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Effects of Adrenergic Agents on Intracellular Ca2+ Homeostasis and Metabolism of Glucose in Astrocytes with an Emphasis on Pyruvate Carboxylation, Oxidative Decarboxylation and Recycling: Implications for Glutamate Neurotransmission and Excitotoxicity

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Abstract

Glucose and glycogen are essential sources of energy for maintaining glutamate homeostasis as well as glutamatergic neurotransmission. The metabolism of glycogen, the location of which is confined to astrocytes, is affected by norepinephrine (NE), and hence, adrenergic signaling in the astrocyte might affect glutamate homeostasis with implications for excitatory neurotransmission and possibly excitotoxic neurodegeneration. In order to study this putative correlation, cultured astrocytes were incubated with 2.5 mM [U-13C]glucose in the presence and absence of NE as a time course for 1 h. Employing mass spectrometry, labeling in intracellular metabolites was determined. Moreover, the involvement of Ca2+ in the noradrenergic response was studied. In unstimulated astrocytes, the labeling pattern of glutamate, aspartate, malate and citrate confirmed important roles for pyruvate carboxylation and oxidative decarboxylation in astrocytic glucose metabolism. Importantly, pyruvate carboxylation was best visualized at 10 min of incubation. The abundance and pattern of labeling in lactate and alanine indicated not only an extensive activity of malic enzyme (initial step for pyruvate recycling) but also a high degree of compartmentalization of the pyruvate pool. Stimulating with 1 μM NE had no effect on labeling patterns and glycogen metabolism, whereas 100 μM NE increased glutamate labeling and decreased labeling in alanine, the latter supposedly due to dilution from degradation of non-labeled glycogen. It is suggested that further experiments uncovering the correlation between adrenergic and glutamatergic pathways should be performed in order to gain further insight into the role of astrocytes in brain function and dysfunction, the latter including excitotoxicity.

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Acknowledgements

We would like to thank Ms. Lene Vigh and Ms. Heidi Marie Nielsen for expert technical assistance. This study was funded by MRC 09-063393 and The Novo Nordisk Foundation.

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  1. Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100, Copenhagen, Denmark

    Linea F. Obel, Karen M. H. Andersen, Lasse K. Bak, Arne Schousboe & Helle S. Waagepetersen

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  1. Linea F. Obel
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  2. Karen M. H. Andersen
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Correspondence to Helle S. Waagepetersen.

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Obel, L.F., Andersen, K.M.H., Bak, L.K. et al. Effects of Adrenergic Agents on Intracellular Ca2+ Homeostasis and Metabolism of Glucose in Astrocytes with an Emphasis on Pyruvate Carboxylation, Oxidative Decarboxylation and Recycling: Implications for Glutamate Neurotransmission and Excitotoxicity. Neurotox Res 21, 405–417 (2012). https://doi.org/10.1007/s12640-011-9296-1

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