate formed. It is concluded that: (I) With 0.5 mM external glutamine, the glutaminase reaction, and not glutamine transport, determines the rate of metabolism of this amino acid. (2) The primary route of glutamine catabolism involves as-Glutamate, glutamine, and related amino acids are central components in brain metabolism and function (Hertz et al., 1983). Glutamate is the primary excitatory neurotransmitter in the CNS and glutamine appears to be an important source of glutamate released during depolarization (
Journal of Neurochemistry, 2006
Neurons are metabolically handicapped in the sense that they are not able to perform de novo synthesis of neurotransmitter glutamate and c-aminobutyric acid (GABA) from glucose. A metabolite shuttle known as the glutamate/GABA-glutamine cycle describes the release of neurotransmitter glutamate or GABA from neurons and subsequent uptake into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as neurotransmitter precursor. In this review, the basic properties of the glutamate/GABA-glutamine cycle will be discussed, including aspects of transport and metabolism. Discussions of stoichiometry, the relative role of glutamate vs. GABA and pathological conditions affecting the glutamate/GABA-glutamine cycling are presented. Furthermore, a section is devoted to the accompanying ammonia homeostasis of the glutamate/GABA-glutamine cycle, examining the possible means of intercellular transfer of ammonia produced in neurons (when glutamine is deamidated to glutamate) and utilized in astrocytes (for amidation of glutamate) when the glutamate/GABA-glutamine cycle is operating. A main objective of this review is to endorse the view that the glutamate/GABA-glutamine cycle must be seen as a bi-directional transfer of not only carbon units but also nitrogen units.
Neurochemistry International, 2007
Brain [2-13 C]g-aminobutyric acid (GABA) signal derived from the glia-specific substrate [2-13 C]acetate reflects the extent of the GABAglutamine neurotransmitter cycling between GABAergic neurons and glial cells. We report, for the first time, in vivo quantification of the GABAglutamine cycling flux. The GABA-glutamine cycling flux rate was determined to be 1.8 AE 0.4 mmol/(g h) (mean AE S.D., n = 6, $6% of total tricarboxylic acid cycle rate) in the neocortex of vigabatrin-treated rats. The relatively small magnitude of glial contribution to the clearance of extracellular GABA measured in this study provided in vivo evidence to support the concept of a significant neuronal reuptake of GABA, which short-circuits the GABA-glutamine cycling pathway for repletion of released neurotransmitter GABA.
Proceedings of the National Academy of Sciences, 2005
Previous studies have shown that the glutamate/glutamine (Glu/Gln) neurotransmitter cycle and neuronal glucose oxidation are proportional (1:1), with increasing neuronal activity above isoelectricity. GABA, a product of Glu metabolism, is synthesized from astroglial Gln and contributes to total Glu/Gln neurotransmitter cycling, although the fraction contributed by GABA is unknown. In the present study, we used 13 C NMR spectroscopy together with i.v. infusions of [1,6- 13 C 2 ]glucose and [2- 13 C]acetate to separately determine rates of Glu/Gln and GABA/Gln cycling and their respective tricarboxylic acid cycles in the rat cortex under conditions of halothane anesthesia and pentobarbital-induced isoelectricity. Under 1% halothane anesthesia, GABA/Gln cycle flux comprised 23% of total (Glu plus GABA) neurotransmitter cycling and 18% of total neuronal tricarboxylic acid cycle flux. In isoelectric cortex, glucose oxidation was reduced >3-fold in glutamatergic and GABAergic neurons, ...
Glutamine in the central nervous system: function and dysfunction
Frontiers in Bioscience, 2007
Introduction 3. Glutamine (Gln) content and regional distribution 4. Gln synthesizing-and degrading enzymes and Gln carriers 4.1. Glutamine synthetase 4.2. Phosphate-activated glutaminase 4.3. Carriers transporting Gln across cell membranes and blood/brain/csf barriers 4.4. Gln transport in mitochondria 5. Gln metabolism in the CNS as studied using 13 C nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) 6. Gln in neurological disorders associated with hyperammonemia 7. Perspective 8. References
Importance of Glutamine for γ‐Aminobutyric Acid Synthesis in Rat Neostriatum In Vivo
Journal of Neurochemistry, 1988
This work was carried out to evaluate the importance of glial cells in providing precursors for the in vivo synthesis of y-aminobutyric acid (GABA). Fluorocitrate, which selectively inhibits the tricarboxylic acid cycle in glial cells, was administered locally in rat neostriatum. Inhibition of the glial cell tricarboxylic acid cycle led to a decrease both in glutamine level and in y-vinyl GABA (GVG)-induced GABA accumulation, an observation indicating reduced GABA synthesis. The role of glutamine, which is synthesized in glial cells as a precursor for GABA, was further investigated by inhibition of glutamine synthetase with intrastriatally administered methionine sulfoximine. In this case, the glutamine level was reduced to near zero values, and the GVGinduced GABA accumulation was only half that of normal. The results show that glutamine is an important precursor for GABA synthesis, but it cannot be the sole precursor because it was not possible to depress the GVG-induced GABA accumulation completely. Key Words: y-Aminobutyric acid-Glutamine-Fluorocitrate-Methionine sulfoximine-Glutamine synthetase. Paulsen R. E. et al. Importance of glutamine for y-aminobutyric acid synthesis in rat neostriatum in vivo.