Glutamine and 2-oxoglutarate as metabolic precursors of the transmitter pools of glutamate and GABA: Correlation of regional uptake by rat brain synaptosomes

Shank, Richard P.; Baldy, William J.; Ash, Charles W.

doi:10.1007/bf01000041

Cited by 40 publications

(20 citation statements)

References 12 publications

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“…These findings are consistent with the observation by Kaufman and Driscoll [14,29] that synthesized TCA cycle constituents or their metabolites are released in large amounts from homogeneous cultures of astrocytes, whereas the net release is much less in mixed neuronal-as trocytic cultures and with that by Shank and Campbell [30][31][32] that a-ketoglutarate is actively accumulated into synaptosomal preparations. Our experiments were the first direct demonstration that a-ketoglutarate itself can actually function as a precursor for transmitter gluta mate, but it had previously been shown by Kihara and Kubo [33] that the release of glutamate from a brain stem preparation is enhanced in the presence of a-ketoglu tarate in the incubation medium.…”

Section: T C a Cycle C Onstituents As P Re Cursors For Transm Itter Gsupporting

confidence: 81%

Utilization of Glutamine and of TCA Cycle Constituents as Precursors for Transmitter Glutamate and GABA

et al. 1993

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In the present review evidence is presented that (1) glutamine synthesis in astrocytes is essential for synthesis of GABA in neurons; (2) α-ketoglutarate in the presence of alanine (as an amino group donor) can replace glutamine as a precursor for synthesis of transmitter glutamate, but maybe not as a precursor for transmitter GABA; (3) differences exist in the intraneuronal metabolic pathways for utilization of α-ketoglutarate plus alanine and of glutamine, and (4) alanine also functions as a substrate for oxidative metabolism in glutamatergic neurons. It should be emphasized that the supply of precursors for transmitter glutamate and GABA in glutamatergic and GABAergic neurons depends on metabolic processes in astrocytes regardless whether glutamine or α-ketoglutarate plus L-alanine function as the transmitter precursors. The key reason that an interaction with astrocytes is essential is that both pyruvate carboxylase, the major enzyme in the brain for net synthesis of tricarboxylic acid cycle intermediates, and glutamine synthetase, the enzyme forming glutamine from glutamate, are specifically located in astrocytes, but not in neurons.

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Section: T C a Cycle C Onstituents As P Re Cursors For Transm Itter Gsupporting

confidence: 81%

Utilization of Glutamine and of TCA Cycle Constituents as Precursors for Transmitter Glutamate and GABA

et al. 1993

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“…Using 14 C-labeled substrates, glutamine has repeatedly been shown to be a GABA precursor [25,29,32,54,55]. From the present study using [U- 13 C]lactate and [U- 13 C]glucose to label the pool of TCA cycle intermediates, it may be suggested that glutamine predominantly has to be metabolized via the TCA cycle prior to synthesis of GABA (fig.…”

Section: Gaba Synthesismentioning

confidence: 87%

“…The TCA cycle constituents ·-ketoglutarate and malate have been studied as alternative candidates as precursors for GABA, but they appear to be quantitatively less important [28][29][30][31]. In addition to be a precursor for the neurotransmitters glutamate and GABA, glutamine is oxidatively metabolized in cerebral cortical neurons [32,33] and to a lesser extent in cerebellar granule neurons [34].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Lactate and Glucose Metabolism in Cultured Neocortical Neurons and Astrocytes Using <sup>13</sup>C-NMR Spectroscopy

