title: Novel model of neuronal bioenergetics: postsynaptic utilization of glucose but not lactate correlates positively with Ca2+ signalling in cultured mouse glutamatergic neurons.
abstract: We have previously investigated the relative roles of extracellular glucose and lactate as fuels for glutamatergic neurons during synaptic activity. The conclusion from these studies was that cultured glutamatergic neurons utilize glucose rather than lactate during NMDA (N-methyl-d-aspartate)-induced synaptic activity and that lactate alone is not able to support neurotransmitter glutamate homoeostasis. Subsequently, a model was proposed to explain these results at the cellular level. In brief, the intermittent rises in intracellular Ca2+ during activation cause influx of Ca2+ into the mitochondrial matrix thus activating the tricarboxylic acid cycle dehydrogenases. This will lead to a lower activity of the MASH (malate-aspartate shuttle), which in turn will result in anaerobic glycolysis and lactate production rather than lactate utilization. In the present work, we have investigated the effect of an ionomycin-induced increase in intracellular Ca2+ (i.e. independent of synaptic activity) on neuronal energy metabolism employing 13C-labelled glucose and lactate and subsequent mass spectrometric analysis of labelling in glutamate, alanine and lactate. The results demonstrate that glucose utilization is positively correlated with intracellular Ca2+ whereas lactate utilization is not. This result lends further support for a significant role of glucose in neuronal bioenergetics and that Ca2+ signalling may control the switch between glucose and lactate utilization during synaptic activity. Based on the results, we propose a compartmentalized CiMASH (Ca2+-induced limitation of the MASH) model that includes intracellular compartmentation of glucose and lactate metabolism. We define pre- and post-synaptic compartments metabolizing glucose and glucose plus lactate respectively in which the latter displays a positive correlation between oxidative metabolism of glucose and Ca2+ signalling.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. laba@farma.ku.dk
authors.forename: Lasse K
authors.initials: LK
authors.lastname: Bak
authors.forename: Linea F
authors.initials: LF
authors.lastname: Obel
authors.forename: Anne B
authors.initials: AB
authors.lastname: Walls
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Sevan A A
authors.initials: SA
authors.lastname: Faek
authors.forename: Farah S
authors.initials: FS
authors.lastname: Jajo
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
mesh_terms: D000818:Animals; D061207:Calcium Ionophores / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000502:physiology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D016716:PC12 Cells; D061251:Primary Cell Culture; D051381:Rats; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D061207:Calcium Ionophores; D019344:Lactic Acid; D018698:Glutamic Acid; D005947:Glucose