• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Oct 25, 1994; 91(22): 10625–10629.

Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.


Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Gasic GP, Hollmann M. Molecular neurobiology of glutamate receptors. Annu Rev Physiol. 1992;54:507–536. [PubMed]
  • Bouvier M, Szatkowski M, Amato A, Attwell D. The glial cell glutamate uptake carrier countertransports pH-changing anions. Nature. 1992 Dec 3;360(6403):471–474. [PubMed]
  • Rosenberg PA, Amin S, Leitner M. Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture. J Neurosci. 1992 Jan;12(1):56–61. [PubMed]
  • Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem. 1977 May;28(5):897–916. [PubMed]
  • Mata M, Fink DJ, Gainer H, Smith CB, Davidsen L, Savaki H, Schwartz WJ, Sokoloff L. Activity-dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem. 1980 Jan;34(1):213–215. [PubMed]
  • Fox PT, Raichle ME, Mintun MA, Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science. 1988 Jul 22;241(4864):462–464. [PubMed]
  • Sorg O, Magistretti PJ. Characterization of the glycogenolysis elicited by vasoactive intestinal peptide, noradrenaline and adenosine in primary cultures of mouse cerebral cortical astrocytes. Brain Res. 1991 Nov 1;563(1-2):227–233. [PubMed]
  • Yu N, Martin JL, Stella N, Magistretti PJ. Arachidonic acid stimulates glucose uptake in cerebral cortical astrocytes. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4042–4046. [PMC free article] [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Rosenberg JC, Rush BF. An enzymatic-spectrophotometric determination of pyruvic and lactic acid in blood. Methodologic aspects. Clin Chem. 1966 May;12(5):299–307. [PubMed]
  • Kanner BI. Glutamate transporters from brain. A novel neurotransmitter transporter family. FEBS Lett. 1993 Jun 28;325(1-2):95–99. [PubMed]
  • Yarowsky P, Boyne AF, Wierwille R, Brookes N. Effect of monensin on deoxyglucose uptake in cultured astrocytes: energy metabolism is coupled to sodium entry. J Neurosci. 1986 Mar;6(3):859–866. [PubMed]
  • Kimelberg HK, Biddelcome S, Narumi S, Bourke RS. ATPase and carbonic anhydrase activities of bulk-isolated neuron, glia and synaptosome fractions from rat brain. Brain Res. 1978 Feb 10;141(2):305–323. [PubMed]
  • Bowman CL, Kimelberg HK. Excitatory amino acids directly depolarize rat brain astrocytes in primary culture. Nature. 1984 Oct 18;311(5987):656–659. [PubMed]
  • Lipton P, Robacker K. Glycolysis and brain function: [K+]o stimulation of protein synthesis and K+ uptake require glycolysis. Fed Proc. 1983 Sep;42(12):2875–2880. [PubMed]
  • Lynch RM, Balaban RS. Coupling of aerobic glycolysis and Na+-K+-ATPase in renal cell line MDCK. Am J Physiol. 1987 Aug;253(2 Pt 1):C269–C276. [PubMed]
  • Paul RJ, Bauer M, Pease W. Vascular smooth muscle: aerobic glycolysis linked to sodium and potassium transport processes. Science. 1979 Dec 21;206(4425):1414–1416. [PubMed]
  • Parker JC, Hoffman JF. The role of membrane phosphoglycerate kinase in the control of glycolytic rate by active cation transport in human red blood cells. J Gen Physiol. 1967 Mar;50(4):893–916. [PMC free article] [PubMed]
  • Mercer RW, Dunham PB. Membrane-bound ATP fuels the Na/K pump. Studies on membrane-bound glycolytic enzymes on inside-out vesicles from human red cell membranes. J Gen Physiol. 1981 Nov;78(5):547–568. [PMC free article] [PubMed]
  • Walz W, Mukerji S. Lactate release from cultured astrocytes and neurons: a comparison. Glia. 1988;1(6):366–370. [PubMed]
  • Dringen R, Gebhardt R, Hamprecht B. Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res. 1993 Oct 1;623(2):208–214. [PubMed]
