Abnormalities in Glutamate Metabolism and Excitotoxicity in the Retinal Diseases

In the physiological condition, glutamate acts as an excitatory neurotransmitter in the retina. However, excessive glutamate can be toxic to retinal neurons by overstimulation of the glutamate receptors. Glutamate excess is primarily attributed to perturbation in the homeostasis of the glutamate metabolism. Major pathway of glutamate metabolism consists of glutamate uptake by glutamate transporters followed by enzymatic conversion of glutamate to nontoxic glutamine by glutamine synthetase. Glutamate metabolism requires energy supply, and the energy loss inhibits the functions of both glutamate transporters and glutamine synthetase. In this review, we describe the present knowledge concerning the retinal glutamate metabolism under the physiological and pathological conditions.

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Effects of inhibiting glutamine synthetase and blocking glutamate uptake on b-wave generation in the isolated rat retina

Visual Neuroscience ◽

10.1017/s095252389916214x ◽

1999 ◽

Vol 16 (2) ◽

pp. 345-353 ◽

Cited By ~ 33

Author(s):

BARRY S. WINKLER ◽

NATALIA KAPOUSTA-BRUNEAU ◽

MATTHEW J. ARNOLD ◽

DANIEL G. GREEN

Keyword(s):

Amino Acids ◽

Glutamine Synthetase ◽

Glutamate Uptake ◽

Müller Cells ◽

Glutamate Transporters ◽

Methionine Sulfoximine ◽

Muller Cells ◽

Rat Retina ◽

Subsequent Conversion ◽

Isolated Rat

The purpose of the present experiments was to evaluate the contribution of the glutamate-glutamine cycle in retinal glial (Müller) cells to photoreceptor cell synaptic transmission. Dark-adapted isolated rat retinas were superfused with oxygenated bicarbonate-buffered media. Recordings were made of the b-wave of the electroretinogram as a measure of light-induced photoreceptor to ON-bipolar neuron transmission. L-methionine sulfoximine (1–10 mM) was added to superfusion media to inhibit glutamine synthetase, a Müller cell specific enzyme, by more than 99% within 5–10 min, thereby disrupting the conversion of glutamate to glutamine in the Müller cells. Threo-hydroxyaspartic acid and D-aspartate were used to block glutamate transporters. The amplitude of the b-wave was well maintained for 1–2 h provided 0.25 mM glutamate or 0.25 mM glutamine was included in the media. Without exogenous glutamate or glutamine the amplitude of the b-wave declined by about 70% within 1 h. Inhibition of glutamate transporters led to a rapid (2–5 min) reversible loss of the b-wave in the presence and absence of the amino acids. In contrast, inhibition of glutamine synthetase did not alter significantly either the amplitude of the b-wave in the presence of glutamate or glutamine or the rate of decline of the b-wave found in the absence of these amino acids. Excellent recovery of the b-wave was found when 0.25 mM glutamate was resupplied to L-methionine sulfoximine–treated retinas. The results suggest that in the isolated rat retina uptake of released glutamate into photoreceptors plays a more important role in transmitter recycling than does uptake of glutamate into Müller cells and its subsequent conversion to glutamine.

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Glutamate metabolism in HIV-infected macrophages: implications for the CNS

AJP Cell Physiology ◽

10.1152/ajpcell.00021.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. C618-C626 ◽

Cited By ~ 28

Author(s):

Fabrice Porcheray ◽

Cathie Léone ◽

Boubekeur Samah ◽

Anne-Cécile Rimaniol ◽

Nathalie Dereuddre-Bosquet ◽

...

