Alanine metabolism, transport, and cycling in the brain

Bröer, Stefan; Bröer, Angelika; Hansen, Jørn Bindslev; Bubb, William A.; Balcar, Vladimír J.; Nasrallah, Fatima A.; Garner, Brett; Rae, Caroline

doi:10.1111/j.1471-4159.2007.04654.x

Cited by 54 publications

(48 citation statements)

References 63 publications

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“…This suggested that AMPA activation is specifically targeting a pool of lactate which is not rapidly accessible to 13 C from glucose. Evidence for such as pool has been presented previously [41] and our own experiments with [3-13 C]pyruvate as a substrate have indicated that more pools are labelled with this substrate than with [1-13 C]-glucose (e.g., [20,42,43]). …”

Section: Discussionmentioning

confidence: 75%

Metabolic Effects of Blocking Lactate Transport in Brain Cortical Tissue Slices Using an Inhibitor Specific to MCT1 and MCT2

2009

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A novel inhibitor of lactate transport, AR-C122982, was used to study the effect of inhibiting the monocarboxylate transporters MCT1 and MCT2 on cortical brain slice metabolism. We studied metabolism of L-[3-13C]lactate, and D-[1-13C]glucose under a range of conditions. Experiments using L-[3-13C]lactate showed that the inhibitor AR-C122982 altered exchange of lactate. Under depolarizing conditions, net flux of label from D-[1-13C]glucose was barely altered by 10 or 100 nM AR-C122982. In the presence of AMPA or glutamate there were increases in net flux of label and metabolic pool sizes. These data suggest lactate may supply compartments in the brain not usually directly accessed by glucose. In general, it would appear that movement of lactate between cell types is not essential for metabolic activity, with the heavy metabolic workloads imposed being unaffected by inhibition of MCT1 and MCT2. Further experiments investigating the mechanism of operation of AR-C122982 are necessary to corroborate this finding.

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Section: Discussionmentioning

confidence: 75%

Metabolic Effects of Blocking Lactate Transport in Brain Cortical Tissue Slices Using an Inhibitor Specific to MCT1 and MCT2

2009

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“…Plasma alanine was considered to have minor contribution to brain metabolism since it exists at only 11.2 ± 3.2% of lactate concentration (quantified in PCA extracts of plasma samples by in vitro NMR spectroscopy). This is further supported by the relative low rate of alanine transport into the brain and contribution to metabolism (Bröer et al, 2007). …”

Section: Resultsmentioning

confidence: 87%

Compartmentalized Cerebral Metabolism of [1,6-13C]Glucose Determined by in vivo13C NMR Spectroscopy at 14.1 T

Duarte¹,

Lanz²,

Gruetter³

2011

Front. Neuroenerg.

215

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Cerebral metabolism is compartmentalized between neurons and glia. Although glial glycolysis is thought to largely sustain the energetic requirements of neurotransmission while oxidative metabolism takes place mainly in neurons, this hypothesis is matter of debate. The compartmentalization of cerebral metabolic fluxes can be determined by 13C nuclear magnetic resonance (NMR) spectroscopy upon infusion of 13C-enriched compounds, especially glucose. Rats under light α-chloralose anesthesia were infused with [1,6-13C]glucose and 13C enrichment in the brain metabolites was measured by 13C NMR spectroscopy with high sensitivity and spectral resolution at 14.1 T. This allowed determining 13C enrichment curves of amino acid carbons with high reproducibility and to reliably estimate cerebral metabolic fluxes (mean error of 8%). We further found that TCA cycle intermediates are not required for flux determination in mathematical models of brain metabolism. Neuronal tricarboxylic acid cycle rate (VTCA) and neurotransmission rate (VNT) were 0.45 ± 0.01 and 0.11 ± 0.01 μmol/g/min, respectively. Glial VTCA was found to be 38 ± 3% of total cerebral oxidative metabolism, accounting for more than half of neuronal oxidative metabolism. Furthermore, glial anaplerotic pyruvate carboxylation rate (VPC) was 0.069 ± 0.004 μmol/g/min, i.e., 25 ± 1% of the glial TCA cycle rate. These results support a role of glial cells as active partners of neurons during synaptic transmission beyond glycolytic metabolism.

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“…This decline and the associated decline in cortical alanine concentration contrast with an increase in the cortical concentration of both amino acids on the same day in control mice. The reciprocal changes in the cortical concentration of glutamine and alanine in GS-deficient and control neonates, which result in a 14-and 7-fold difference, respectively, indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the developmental increase in the activity of the glutamineglutamate and the associated alanine-lactate cycles (Broer et al, 2007;Mackenzie and Erickson, 2004;Zwingmann and Leibfritz, 2003).…”

Section: Gs Excision Is Complete Well Before Functional Impairment Dementioning

confidence: 96%

Glutamine synthetase deficiency in murine astrocytes results in neonatal death

Hakvoort

Vermeulen

et al. 2010

Glia

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Glutamine synthetase (GS) is a key enzyme in the "glutamine-glutamate cycle" between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS(fl/lacZ) or GS(fl/fl) mice with hGFAP-Cre mice resulted in prenatal excision of the GS(fl) allele in astrocytes. "GS-KO/A" mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14-fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6-fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS-KO/A mice. The temporal dissociation between GS(fl) elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS-deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine-glutamate and the associated alanine-lactate cycles.

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Alanine metabolism, transport, and cycling in the brain

Cited by 54 publications

References 63 publications

Metabolic Effects of Blocking Lactate Transport in Brain Cortical Tissue Slices Using an Inhibitor Specific to MCT1 and MCT2

Metabolic Effects of Blocking Lactate Transport in Brain Cortical Tissue Slices Using an Inhibitor Specific to MCT1 and MCT2

Compartmentalized Cerebral Metabolism of [1,6-13C]Glucose Determined by in vivo13C NMR Spectroscopy at 14.1 T

Glutamine synthetase deficiency in murine astrocytes results in neonatal death

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