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.
Pellerin
L
L
Institut de Physiologie, Université de Lausanne, Switzerland.
Magistretti
P J
PJ
D000332:Aerobiosis; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D007773:Lactates / Q000378:metabolism; D051379:Mice; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D011877:Radionuclide Imaging; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014316:Tritium
D018691:Excitatory Amino Acid Antagonists; D007773:Lactates; D014316:Tritium; D018698:Glutamic Acid; D003847:Deoxyglucose; D000254:Sodium-Potassium-Exchanging ATPase