Waagepetersen¹,

Bakken²,

Larsson³

et al. 1998

Dev Neurosci

136

108

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In cerebral cortical neurons, synthesis of the tricarboxylic acid (TCA) cycle-derived amino acids, glutamate and aspartate as well as the neurotransmitter of these neurons, γ-aminobutyrate (GABA), was studied incubating the cells in media containing 0.5 mM [U-¹³C]glucose in the absence or presence of glutamine (0.5 mM). Lyophilized cell extracts were analyzed by ¹³C nuclear magnetic resonance (NMR) spectroscopy and HPLC. The present findings were compared to results previously obtained using 1.0 mM [U-¹³C]lactate as the labeled substrate for the neurons. Regardless of the amino acids studied, incubation periods of 1 and 4 h resulted in identical amounts of ¹³C incorporated. Furthermore, the metabolism of lactate was studied under analogous conditions in cultured cerebral cortical astrocytes. The incorporation of ¹³C from lactate into glutamate was much lower in the astrocytes than in the neurons. In cerebral cortical neurons the total amount of ¹³C in GABA, glutamate and aspartate was independent of the labeled substrate. The enrichment in glutamate and aspartate was, however, higher in neurons incubated with lactate. Thus, lactate appears to be equivalent to glucose with regard to its access to the TCA cycle and subsequent labeling of glutamate, aspartate and GABA. It should be noted, however, that incubation with lactate in place of glucose led to lower cellular contents of glutamate and aspartate. The presence of glutamine affected the metabolism of glucose and lactate differently, suggesting that the metabolism of these substrates may be compartmentalized.

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“…However, more substantive explanations may also pertain, including the expression of other variant forms of GLT1 not yet recognized, or other transporters, such as EAAC1 (He et al, 2000), post-translational modification, or interacting proteins interfering with antibody binding. In addition, some axon terminals may use alternate pathways to resupply excitatory terminals with glutamate (Fonnum, 1984;Shank et al, 1989;Lehmann et al, 1993;Sonnewald et al, 1993;Westergaard et al, 1995;Hertz et al, 1999;Hassel and Brathe, 2000a,b).…”

Section: Glt1 Is Expressed In a Subpopulation Of Axon Terminalsmentioning

confidence: 99%

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

Chen¹,

Mahadomrongkul²,

Berger³

et al. 2004

J. Neurosci.

248

250

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GLT1 is the major glutamate transporter of the brain and has been thought to be expressed exclusively in astrocytes. Although excitatory axon terminals take up glutamate, the transporter responsible has not been identified. GLT1 is expressed in at least two forms varying in the C termini, GLT1a and GLT1b. GLT1 mRNA has been demonstrated in neurons, without associated protein. Recently, evidence has been presented, using specific C terminus-directed antibodies, that GLT1b protein is expressed in neurons in vivo. These data suggested that the GLT1 mRNA detected in neurons encodes GLT1b and also that GLT1b might be the elusive presynaptic transporter. To test these hypotheses, we used variant-specific probes directed to the 3Ј-untranslated regions for GLT1a and GLT1b to perform in situ hybridization in the hippocampus. Contrary to expectation, GLT1a mRNA was the more abundant form. To investigate further the expression of GLT1 in neurons in the hippocampus, antibodies raised against the C terminus of GLT1a and against the N terminus of GLT1, found to be specific by testing in GLT1 knock-out mice, were used for light microscopic and EM-ICC. GLT1a protein was detected in neurons, in 14 -29% of axons in the hippocampus, depending on the region. Many of the labeled axons formed axo-spinous, asymmetric, and, thus, excitatory synapses. Labeling also occurred in some spines and dendrites. The antibody against the N terminus of GLT1 also produced labeling of neuronal processes. Thus, the originally cloned form of GLT1, GLT1a, is expressed as protein in neurons in the mature hippocampus and may contribute significantly to glutamate uptake into excitatory terminals.

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Glutamine and 2-oxoglutarate as metabolic precursors of the transmitter pools of glutamate and GABA: Correlation of regional uptake by rat brain synaptosomes

Cited by 40 publications

References 12 publications

Utilization of Glutamine and of TCA Cycle Constituents as Precursors for Transmitter Glutamate and GABA

Utilization of Glutamine and of TCA Cycle Constituents as Precursors for Transmitter Glutamate and GABA

Comparison of Lactate and Glucose Metabolism in Cultured Neocortical Neurons and Astrocytes Using <sup>13</sup>C-NMR Spectroscopy

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

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