Fine structural localization of glutamine synthetase in astrocytes of rat brain

Norenberg, Michael D.; Martínez-Hernández, Antonio

doi:10.1016/0006-8993(79)90071-4

Cited by 1,310 publications

(690 citation statements)

References 20 publications

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“…This means that any differences in concentrations and/or extent of labeling when comparing sham þ MSO vs. sham þ vehicle and þ . Under normal conditions, the majority of 15 N-ammonia taken up from blood reacts rapidly with glutamate, forming mono-labeled [5][6][7][8][9][10][11][12][13][14][15] N]glutamine in a reaction catalyzed by glutamine synthetase (GS), which in brain is found only in astrocytes. 5 Figure 2); double-labeling was low and unaffected by MSO (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…When bloodborne ammonia enters the brain, it is rapidly incorporated into glutamine by glutamine synthetase (GS) which is located in astrocytes. [4][5][6] Glutamine concentrations were increased in brains of animals with experimental liver failure [7][8][9] and in patients with acute liver failure studied with cerebral microdialysis. 10 Glutamine acts directly as an osmolyte causing brain edema 11 and studies suggest that high intracellular concentrations of glutamine may also compromise mitochondrial function 12 and lead to oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Glutamine Synthetase Inhibition on Brain and Interorgan Ammonia Metabolism in Bile Duct Ligated Rats

Fries

Dadsetan

Keiding

et al. 2013

J Cereb Blood Flow Metab

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Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of 15 NH 4 þ into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of 15 NH 4 þ into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of 15 NH 4 þ into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of 15 N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Glutamine Synthetase Inhibition on Brain and Interorgan Ammonia Metabolism in Bile Duct Ligated Rats

Fries

Dadsetan

Keiding

et al. 2013

J Cereb Blood Flow Metab

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show abstract

“…Therefore, glutamate uptake is not immediately dependent on energy, whereas the subsequent Na + extrusion, catalyzed by the Na + ,K + -ATPase, consumes ATP ( Figure 3). A pathway for glutamate return to neurons is called the glutamate-glutamine cycle, and involves its ATP-requiring conversion to glutamine by the astrocyte-specific glutamine synthetase (Norenberg and Martinez-Hernandez, 1979;Derouiche, 2004); this process is well established, as is oxidative degradation of part of the accumulated Figure 2 Glucose metabolism in astrocytes and energetics of glucose oxidation and of glutamate formation. (A) Glucose contains six carbon atoms (C6) and is glycolytically converted into two 3-carbon (C3) pyruvate.…”

Section: Discussionmentioning

confidence: 99%

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

Hertz

Peng

Dienel

2007

J Cereb Blood Flow Metab

526

573

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Astrocytic energy demand is stimulated by K + and glutamate uptake, signaling processes, responses to neurotransmitters, Ca 2 + fluxes, and filopodial motility. Astrocytes derive energy from glycolytic and oxidative pathways, but respiration, with its high-energy yield, provides most adenosine 5 0 triphosphate (ATP). The proportion of cortical oxidative metabolism attributed to astrocytes (B30%) in in vivo nuclear magnetic resonance (NMR) spectroscopic and autoradiographic studies corresponds to their volume fraction, indicating similar oxidation rates in astrocytes and neurons. Astrocyte-selective expression of pyruvate carboxylase (PC) enables synthesis of glutamate from glucose, accounting for two-thirds of astrocytic glucose degradation via combined pyruvate carboxylation and dehydrogenation. Together, glutamate synthesis and oxidation, including neurotransmitter turnover, generate almost as much energy as direct glucose oxidation. Glycolysis and glycogenolysis are essential for astrocytic responses to increasing energy demand because astrocytic filopodial and lamellipodial extensions, which account for 80% of their surface area, are too narrow to accommodate mitochondria; these processes depend on glycolysis, glycogenolysis, and probably diffusion of ATP and phosphocreatine formed via mitochondrial metabolism to satisfy their energy demands. High glycogen turnover in astrocytic processes may stimulate glucose demand and lactate production because less ATP is generated when glucose is metabolized via glycogen, thereby contributing to the decreased oxygen to glucose utilization ratio during brain activation. Generated lactate can spread from activated astrocytes via low-affinity monocarboxylate transporters and gap junctions, but its subsequent fate is unknown. Astrocytic metabolic compartmentation arises from their complex ultrastructure; astrocytes have high oxidative rates plus dependence on glycolysis and glycogenolysis, and their energetics is underestimated if based solely on glutamate cycling. Keywords: acetate; glucose metabolism; glutamate; neurotransmitters; potassium; pyruvate carboxylation Introduction Astrocytes are More Than HousekeepersRecent studies in many different fields have shown much more active roles of astrocytes in brain function than previously portrayed by their traditionally ascribed 'bystander or housekeeping' functions. Emerging roles of astrocytes include their interactions with the vasculature, neurons, and other astrocytes via signaling, biosynthetic, and transport processes to regulate blood flow, modulate impulse transmission, and synthesize and degrade glucose-derived neurotransmitters, for example, glutamate and g-aminobutyric acid (GABA) (Takano et al, 2006;Hertz and Zielke, 2004;Volterra and Meldolesi, 2005). All of these processes are energyrequiring or dependent on energy-related metabolic pathways, thereby directly linking astrocyte functions, energetics, and metabolite fluxes.The narrow astrocytic surface extensions (lamellae and filopodia, also called peripheral ast...

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“…25,26 Astrocytes are involved in numerous functions in the brain, such as the provision of nutrients and mechanical support to surrounding neurones, the regulation of ion transport and neurotransmitter uptake in the brain, as well as being key components of the blood-brain barrier (BBB). Whilst astrocytes are sensitive to the effects of ammonia, neurones are almost completely unaffected by exposure to this neurotoxin.…”

Section: Ammonia and The Brain: The Sick Astrocytementioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

246

190

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The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

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Fine structural localization of glutamine synthetase in astrocytes of rat brain

Cited by 1,310 publications

References 20 publications

Effect of Glutamine Synthetase Inhibition on Brain and Interorgan Ammonia Metabolism in Bile Duct Ligated Rats

Effect of Glutamine Synthetase Inhibition on Brain and Interorgan Ammonia Metabolism in Bile Duct Ligated Rats

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

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