Keyword(s):

Gene Expression ◽

Glutamine Synthetase ◽

Hiv Infection ◽

Excitatory Amino Acid ◽

Glutamate Uptake ◽

Glutamate Transport ◽

Activated Macrophages ◽

Glutamate Metabolism ◽

Excitatory Amino Acid Transporter ◽

Hiv Encephalitis

Central nervous system disorders are still a common complication of human immunodeficiency virus (HIV) infection and can lead to dementia and death. They are mostly the consequences of an inflammatory macrophagic activation and relate to glutamate-mediated excitotoxicity. However, recent studies also suggest neuroprotective aspects of macrophage activation through the expression of glutamate transporters and glutamine synthetase. We thus aimed to study whether HIV infection or activation of macrophages could modulate glutamate metabolism in these cells. We assessed the effect of HIV infection on glutamate transporter expression as well as on glutamate uptake by macrophages and showed that glutamate transport was partially decreased in the course of virus replication, whereas excitatory amino acid transporter-2 (EAAT-2) gene expression was dramatically increased. The consequences of HIV infection on glutamine synthetase were also measured and for the first time we show the functional expression of this key enzyme in macrophages. This expression was repressed during virus production. We then quantified EAAT-1 and EAAT-2 gene expression as well as glutamate uptake in differentially activated macrophages and show that the effects of HIV are not directly related to pro- or anti-inflammatory mediators. Finally, this study shows that glutamate transport by macrophages is less affected than what has been described in astrocytes. Macrophages may thus play a role in neuroprotection against glutamate in the infected brain, through their expression of both EAATs and glutamine synthetase. Because glutamate metabolism by activated macrophages is sensitive to both HIV infection and inflammation, it may thus be of potential interest as a therapeutic target in HIV encephalitis.

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Acute Liver Toxicity Modifies Protein Expression of Glutamate Transporters in Liver and Cerebellar Tissue

Frontiers in Neuroscience ◽

10.3389/fnins.2020.613225 ◽

2021 ◽

Vol 14 ◽

Author(s):

Catya Jiménez-Torres ◽

Hoda El-Kehdy ◽

Luisa C. Hernández-Kelly ◽

Etienne Sokal ◽

Arturo Ortega ◽

...

Keyword(s):

Glutamine Synthetase ◽

Liver Toxicity ◽

Excitatory Amino Acid ◽

Glutamate Uptake ◽

Wide Spectrum ◽

Glutamate Transporters ◽

Dependent Manner ◽

Present Contribution ◽

Differential Expression Pattern ◽

The Brain

Glutamate is the main excitatory amino acid acting at the level of pre and postsynaptic neurons, as well as in glial cells. It is involved in the coordinated modulation of energy metabolism, glutamine synthesis, and ammonia detoxification. The relationship between the functional status of liver and brain has been known for many years. The most widely recognized aspect of this relation is the brain dysfunction caused by acute liver injury that manifests a wide spectrum of neurologic and psychiatric abnormalities. Inflammation, circulating neurotoxins, and impaired neurotransmission have been reported in this pathophysiology. In the present contribution, we report the effect of a hepatotoxic compound like CCl4 on the expression of key proteins involved in glutamate uptake and metabolism as glutamate transporters and glutamine synthetase in mice liver, brain, and cerebellum. Our findings highlight a differential expression pattern of glutamate transporters in cerebellum. A significant Purkinje cells loss, in parallel to an up-regulation of glutamine synthetase, and astrogliosis in the brain have also been noticed. In the intoxicated liver, glutamate transporter 1 expression is up-regulated, in contrast to glutamine synthetase which is reduced in a time-dependent manner. Taken together our results demonstrate that the exposure to an acute CCl4 insult, leads to the disruption of glutamate transporters expression in the liver-brain axis and therefore a severe alteration in glutamate-mediated neurotransmission might be present in the central nervous system.

