共查询到20条相似文献,搜索用时 750 毫秒
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Ramírez-Sotelo G López-Bayghen E Hernández-Kelly LC Arias-Montaño JA Bernabé A Ortega A 《Neurochemical research》2007,32(1):73-80
Appropriate removal of l-glutamate from the synaptic cleft is important for prevention of the excitotoxic effects of this neurotransmitter. The Na+-dependent glutamate/aspartate transporter GLAST is regulated in the short term, by a transporter-dependent decrease in uptake
activity while in the long term, a receptor’s-dependent decrease in GLAST protein levels leads to a severe reduction in glutamate
uptake. The promoter region of the mouse glast gene harbors an Activator Protein-1 site (AP-1). To gain insight into the molecular mechanisms triggered by Glu-receptors
activation involved in GLAST regulation, we took advantage of the neonatal mouse cerebellar prisms model. We characterized
the glutamate uptake activity; the glutamate-dependent effect on GLAST protein levels and over the interaction of nuclear
proteins with a mouse glast promoter AP-1 probe. A time and dose dependent decrease in transporter activity matching with a decrease in GLAST levels
was recorded upon glutamate treatment. Moreover, a significant increase in glast AP-1 DNA binding was found. Pharmacological experiments established that both effects are mediated through α-amino-3-hydroxy-5-methyl-4-isoxazole
propionate receptors, favoring the notion of the critical involvement of glutamate in the regulation of its binding partners:
receptors and transporters. 相似文献
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In the central nervous system (CNS), extracellular concentrations of amino acids (e.g., aspartate, glutamate) and divalent metals (e.g., zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate homeostasis and control over extracellular concentrations of these excitotoxic amino acids are essential for the normal functioning of the brain. Not only is glutamate of central importance for nitrogen metabolism but, along with aspartate, it is the primary mediator of excitatory pathways in the brain. Similarly, the maintenance of proper Mn levels is important for normal brain function. Brain glutamate is removed from the extracellular fluid mainly by astrocytes via high affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). The effects of Mn on specific glutamate transporters have yet to be determined. As a first step in this process, we examined the effects of Mn on the transport of [D-2, 3-3H]D-aspartate, a non-metabolizable glutamate analog, in Chinese hamster ovary cells (CHO) transfected with two glutamate transporter subtypes, GLAST (EAAT1) or GLT-1 (EAAT2). Mn-mediated inhibition of glutamate transport in the CHO-K1 cell line DdB7 was pronounced in both the GLT-1 and GLAST transfected cells. This resulted in a statistically significant inhibition (p<0.05) of glutamate uptake compared with transfected control in the absence of Mn treatment. These studies suggest that Mn accumulation in the CNS might contribute to dysregulation of glutamate homeostasis. 相似文献
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Neuronal Soluble Factors Differentially Regulate the Expression of the GLT1 and GLAST Glutamate Transporters in Cultured Astroglia 总被引:10,自引:5,他引:5
Georgi Gegelashvili Niels Christian Danbolt Arne Schousboe 《Journal of neurochemistry》1997,69(6):2612-2615
Abstract: The glutamate transporters in the plasma membranes of neural cells secure termination of the glutamatergic synaptic transmission and keep the glutamate levels below toxic concentrations. Astrocytes express two types of glutamate transporters, GLAST (EAAT1) and GLT1 (EAAT2). GLT1 predominates quantitatively and is responsible for most of the glutamate uptake activity in the juvenile and adult brain. However, GLT1 is severely down-regulated in amyotrophic lateral sclerosis, a progressive neurodegenerative disease. Furthermore, selective loss of this transporter occurs in cultured astroglia. Expression of GLAST, but not of GLT1, seems to be regulated via the glutamate receptor signalling. The present study was undertaken to examine whether neuronal factors, other than glutamate, influence the expression of astroglial glutamate transporters. The expression of GLT1 and GLAST was examined in primary cultures of cerebellar granule neurons, cortical neurons, and astrocytes under different experimental conditions, including those that mimic neuron-astrocyte interactions. Pure astroglial cultures expressed only GLAST, whereas astrocytes grown in the presence of neurons expressed both GLAST (at increased levels) and GLT1. The induction of GLT1 protein and its mRNA was reproduced in pure cortical astroglial cultures supplemented with conditioned media from cortical neuronal cultures or from mixed neuron-glia cultures. This treatment did not change the levels of GLAST. These results suggest that soluble neuronal factors differentially regulate the expression of GLT1 and GLAST in cultured astroglia. Further elucidation of the molecular nature of the secreted neuronal factors and corresponding signalling pathways regulating the expression of the astroglial glutamate transporters in vitro may reveal mechanisms important for the understanding and treatment of neurological diseases. 相似文献
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Mutkus L Aschner JL Syversen T Shanker G Sonnewald U Aschner M 《Biological trace element research》2006,109(3):267-280
Glutamate is removed mainly by astrocytes from the extracellular fluid via high-affinity astroglial Na+-dependent excitatory amino acid transporters, glutamate/aspartate transporter (GLAST), and glutamate transporter-1 (GLT-1).