  • Tsacopoulos M, Evêquoz-Mercier V, Perrottet P, Buchner E. Honeybee retinal glial cells transform glucose and supply the neurons with metabolic substrate. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8727–8731. [PMC free article] [PubMed]
  • Poitry-Yamate C, Tsacopoulos M. Glial (Müller) cells take up and phosphorylate [3H]2-deoxy-D-glucose in mammalian retina. Neurosci Lett. 1991 Jan 28;122(2):241–244. [PubMed]
  • Derouiche A, Frotscher M. Astroglial processes around identified glutamatergic synapses contain glutamine synthetase: evidence for transmitter degradation. Brain Res. 1991 Jun 28;552(2):346–350. [PubMed]
  • McLennan H. The autoradiographic localization of L-[3h]glutamate in rat brain tissue. Brain Res. 1976 Oct 8;115(1):139–144. [PubMed]
  • Kadekaro M, Crane AM, Sokoloff L. Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc Natl Acad Sci U S A. 1985 Sep;82(17):6010–6013. [PMC free article] [PubMed]
  • Kennedy C, Des Rosiers MH, Sakurada O, Shinohara M, Reivich M, Jehle JW, Sokoloff L. Metabolic mapping of the primary visual system of the monkey by means of the autoradiographic [14C]deoxyglucose technique. Proc Natl Acad Sci U S A. 1976 Nov;73(11):4230–4234. [PMC free article] [PubMed]
  • Dringen R, Wiesinger H, Hamprecht B. Uptake of L-lactate by cultured rat brain neurons. Neurosci Lett. 1993 Nov 26;163(1):5–7. [PubMed]
  • Schurr A, West CA, Rigor BM. Lactate-supported synaptic function in the rat hippocampal slice preparation. Science. 1988 Jun 3;240(4857):1326–1328. [PubMed]
  • Izumi Y, Benz AM, Zorumski CF, Olney JW. Effects of lactate and pyruvate on glucose deprivation in rat hippocampal slices. Neuroreport. 1994 Jan 31;5(5):617–620. [PubMed]
  • Larrabee MG. Lactate uptake and release in the presence of glucose by sympathetic ganglia of chicken embryos and by neuronal and nonneuronal cultures prepared from these ganglia. J Neurochem. 1983 May;40(5):1237–1250. [PubMed]
  • Pardridge WM, Oldendorf WH. Transport of metabolic substrates through the blood-brain barrier. J Neurochem. 1977 Jan;28(1):5–12. [PubMed]
  • Mita M, Hall PF. Metabolism of round spermatids from rats: lactate as the preferred substrate. Biol Reprod. 1982 Apr;26(3):445–455. [PubMed]
  • Swanson RA. Astrocyte glutamate uptake during chemical hypoxia in vitro. Neurosci Lett. 1992 Dec 7;147(2):143–146. [PubMed]
  • Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, Avison M, Howseman A, Hanstock C, Shulman R. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5829–5831. [PMC free article] [PubMed]
  • Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW. Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 1992 Jul;12(4):584–592. [PubMed]
  • Ueki M, Linn F, Hossmann KA. Functional activation of cerebral blood flow and metabolism before and after global ischemia of rat brain. J Cereb Blood Flow Metab. 1988 Aug;8(4):486–494. [PubMed]
  • Fellows LK, Boutelle MG, Fillenz M. Physiological stimulation increases nonoxidative glucose metabolism in the brain of the freely moving rat. J Neurochem. 1993 Apr;60(4):1258–1263. [PubMed]
  • Fox PT, Raichle ME. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1140–1144. [PMC free article] [PubMed]
  • Ogawa S, Tank DW, Menon R, Ellermann JM, Kim SG, Merkle H, Ugurbil K. Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5951–5955. [PMC free article] [PubMed]
  • Kwong KK, Belliveau JW, Chesler DA, Goldberg IE, Weisskoff RM, Poncelet BP, Kennedy DN, Hoppel BE, Cohen MS, Turner R, et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5675–5679. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...