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Glutamate triggers rapid glucose transport stimulation in astrocytes as evidenced by real-time confocal microscopy.
Open accessAbstract
Glutamate stimulates glycolysis in astrocytes, a phenomenon that couples astrocytic metabolism with neuronal activity. However, it is not known whether glutamate also affects glucose transporter-1 (GLUT1), the transporter responsible for glucose entry into astrocytes. To address this question, two different real-time single-cell hexose uptake assays were applied to cultured hippocampal astrocytes using confocal epifluorescence microscopy. Glutamate caused a twofold to threefold increase in the zero-trans uptake rates of the fluorescent hexoses 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) and 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-6-deoxyglucose (6-NBDG). Galactose uptake, determined by the calcein volumetric assay, was stimulated to a similar extent, confirming the fluorescent hexose data, and also demonstrating that glutamate stimulation is a Vmax effect. Remarkably, glucose transport stimulation developed fully inside 10 sec, which is 100 times faster than acute stimulations of glucose transport in other cell types. Glutamate did not significantly affect the rate of 6-NBDG uptake by GLUT1-expressing epithelial Clone 9 cells, suggesting that an astrocyte-specific factor is required for transport stimulation. We conclude that glucose transport stimulation occurs early during astrocytic activation by glutamate, which provides a novel regulatory node to current models of brain energy metabolism. This mechanism should also be considered for the interpretation of functional imaging data based on hexoses.
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“As a consequence, the total glucose use by neurons and astrocytes together is coupled directly to glutamate-mediated synaptic transmission [32], [34], [36], which accounts for 80–90% of total glucose use in the cerebral cortex [32].”
From Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution (2011) · cites this paper as [36]
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Rönnbäck, L., & Hansson, E. (2004) · Journal of Neuroinflammation · doi:10.1186/1742-2094-1-22 · Cited by 105
Arce‐Molina, R., Cortés‐Molina, F., Sandoval, P. Y., Galaz, A., Alegría, K., Schirmeier, S., Barros, L. F., & Martín, A. S. (2020) · eLife · doi:10.7554/elife.53917 · Cited by 102
Ion changes and signalling in perisynaptic glia
Deitmer, J. W., & Rose, C. R. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.10.006 · Cited by 98
“…transporter GLUT1, responsible for glucose uptake into astrocytes, requires the concurrence of both sodium and calcium signals in astrocytes (Loaiza et al., 2003; Porras et al., 2008), suggesting an interaction between these two ions and glucose utilization (see chapter by Barros and…”
BackgroundBehavioral and neurochemical effects of proline
Wyse, Â. T. D. S., & Netto, C. A. (2011) · Metabolic Brain Disease · doi:10.1007/s11011-011-9246-x · Cited by 93
“Such sodium elevations stimulate Na,K-ATPase and cause increased ATP consumption and glucose uptake by astrocytes (Chatton et al. 2000; Loaiza et al. 2003; Pellerin and Magistretti 1994; Porras et al. 2008).”
BackgroundKhatri, N., & Man, H. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00199 · Cited by 96
“Processes of astrocytes grow in the close proximity to neurons, often wrapping the synaptic cleft, as evidenced by a concentration of the astrocytic glucose transporter GLUT1 around synapses, where glutamate released during synaptic transmission is sensed by the glia and stimulate glial glucose uptake (39, 40).”
BackgroundKreft, M., Bak, L. K., Waagepetersen, H. S., & Schousboe, A. (2012) · ASN Neuro · doi:10.1042/an20120007 · Cited by 88
“The rate of glucose flux through GLUT1 (glucose transporter 1), the major GLUT in astrocytes (Loaiza et al., 2003), is thus in balance with the rate of utilization by hexokinase activity.”
BackgroundInfluentialPellerin, L. (2010) · Diabetes & Metabolism · doi:10.1016/s1262-3636(10)70469-9 · Cited by 86
NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting
Lerchundi, R., Fernández‐Moncada, I., Contreras‐Baeza, Y., Sotelo-Hitschfeld, T., Mächler, P., Wyss, M. T., Stobart, J. L., Baeza‐Lehnert, F., Alegría, K., Weber, B., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508259112 · Cited by 89
“In the short term (seconds), glutamate stimulates the glucose transporter GLUT1 via Na and Ca transients mediated by the Na-glutamate cotransporter (44, 45).”
BackgroundStructural Basis of GLUT1 Inhibition by Cytoplasmic ATP
Blodgett, D. M., Zutter, J. K. D., Levine, K. B., Karim, P., & Carruthers, A. (2007) · The Journal of General Physiology · doi:10.1085/jgp.200709818 · Cited by 86
Zhong, N., Ramaswamy, G., & Weisgraber, K. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.014464 · Cited by 87
Kim, W. H., Lee, J., Jung, D., & Williams, D. R. (2012) · Sensors · doi:10.3390/s120405005 · Cited by 83
“In addition, 6-NBDG has been used to measure glial cell glucose transport in real-time using confocal microscopy cells [29].”
