Glycolysis and Glutamate Accumulation into Synaptic Vesicles
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Glucose is the major source of brain energy and is essential for maintaining normal brain and neuronal function. Hypoglycemia causes impaired synaptic transmission. This occurs even before significant reduction in global cellular ATP concentration, and relationships among glycolysis, ATP supply, and synaptic transmission are not well understood. We demonstrate that the glycolytic enzymes glyceraldehyde phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate kinase (3-PGK) are enriched in synaptic vesicles, forming a functional complex, and that synaptic vesicles are capable of accumulating the excitatory neurotransmitter glutamate by harnessing ATP produced by vesicle-bound GAPDH/3-PGK at the expense of their substrates. The GAPDH inhibitor iodoacetate suppressed GAPDH/3-PGK-dependent, but not exogenous ATP-dependent, [(3)H]glutamate uptake into isolated synaptic vesicles. It also decreased vesicular [(3)H]glutamate content in the nerve ending preparation synaptosome; this decrease was reflected in reduction of depolarization-induced [(3)H]glutamate release. In contrast, oligomycin, a mitochondrial ATP synthase inhibitor, had minimal effect on any of these parameters. ADP at concentrations above 0.1 mm inhibited vesicular glutamate and dissipated membrane potential. This suggests that the coupled GAPDH/3-PGK system, which converts ADP to ATP, ensures maximal glutamate accumulation into presynaptic vesicles. Together, these observations provide insight into the essential nature of glycolysis in sustaining normal synaptic transmission.
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Glycolytic enzymes may be localized at the plasma membrane and on synaptic vesicles where major ion pumping is performed by transport ATPases.
“There is also evidence that the glycolytic enzymes may be localized right where the neuron most requires acute resupply of ATP: at the plasma membrane and on the synaptic vesicles where major ion pumping is performed by transport ATPases (Ikemoto et al., 2003; Dhar-Chowdhury et al., 2007; Hinckelmann et al., 2016).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Ikemoto et al., 2003
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“There is also evidence that the glycolytic enzymes may be localized right where the neuron most requires acute resupply of ATP: at the plasma membrane and on the synaptic vesicles where major ion pumping is performed by transport ATPases (Ikemoto et al., 2003; Dhar-Chowdhury et al., 2007; Hinckelmann et al., 2016).”
BackgroundGlycolytic enzymes localize to synapses under energy stress to support synaptic function
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- Authors
- Ikemoto, A., Bole, D. G., & Ueda, T.
- Affiliations
- Mental Health Research Institute (AU)
- Corresponding author
- Ueda, Tetsufumi
- ORCID
- Ueda, Tetsufumi
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-02
- Volume
- 278
- Issue
- 8
- Pages
- 5929-5940
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1980439311
- Cited by
- 193
- References
- 63
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 7 · 2021: 9 · 2020: 3 · 2019: 9 · 2018: 7 · 2017: 19 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 4 · 2012: 11
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns024384-03, 5r01ns036656-03)
- National Institute of Neurological Disorders and Stroke (R01NS042200, NS24384, NS 42200, NS 36656)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- glycolysis, glutamate accumulation, synaptic vesicles, glyceraldehyde-3-phosphate dehydrogenase, 3-phosphoglycerate kinase, ATP production, synaptic transmission, hypoglycemia, iodoacetate, ADP, vesicular glutamate release, synaptosomes, presynaptic vesicles, brain energy metabolism
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Animals, Brain, Cattle, Energy Metabolism, Glyceraldehyde-3-Phosphate Dehydrogenases, Glycolysis, Kinetics, Phosphoglycerate Kinase, Synaptic Vesicles, Glutamic Acid
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