NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?

Tranberg, Mattias; Stridh, Malin H.; Guy, Yifat; Jilderos, Barbro; Wigström, Holger; Weber, Stephen G.; Sandberg, Mats

doi:10.1016/j.neuint.2004.06.005

Cited by 25 publications

(37 citation statements)

References 57 publications

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“…Efflux Experiments and Cell Death Analysis-The efflux experiments and cell death estimations were carried out as described previously (13). In brief, we used PI uptake, which correlates well with other markers of cell death (18).…”

Section: Methodsmentioning

confidence: 99%

“…This may occur via influx of inorganic ions followed by water influx and volume changes that open volume-sensitive anion channels (12). In addition, increased intracellular Ca 2ϩ can activate opening of channels that mediate efflux of anions from neurons (13). Adding to the complexity in studying these channels is that some of the antagonists used in studying hemichannels, P2X 7 receptors and anion channels show cross-reactivity (14,15).…”

mentioning

confidence: 99%

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Stimulated Efflux of Amino Acids and Glutathione from Cultured Hippocampal Slices by Omission of Extracellular Calcium

Stridh

Tranberg

Weber

et al. 2008

Journal of Biological Chemistry

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Omission of extracellular Ca2؉ for 15 min from the incubation medium of cultured hippocampal slices stimulated the efflux of glutathione, phosphoethanolamine, hypotaurine, and taurine. The efflux was reduced by several blockers of gap junctions, i.e. carbenoxolone, flufenamic acid, and endothelin-1, and by the connexin43 hemichannel blocking peptide Gap26 but was unchanged by the P2X 7 receptor inhibitor oxidized ATP, a pannexin1 hemichannel blocking peptide and an inactive analogue of carbenoxolone. Pretreatment of the slices with the neurotoxin N-methyl-D-aspartate left the efflux by Ca 2؉ omission unchanged, indicating that the stimulated efflux primarily originated from glia. Elevated glutamate efflux was detected when Ca 2؉ omission was combined with the glutamate uptake blocker L-trans-pyrrolidine-2,4-dicarboxylate and when both Ca 2؉ and Mg 2؉ were omitted from the medium. Omission of Ca 2؉ for 15 min alone did not induce delayed toxicity, but in combination with blocked glutamate uptake, significant cell death was observed 24 h later. Our results indicate that omission of extracellular Ca 2؉ stimulates efflux of glutathione and specific amino acids including glutamate via opening of glial hemichannels.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Stimulated Efflux of Amino Acids and Glutathione from Cultured Hippocampal Slices by Omission of Extracellular Calcium

Stridh

Tranberg

Weber

et al. 2008

Journal of Biological Chemistry

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“…Therefore it is possible that as the brain's nitrogen load is increased, Asp-NAT could act to trap some aspartate as NAA, and neurons could increase their release of NAA to the extracellular space. It has been reported that NMDA application can stimulate a calciumdependent release of NAA from neurons, but release was not stimulated by hyperosmotic conditions or potassium-induced depolarization (Tranberg et al, 2004). In another study, application of NMDA to brain slices resulted in the release of different metabolites than were released after potassium induced depolarization or glutamate application (Thatcher et al, 2002).…”

Section: Four Cell-type Model For Naa Synthesis Utilization Breakdomentioning

confidence: 99%

“…Using organotypic hippocampal slice preparations, Tranberg and colleagues showed that the addition of 10 mM NAA to the culture medium had no effect on increasing cell death after 24 hours, indicating that NAA is not toxic to neurons or glia at extracellular concentrations far higher than normal (Tranberg et al, 2004). The potential toxic or excitotoxic actions of NAA have not been fully explored, but the evidence suggests that high levels of NAA in the brains of Canavan disease patients may be involved in some aspects of the pathogenesis, possibly by inducing seizure activity.…”

Section: Naa Neurotoxicitymentioning

confidence: 99%

“…Currently, NAA does not meet all of these criteria for molecular water pump status, including the fact that no cotransport protein has been identified, and there is only scant evidence on possible gating mechanisms that specifically regulate NAA release from neurons. Results with organotypic hippocampal slices have been instrumental in demonstrating that NAA is not released under hyper-osmotic conditions, but that it is released in a calcium-dependent manner upon stimulation of neuronal NMDA receptors (Tranberg et al, 2004). NAA release in this system was not stimulated by potassium depolarization, but was prolonged for 20 minutes after a 5 minute application of 60 μM NMDA.…”

Section: Naa-related Osmotic/hydrostatic Pressure In Canavan Diseasementioning

confidence: 99%

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N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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AMP‐activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics

Voss

Andersen

Jakobsen

et al. 2020

Glia

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AMP‐activated protein kinase (AMPK) is an important energy sensor located in cells throughout the human body. From the periphery, AMPK is known to be a metabolic master switch controlling the use of energy fuels. The energy sensor is activated when the energy status of the cell is low, initiating energy‐producing pathways and deactivating energy‐consuming pathways. All brain cells are crucially dependent on energy production for survival, and the availability of energy substrates must be closely regulated. Intriguingly, the role of AMPK in the regulation of brain cell metabolism has been sparsely investigated, particularly in astrocytes. By investigating metabolism of 13C‐labeled energy substrates in acutely isolated hippocampal slices and cultured astrocytes, with subsequent mass spectrometry analysis, we here show that activation of AMPK increases glycolysis as well as the capacity of the TCA cycle, that is, anaplerosis, through the activity of pyruvate carboxylase (PC) in astrocytes. In addition, we demonstrate that AMPK activation leads to augmented astrocytic glutamate oxidation via pyruvate recycling (i.e., cataplerosis). This regulatory mechanism induced by AMPK activation is mediated via glutamate dehydrogenase (GDH) shown in a CNS‐specific GDH knockout mouse. Collectively, these findings demonstrate that AMPK regulates TCA cycle dynamics in astrocytes via PC and GDH activity. AMPK functionality has been shown to be hampered in Alzheimer's and Parkinson's disease and our findings may therefore add to the toolbox for discovery of new metabolic drug targets.

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NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?

Cited by 25 publications

References 57 publications

Stimulated Efflux of Amino Acids and Glutathione from Cultured Hippocampal Slices by Omission of Extracellular Calcium

Stimulated Efflux of Amino Acids and Glutathione from Cultured Hippocampal Slices by Omission of Extracellular Calcium

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

AMP‐activated protein kinase (AMPK) regulates astrocyte oxidative metabolism by balancing TCA cycle dynamics

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