MethodBarros, L. F., Courjaret, R. J., Jakoby, P., Loaiza, A., Lohr, C., & Deitmer, J. W. (2008) · Glia · doi:10.1002/glia.20820 · Cited by 83
“In recent years, the transport and metabolism of glucose by cells cultured from the brain and other tissues have been studied using fluorescent glucose analogs, which allow to resolve the contribution of individual cells (Loaiza et al., 2003; Porras et al., 2004, 2008; Yamada et al., 2007).”
BackgroundMethodResultInfluentialSelf-citationGenç, S., Kurnaz, I. A., & Özilgen, M. (2011) · BMC Systems Biology · doi:10.1186/1752-0509-5-162 · Cited by 92
“As a matter of fact, it was shown that glutamate can stimulate glycolysis in astrocytes, by stimulating GLUT1 activity [20].”
BackgroundVindogentianine, a hypoglycemic alkaloid from Catharanthus roseus (L.) G. Don (Apocynaceae)
Tiong, S. H., Looi, C. Y., Arya, A., Wong, W. F., Hazni, H., Mustafa, M. R., & Awang, K. (2015) · Fitoterapia · doi:10.1016/j.fitote.2015.01.019 · Cited by 83
“) [37].”
Traumatic Brain Injury: A Comprehensive Review of Biomechanics and Molecular Pathophysiology
Orr, T. J., Lesha, E., Kramer, A. H., Cecia, A. F., Dugan, J. E., Schwartz, B., & Einhaus, S. L. (2024) · World Neurosurgery · doi:10.1016/j.wneu.2024.01.084 · Cited by 96
Na+‐Ca2+ cosignaling in the stimulation of the glucose transporter GLUT1 in cultured astrocytes
Porras, O. H., Ruminot, I., Loaiza, A., & Barros, L. F. (2007) · Glia · doi:10.1002/glia.20589 · Cited by 81
“VC 2007 Wiley-Liss, Inc. glial cells were prepared from 1–3 day-old neonatal as in Loaiza et al. (2003).”
BackgroundMethodInfluentialSelf-citationBrain energetics (thought needs food)
Pellerin, L. (2008) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e328312c368 · Cited by 79
Glucose transporter plasticity during memory processing
Choeiri, C., Staines, W. A., Miki, T., Seino, S., & Messier, C. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.09.011 · Cited by 76
Sánchez‐Alvarez, R., Tabernero, A., & Medina, J. M. (2004) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2004.02398.x · Cited by 76
“Glutamate also triggers a rapid increase in glucose uptake in astrocytes (Loaiza et al. 2003), although the mechanism proposed is the activation of the transporter rather than its translocation.”
Kinetic validation of 6‐NBDG as a probe for the glucose transporter GLUT1 in astrocytes
Barros, L. F., Bittner, C. X., Loaiza, A., Ruminot, I., Larenas, V., Moldenhauer, H. J., Oyarzún, C., & Alvarez, M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05885.x · Cited by 74
“…the glucose transporter has also been studied by confocal microscopy, first by following volume changes induced by sugar movements in and out of calcein-loaded cells (Barros 1999; Loaiza et al. 2003) and then by direct measurement of hexose movement using fluorescent hexoses (Loaiza et al. 2003).”
BackgroundMethodInfluentialSelf-citationSodium signaling and astrocyte energy metabolism
Chatton, J., Magistretti, P. J., & Barros, L. F. (2016) · Glia · doi:10.1002/glia.22971 · Cited by 73
“The first metabolic control point beyond the bloodbrain barrier is the astrocytic glucose transporter GLUT-1, which is activated by glutamate via the Na(1)/glutamate transporter (Loaiza et al., 2003).”
BackgroundMamczur, P., Borsuk, B., Paszko, J., Sas, Z., Mozrzymas, J., Wiśniewski, J. R., Gizak, A., & Rakus, D. (2015) · Glia · doi:10.1002/glia.22753 · Cited by 71
“In contrast, glutamate released from synaptically active neu- rons stimulates glucose consumption and lactate release from astrocytes (Loaiza et al., 2003; Pellerin and Magistretti, View this article online at wileyonlinelibrary.com.”
