Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes.

Erecińska, Maria; Dagani, F.

doi:10.1085/jgp.95.4.591

Cited by 145 publications

(43 citation statements)

References 91 publications

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“…However, the activity of citrate synthetase (125 Ìmol/min/g tissue) is at least 10 times greater than that of pyruvate dehydrogenase in both whole brain [20] and synaptosomes [38]. Basal flux through pyruvate dehydrogenase barely equals the rate of synaptosomal respiration [39].…”

Section: Discussionmentioning

confidence: 96%

Ketone Bodies and Brain Glutamate and GABA Metabolism

Daikhin

Yudkoff

1998

Dev Neurosci

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The effects of ketone bodies on brain metabolism of glutamate and GABA were studied in three different systems: synaptosomes, cultured astrocytes and the whole animal. In synaptosomes the addition of either acetoacetate or 3-OH-butyrate was associated with diminished consumption of glutamate via transamination to aspartate and increased formation of labelled GABA from either L-[²H₅-2,3,3,4,4]glutamine or L-[¹⁵N]glutamine. There was no effect of ketone bodies on synaptosomal GABA transamination. An increase of total forebrain GABA and a diminution of aspartate was noted when mice were injected intraperitoneally with 3-OH-butyrate. In cultured astrocytes the addition of acetoacetate to the medium was associated with a significantly enhanced rate of citrate production and with a diminution in the rate of conversion of [¹⁵N]glutamate to [¹⁵N]aspartate. These data are consistent with the hypothesis that the metabolism of ketone bodies to acetyl-CoA results in a diminution of the pool of brain oxaloacetate, which is consumed in the citrate synthetase reaction (oxaloacetate + acetyl-CoA → citrate). As less oxaloacetate is available to the aspartate aminotransferase reaction, thereby lowering the rate of glutamate transamination, more glutamate becomes accessible to the glutamate decarboxylase pathway, thereby favoring the synthesis of GABA.

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Section: Discussionmentioning

confidence: 96%

Ketone Bodies and Brain Glutamate and GABA Metabolism

Daikhin

Yudkoff

1998

Dev Neurosci

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“…Moreover, the capacity for lactate oxidation in synaptic terminals is 2-to 3-fold higher than in astrocytes [4]. These differences in the relative capacity to use lactate for energy would be even greater during neuronal excitation since oxidative metabolism in synaptic terminals and neurons is greatly enhanced by depolarization, whereas oxidative metabolism in astrocytes is not increased [60,61]. The selective localization of LDH5 (M-4) in astrocytes and LDH1 (H-4) in neurons [10,17], as well as the higher release of lactate from glial versus neuronal tissue [58,59,62] also support the concept of a dynamic, functionallylinked trafficking of lactate between astrocytes and neurons in brain [4,9,17].…”

Section: Discussionmentioning

confidence: 99%

Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity

et al. 1998

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Since lactate released by glial cells may be a key substrate for energy in neurons, the kinetics for the uptake of L-[U-¹⁴C]lactate by cortical synaptic terminals from 7- to 8-week-old rat brain were determined. Lactate uptake was temperature-dependent, and increased by 64.9% at pH 6.2, and decreased by 43.4% at pH 8.2 relative to uptake at pH 7.3. Uptake of monocarboxylic acids was saturable with increasing substrate concentration. Eadie-Hofstee plots of the data gave evidence of two carrier-mediated uptake mechanisms with a high-affinity K_m of 0.66 mM and V_max of 3.66 mM for pyruvate, and a low-affinity system with a K_m of 9.9 mM for both lactate and pyruvate and V_max values of 16.6 and 23.1 nmol/30 s/mg protein for lactate and pyruvate, respectively. Saturable uptake was seen in the presence of 10 mM α-cyano-4-hydroxycinnamate. Lactate transport by synaptic terminals was much more sensitive to inhibition by sulfhydryl reagents than transport in astrocytes. Addition of 0.5 and 2 mM mersalyl decreased the uptake of 1 mM lactate by synaptic terminals by 59.3 and 66.37%, respectively. Pyruvate moderately decreased lactate transport, whereas 3-hydroxybutyrate had little effect. Quercetin, an inhibitor of lactate release, had little effect on the content of ¹⁴C lactate in synaptic terminals, supporting the concept that the majority of lactate produced within brain is from glial cells. Oxidation of L-[U-¹⁴C]lactate by synaptosomes was saturable, and yielded a K_m of 1.23 mM and a V_max of 116 nmol/h/mg protein. Overall the studies show that synaptic terminals from adult brain have a high capacity for transport and oxidation of lactate, consistent with the proposed role for this compound in metabolic trafficking in brain. Furthermore, the data provide kinetic evidence of two carrier-mediated mechanisms for monocarboxylic acid transport by synaptosomes and demonstrate that uptake of lactate by synaptic terminals is regulated differently than transport by astrocytes. Uptake of lactate by synaptic terminals also has differences from the systems described for neurons.