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Glutamate Metabolism in Mitochondria is Closely Related to Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210595 ◽

2021 ◽

pp. 1-22

Author(s):

Jiayi Song ◽

Xuehan Yang ◽

Ming Zhang ◽

Chunyan Wang ◽

Li Chen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Central Nervous System ◽

Important Determinant ◽

Glutamate Uptake ◽

Glutamate Metabolism ◽

Metabolic Balance ◽

Excitatory Neurotransmitter ◽

The Brain

Glutamate is the main excitatory neurotransmitter in the brain, and its excitatory neurotoxicity is closely related to the occurrence and development of Alzheimer’s disease. However, increasing evidence shows that in the process of Alzheimer’s disease, glutamate is not only limited to its excitotoxicity as a neurotransmitter but also related to the disorder of its metabolic balance. The balance of glutamate metabolism in the brain is an important determinant of central nervous system health, and the maintenance of this balance is closely related to glutamate uptake, glutamate circulation, intracellular mitochondrial transport, and mitochondrial metabolism. In this paper, we intend to elaborate the key role of mitochondrial glutamate metabolism in the pathogenesis of Alzheimer’s disease and review glutamate metabolism in mitochondria as a potential target in the treatment of Alzheimer’s disease.

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Nicergoline Enhances Glutamate Uptake via Glutamate Transporters in Rat Cortical Synaptosomes

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.27.817 ◽

2004 ◽

Vol 27 (6) ◽

pp. 817-820 ◽

Cited By ~ 9

Author(s):

Atsushi Nishida ◽

Hiroshi Iwata ◽

Yukitsuka Kudo ◽

Tsutomu Kobayashi ◽

Yuzo Matsuoka ◽

...

Keyword(s):

Glutamate Uptake ◽

Glutamate Transporters

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Hippocampal glutamine synthetase: insensitivity to glucocorticoids and stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.5.e894 ◽

1990 ◽

Vol 258 (5) ◽

pp. E894-E897 ◽

Cited By ~ 1

Author(s):

G. C. Tombaugh ◽

R. M. Sapolsky

Keyword(s):

Skeletal Muscle ◽

Central Nervous System ◽

Nervous System ◽

Glutamine Synthetase ◽

Glutamate Metabolism ◽

Glutamatergic Synapses ◽

Adult Rats ◽

Glucocorticoid Induction ◽

The Central Nervous System ◽

The Brain

Glucocorticoids enhance the neurotoxic potential of several insults to the rat hippocampus that involve overactivation of glutamatergic synapses. These hormones also stimulate the synthesis of glutamine synthetase (GS) in peripheral tissue. Because this enzyme helps regulate glutamate metabolism in the central nervous system, glucocorticoid induction of GS in the brain may underlie the observed synergy. We have measured GS activity in the hippocampus and skeletal muscle (plantaris) of adult rats after bilateral adrenalectomy (ADX), corticosterone (Cort) replacement, or stress. No significant changes in GS were observed in hippocampal tissue, whereas muscle GS was significantly elevated after Cort treatment or stress and was reduced after ADX. These results suggest that Cort-induced shifts in GS activity probably do not explain Cort neurotoxicity, although the stress-induced rise in muscle GS may be relevant to certain types of myopathy.

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Glutamine synthetase gene expression and glutamate transporters in C6-glioma cells

Metabolic Brain Disease ◽

10.1007/s11011-010-9223-9 ◽

2010 ◽

Vol 25 (4) ◽

pp. 413-418 ◽

Cited By ~ 11

Author(s):

Zafeer Baber ◽

Nasrin Haghighat

Keyword(s):

Gene Expression ◽

Glutamine Synthetase ◽

Glioma Cells ◽

Glutamate Transporters ◽

C6 Glioma ◽

C6 Glioma Cells ◽

Glutamine Synthetase Gene

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Mechanisms of Glutamate Transport

Physiological Reviews ◽

10.1152/physrev.00007.2013 ◽

2013 ◽

Vol 93 (4) ◽

pp. 1621-1657 ◽

Cited By ~ 162

Author(s):

Robert J. Vandenberg ◽

Renae M. Ryan

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glutamate Transporter ◽

Glutamate Transporters ◽

Structural Basis ◽

Broad Perspective ◽

Excitatory Neurotransmitter ◽

Brain Functions ◽

Transporter Family ◽

The Central Nervous System

l-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurological disorders. The control of glutamate concentrations is critical to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concentrations to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystallized and its structure determined. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.

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