Mercuric chloride (HgCl2) is a highly toxic compound that inhibits glutamate uptake in astrocytes, resulting in excessive extracellular glutamate
accumulation, leading to excitotoxicity and neuronal cell death. The mechanisms associated with the inhibitory effects of
HgCl2 on glutamate uptake are unknown. This study examines the effects of HgCl2 on the transport of 3H-d-aspartate, a nonmetabolizable glutamate analog, using Chinese hamster ovary cells (CHO) transfected with two glutamate transporter
subtypes, GLAST (EAAT1) and GLT-1 (EAAT2), as a model system. Additionally, studies were undertaken to determine the effects
of HgCl2 on mRNA and protein levels of these transporters. The results indicate that (1) HgCl2 leads to significant (p<0.001) inhibition of glutamate uptake via both transporters, but is a more potent inhibitor of glutamate transport via GLAST
and (2) the effect of HgCl2 on inhibition of glutamate uptake in transfected CHO cells is not associated with changes in transporter protein levels despite
a significant decrease in mRNA expression; thus, (3) HgCl2 inhibition is most likely related to its direct binding to the functional thiol groups of the transporters and interference
with their uptake function. 相似文献
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Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics 总被引:1,自引:0,他引:1
Kim K Lee SG Kegelman TP Su ZZ Das SK Dash R Dasgupta S Barral PM Hedvat M Diaz P Reed JC Stebbins JL Pellecchia M Sarkar D Fisher PB 《Journal of cellular physiology》2011,226(10):2484-2493
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Rodriguez-Kern A Gegelashvili M Schousboe A Zhang J Sung L Gegelashvili G 《Neurochemistry international》2003,43(4-5):363-370
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Mutkus L Aschner JL Syversen T Shanker G Sonnewald U Aschner M 《Biological trace element research》2005,105(1-3):71-86
Thimerosal, also known as thimersal, Merthrolate, or sodiumethyl-mercurithiosalicylate, is an organic mercurial compound that
is used in a variety of commercial as well as biomedical applications. As a preservative, it is used in a number of vaccines
and pharmaceutical products. Its active ingredient is ethylmercury. Both inorganic and organic mercurials are known to interfere
with glutamate homeostasis. Brain glutamate is removed mainly by astrocytes from the extracellular fluid via high-affinity
astroglial Na+-dependent excitatory amino acid transporters, glutamate/ aspartats transporter (GLAST) and glutamate transporter-1 (GLT-1).
The effects of thimerosal on glutamate homeostasis have yet to be determined. As a first step in this process, we examined
the effects of thimerosal on the transport of [3H]-D-aspartate, a nonmetabolizable glutamate analog, in Chinese hamster ovary (CHO) cells transfected with two glutamate transporter
subtypes, GLAST (EAAT1) and GLT-1 (EAAT2). Additionally, studies were undertaken to determine the effects of thimerosal on
mRNA and protein levels of these transporters. The results indicate that thimerosal treatment caused significant but selective
changes in both glutamate transporter mRNA and protein expression in CHO cells. Thimerosal-mediated inhibition of glutamate
transport in the CHO-K1 cell line DdB7 was more pronounced in the GLT-1-transfected cells compared with the GLAST-transfected
cells. These studies suggest that thimerosal accumulation in the central nervous system might contribute to dysregulation
of glutamate homeostasis. 相似文献