BackgroundFluorometric Determination of Glucose Utilization in Neurons in Vitro and in Vivo
Itoh, Y., Abe, T., Takaoka, R., & Tanahashi, N. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000127661.07591.de · Cited by 72
“…transport in vascular smooth muscle cells (Lloyd et al., 1999), Escherichia coli (Natarajan and Srienc, 2000; Yoshioka et al., 1996b), astrocytes (Loaiza et al., 2003), cardiomyocytes (Ball et al., 2002), enterocytes Address correspondence to Yoshiaki Itoh, Department of Neurology, Keio…”
BackgroundAerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur
Barros, L. F., Ruminot, I., Martín, A. S., Lerchundi, R., Fernández‐Moncada, I., & Baeza‐Lehnert, F. (2020) · Neurochemical Research · doi:10.1007/s11064-020-02964-w · Cited by 77
The insulin‐like growth factor I receptor regulates glucose transport by astrocytes
Hernández-Garzón, E., Fernandez, A. M., Pérez‐Alvarez, A., Genı́s, L., Bascuñana, P., de la Rosa, R. F., Delgado, M., Pozo, M. A., Moreno, E., McCormick, P. J., et al. (2016) · Glia · doi:10.1002/glia.23035 · Cited by 74
“While diverse mechanisms have been invoked to explain the ample spectrum of beneficial actions of reduced IGF-IR activity (Gazit et al. 2016; Kenyon 2010; Lopez-Otin et al. 2013; Vilchez et al. 2014), it is possible that IGF-IR targets additional mechanisms of wide functional impact such as energy balance, as insulin-…”
BackgroundRuminot, I., Schmälzle, J., Leyton, B., Barros, L. F., & Deitmer, J. W. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17737012 · Cited by 73
Why glucose transport in the brain matters for PET
Barros, L. F., Porras, O. H., & Bittner, C. X. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.01.002 · Cited by 72
Ribeiro, C. A. J., Sgaravatti, Â. M., Rosa, R. B., Schuck, P. F., Grando, V., Schmidt, A. L., Ferreira, G. C., Perry, M. L. S., Dutra‐Filho, C. S., & Wajner, M. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9423-9 · Cited by 69
“Since glutamate stimulates cerebral glucose utilization [ 38 , 39] and the nitrogen of the BCAA is used to form glutamate by”
BackgroundFunctional magnetic resonance imaging
Buchbinder, B. R. (2016) · Handbook of clinical neurology · doi:10.1016/b978-0-444-53485-9.00004-0 · Cited by 75
Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia
Sullivan, C. R., Mielnik, C. A., Funk, A., O'Donovan, S. M., Bentea, E., Pletnikov, M. V., Ramsey, A. J., Wen, Z., Rowland, L. M., & McCullumsmith, R. E. (2019) · Scientific Reports · doi:10.1038/s41598-019-41572-9 · Cited by 69
Pugliese, M., Carrasco, J. L., Andrade, C., Mas, E., Mascort, J., & Mahy, N. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2005.01.017 · Cited by 68
Astrocyte sodium signaling and neuro-metabolic coupling in the brain
Rose, C. R., & Chatton, J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.03.002 · Cited by 68
Connexins protect mouse pancreatic β cells against apoptosis
Klee, P., Allagnat, F., Pontes, H., Cederroth, M., Charollais, A., Caille, D., Britan, A., Haefliger, J., & Meda, P. (2011) · Journal of Clinical Investigation · doi:10.1172/jci40509 · Cited by 67
“To investigate such a difference, we assessed whether increased levels of Cx36 abolished the expression and function of the GLUT-2 transporter, preventing the uptake of both STZ and AX (11, 17, 18), in islets of RIP-Cx36 mice.”
BackgroundLanger, J., Gerkau, N. J., Derouiche, A., Kleinhans, C., Moshrefi-Ravasdjani, B., Fredrich, M., Kafitz, K. W., Seifert, G., Steinhäuser, C., & Rose, C. R. (2016) · Glia · doi:10.1002/glia.23092 · Cited by 63
Arya, A., Looi, C. Y., Cheah, S., Mustafa, M. R., & Mohd, M. A. (2012) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2012.08.014 · Cited by 64
“The uptake of the fluorescent hexose 2-NBDG, a glucose analog, was assayed as described by Loaiza et al. (2003) with modifications.”
MethodFunctional Astrocyte-Neuron Lactate Shuttle in a Human Stem Cell-Derived Neuronal Network
Tarczyluk, M. A., Nagel, D. A., O’Neil, J. D., Parri, H. R., Tse, E. H. Y., Coleman, M. D., & Hill, E. J. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.81 · Cited by 63
“A cultures was investigated using methods described by.(27) Briefly, before measurement, culture medium was removed and the cells were washed with Krebs’–Ringer HEPES (KRH) buffer supplemented with 5mM glucose.”
Method
Metadata
- Authors
- Loaiza, A., Porras, O. H., & Barros, L. F.
- Affiliations
- Centro de Estudios Científicos (CL)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-08-13
- Volume
- 23
- Issue
- 19
- Pages
- 7337-7342
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740433
- OpenAlex
- W2119476349
- Cited by
- 254
- References
- 34
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 10 · 2020: 10 · 2019: 15 · 2018: 8 · 2017: 14 · 2016: 13 · 2015: 10 · 2014: 13 · 2013: 13 · 2012: 9
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tinker Foundation
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glutamate, glucose transport, GLUT1, astrocytes, astrocyte-neuron interaction, glycolysis, hippocampal astrocytes, 2-NBDG, galactose uptake, brain energy metabolism, astrocyte activation
- MeSH terms
- Animals, Astrocytes, Biological Transport, Deoxyglucose, Fluorescent Dyes, Glucosamine, Glucose, Hippocampus, Kinetics, 4-Chloro-7-nitrobenzofurazan, Neurons, Rats, Sprague-Dawley, Microscopy, Confocal, Glutamic Acid, Coculture Techniques, Rats
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