The Glutamine–Glutamate/GABA Cycle: Function, Regional Differences in Glutamate and GABA Production and Effects of Interference with GABA Metabolism
Abstract
The operation of a glutamine-glutamate/GABA cycle in the brain consisting of the transfer of glutamine from astrocytes to neurons and neurotransmitter glutamate or GABA from neurons to astrocytes is a well-known concept. In neurons, glutamine is not only used for energy production and protein synthesis, as in other cells, but is also an essential precursor for biosynthesis of amino acid neurotransmitters. An excellent tool for the study of glutamine transfer from astrocytes to neurons is [(14)C]acetate or [(13)C]acetate and the glial specific enzyme inhibitors, i.e. the glutamine synthetase inhibitor methionine sulfoximine and the tricarboxylic acid cycle (aconitase) inhibitors fluoro-acetate and -citrate. Acetate is metabolized exclusively by glial cells, and [(13)C]acetate is thus capable when used in combination with magnetic resonance spectroscopy or mass spectrometry, to provide information about glutamine transfer. The present review will give information about glutamine trafficking and the tools used to map it as exemplified by discussions of published work employing brain cell cultures as well as intact animals. It will be documented that considerably more glutamine is transferred from astrocytes to glutamatergic than to GABAergic neurons. However, glutamine does have an important role in GABAergic neurons despite their capability of re-utilizing their neurotransmitter by re-uptake.
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Glutamine can be reconverted into glutamate for use as a neurotransmitter or energy substrate.
“which in turn can be reconverted into glutamate for use either as a neurotransmitter or energy substrate [21, 22, 23, 24, 25, 26, 27].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [21]
Astroglial cells are the main regulators of cerebral glutamate clearance and metabolism.
“The astroglial cells are the main regulators of cerebral glutamate clearance and metabolism [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [21]
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- Authors
- Walls, A. B., Waagepetersen, H. S., Bak, L. K., Schousboe, A., & Sonnewald, U.
- Affiliations
- University of Copenhagen (DK)
- Norwegian University of Science and Technology (NO)
- Corresponding author
- Sonnewald, Ursula
- Venue
- Neurochemical Research
- Published
- 2014-11-08
- Volume
- 40
- Issue
- 2
- Pages
- 402-409
- ISSN
- 0364-3190 (ISSN-L)
- 1573-6903
- OpenAlex
- W2020838403
- Cited by
- 223
- References
- 46
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 21 · 2023: 28 · 2022: 27 · 2021: 48 · 2020: 21 · 2019: 11 · 2018: 7 · 2017: 11 · 2016: 21 · 2015: 6
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurochemical Research (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- astrocytes, neurons, glutamate, GABA, glutamine synthetase, methionine sulfoximine, aconitase inhibition, fluoroacetate, citrate, glutamatergic neurons, GABAergic neurons, brain energy metabolism
- MeSH terms
- Animals, Brain, gamma-Aminobutyric Acid, Glutamine, Humans, Magnetic Resonance Spectroscopy, Glutamic Acid, Mice
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