Pyruvate car☐ylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools

Shank, Richard P.; Bennett, Gudrun S.; Freytag, Svend O.; Campbell, Graham LeM.

doi:10.1016/0006-8993(85)90552-9

Cited by 468 publications

(396 citation statements)

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“…When injected intravenously, the bicarbonate enters the brain by passing through the astrocytic end feet that surround brain capillaries, thereby being exposed primarily to the astrocytic pyruvate-carboxylating enzymes, whereas the intracerebral administration bypasses this astrocytic interphase. The previous finding that the enzyme pyruvate carboxylase has a strictly astrocytic expression in the brain (Yu et al, 1983;Shank et al, 1985;Cesar and Hamprecht, 1995) has been a main reason for ascribing all cerebral pyruvate carboxylation to astrocytes. However, mitochondrial malic enzyme was recently reported to be expressed in neurons (Vogel et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In the brain the only truly anaplerotic reaction is carboxylation of pyruvate to the TCA cycle intermediates malate or oxaloacetate. This process has been thought to occur in astrocytes and not in neurons, because pyruvate carboxylase, one of the pyruvatecarboxylating enzymes in the brain (Patel, 1974), is only expressed in astrocytes (Yu et al, 1983;Shank et al, 1985;Cesar and Hamprecht, 1995), and because intravenous administration of radiolabeled bicarbonate to rats leads to stronger labeling of glutamine than of glutamate (Waelsch et al, 1964), a sign of astrocytic metabolism (Van den Berg et al, 1969;Hassel et al, 1992). The resulting conclusion has been that astrocytes maintain a net export of glutamine to glutamatergic neurons and that these neurons are completely dependent on astrocytes for neurotransmission.…”

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confidence: 99%

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Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

Hassel

Bråthe

2000

J. Neurosci.

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Release of transmitter glutamate implies a drain of ␣-ketoglutarate from neurons, because glutamate, which is formed from ␣-ketoglutarate, is taken up by astrocytes. It is generally believed that this drain is compensated by uptake of glutamine from astrocytes, because neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates, which requires pyruvate carboxylation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

Hassel

Bråthe

2000

J. Neurosci.

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“…Secondly, high extracellular concentration of glutamate is neurotoxic and it has been shown that excessive glutamate release plays a part in the pathophysiology of many brain disorders. Thirdly, neurons are not capable of net synthesis of glutamate and related metabolites, since they lack the main anaplerotic enzyme in the brain, pyruvate carboxylase (Shank et al, 1985). Thus, they depend on astrocytic supply of tricarboxylic acid (TCA) cycle intermediates since the drain of amino-acid neurotransmitters would otherwise lead to a shortage of neurotransmitter precursors (Sonnewald et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-13 C]glucose and [1,2-13 C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by 13 C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-13 C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-13 C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

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“…CO2 fixation in the brain has been extensively investigated since 1962 (Berl et al, 1962;Waelsch et al, 1964), and it is recognized that most of the C02-fixing, anaplerotic activity in the brain is catalyzed by pyruvate carboxy!ase (Patel, 1989). Pyruvate carboxylase in the brain (Yu et al, 1983;Shank et al, 1985), along with g!utamine synthetase (Martinez-Hernandez et al, 1977;Norenberg, 1979), is found exclusively in the astrocytes as indicated in Scheme 1. Scheme I illustrates the flow of carbon between the astrocytes and neurons, the transfer of glutamate carbon to the citric acid cycle in astrocytes, followed by decarboxylation of malate to pyruvate and the cycling of carbon between citric acid cycle intermediates and pyruvate via pyruvate carboxy!ase.…”

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confidence: 99%

Role of Pyruvate Carboxylase in Facilitation of Synthesis of Glutamate and Glutamine in Cultured Astrocytes

Gamberino

Berkich

Lynch

et al. 1997

Journal of Neurochemistry

101

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CO 2 fixation was measured in cultured astrocytes isolated from neonatal rat brain to test the hypothesis that the activity of pyruvate carboxylase influences the rate of de novo glutamate and glutamine synthesis in astrocytes. Astrocytes were incubated with 14002 and the incorporation of 140 into medium or cell extract products was determined. After chromatographic separation of 140-Iabelled products, the fractions of 140 cycled back to pyruvate, incorporated into citric acid cycle intermediates, and converted to the amino acids glutamate and glutamine were determined as a function of increasing pyruvate carboxylase flux. The consequences of increasing pyruvate, bicarbonate, and ammonia were investigated. Increasing extracellular pyruvate from 0 to 5 mM increased pyruvate carboxylase flux as observed by increases in the 140 incorporated into pyruvate and citric acid cycle intermediates, but incorporation into glutamate and glutamine, although relatively high at low pyruvate levels, did not increase as pyruvate carboxylase flux increased. Increasing added bicarbonate from 15 to 25 mM almost doubled 002 fixation. When 25 mM bicarbonate plus 0.5 mM pyruvate increased pyruvate carboxylase flux to approximately the same extent as 15 mM bicarbonate pIus 5 mM pyruvate, the rate of appearance of [14C]glutamate and glutamine was higher with the lower level of pyruvate. The conclusion was drawn that, in addition to stimulating pyruvate carboxylase, added pyruvate (but not added bicarbonate) increases alanine aminotransferase flux in the direction of glutamate utilization, thereby decreasing glutamate as pyruvate + glutamate -~a-ketoglutarate + alanine. In contrast to previous in vivo studies, the addition of ammonia (0.1 and 5 mM) had no effect on net 14002 fixation, but did alter the distribution of 14C-labelled products by decreasing glutamate and increasing glutamine. Rather unexpectedly, ammonia did not increase the sum of glutamate plus glutamine (mass amounts or 140 incorporation). Low rates of conversion of cr- [140]ketoglutarate to [14C]glutamate,even in the presence of excess added ammonia, suggested that reductive amination of a-ketoglutarate is inactive under conditions studied in these cultured astrocytes. We conclude that pyruvate carboxylase is required for de novo synthesis of glutamate plus glutamine, but that conversion of aketoglutarate to glutamate may frequently be the ratelimiting step in this process of glutamate synthesis.

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Pyruvate car☐ylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools

Cited by 468 publications

References 9 publications

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Role of Pyruvate Carboxylase in Facilitation of Synthesis of Glutamate and Glutamine in Cultured Astrocytes

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