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“…It has been estimated that ion pumps consume over 70 % of all neuronal ATP [1, 2, 3]. Neuronal activation accompanied by an rise in [Ca 2+ ] i leads to a transient increase in ATP demand, which is satisfied by glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…An ion influx into the cell is governed by the electrochemical gradient, whereas efflux or ion clearance from the cell requires energy in the form of ATP [1]. In fact, nearly 70 % of all neuronal ATP is consumed to reverse ion fluxes [2, 3].…”

Section: Introductionmentioning

confidence: 99%

Calcium clearance and its energy requirements in cerebellar neurons

2010

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Quick cytosolic calcium clearance is essential for the effective modulation of various cellular functions. An excess of cytosolic calcium after influx is largely removed via ATP-dependent mechanisms located in the plasma membrane and the endoplasmic reticulum. Therefore, calcium clearance depends critically on the adequate supply of ATP, which may come from either glycolysis or mitochondria, or both. However, it presently remains unknown the degree to which individual ATP generating pathways -glycolysis and mitochondria power ATP-dependent calcium as well as other vital ion clearance mechanisms in neurons. In this study, we explored the relationship between the energy generating pathways and ion clearance mechanisms in neurons by characterizing the effects of glycolytic and mitochondrial inhibitors of ATP synthesis on calcium clearance kinetics in the soma, dendrites and spines. Stimulation of cultured cerebellar granule cells by brief pulses of 60 mM potassium ACSF, and electrical stimulation of purkinje cells in acutely prepared slices led to a transient calcium influx, whose clearance was largely mediated by the plasma membrane Ca 2+ -ATPase pump. Inhibition of glycolysis by deoxyglucose or iodoacetic acid resulted in a marked slowing in calcium clearance in the soma, dendrites, and spines with the spines affected the most. However, inhibition of the mitochondrial citric acid cycle with fluoroacetate and arsenite, or mitochondrial ATP-synthase with oligomycin did not produce any immediate effects on calcium clearance kinetics in any of those neuronal regions. Although cytosolic calcium clearance was not affected by the inhibition of mitochondria, the magnitude of the calcium clearance delay induced by glycolytic inhibitors in different neuronal compartments was related to their mitochondrial density. Conversely, the endoplasmic reticulum Ca 2+ -ATPase pump activity is fuelled by both glycolytic and mitochondrial ATP, as evidenced by a minimal change in the endoplasmic reticulum calcium contents in cells treated with either deoxyglucose supplemented with lactate or arsenite. Taken together, these data suggest that calcium clearance in cerebellar granule and purkinje cells relies on the plasma membrane Ca 2+ -ATPase, and is powered by glycolysis.

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Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes.

Cited by 145 publications

References 91 publications

Ketone Bodies and Brain Glutamate and GABA Metabolism

Ketone Bodies and Brain Glutamate and GABA Metabolism

Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity

Calcium clearance and its energy requirements in cerebellar neurons

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