Abstract
We have recently found that Alzheimer's disease amyloid beta protein (Abeta) activates the extracellular signal-regulated kinase (ERK) and promotes L-glutamate uptake in astrocytes. To elucidate the relationship between the Abeta-induced ERK phosphorylation and promotion of L-glutamate uptake, we investigated the effects of U0126 and PD98059, specific inhibitors of the ERK-activating enzyme MEK, in cultured rat cortical astrocytes. Abeta-induced ERK phosphorylation was completely blocked by the MEK inhibitors, while Abeta-induced promotion of extracellular L-glutamate clearance was enhanced by the presence of the MEK inhibitors. Abeta-induced increase of the glutamate transporter GLAST expression was also enhanced by the presence of MEK inhibitors. The effective concentrations of MEK inhibitors in enhancing Abeta-induced promotion of glutamate clearance and GLAST expression were consistent with those in blocking Abeta-induced ERK phosphorylation. These results suggest that the MEK/ERK signal functions to suppress Abeta-induced upregulation of a glutamate uptake system in astrocytes.
MeSH terms
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Adenosine Monophosphate / analysis
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Amino Acid Transport System X-AG / biosynthesis
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Amino Acid Transport System X-AG / drug effects
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Amyloid beta-Peptides / metabolism*
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Animals
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Animals, Newborn
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Antioxidants / pharmacology
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Astrocytes / drug effects
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Astrocytes / metabolism*
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Blotting, Western
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Butadienes / pharmacology
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Cells, Cultured
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Cerebral Cortex / metabolism
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Cycloheximide / pharmacology
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Electrophoresis, Polyacrylamide Gel
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Enzyme Inhibitors / pharmacology
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Extracellular Space / chemistry
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Flavonoids / pharmacology
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Glutamic Acid / drug effects
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Glutamic Acid / metabolism*
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism*
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Nitriles / pharmacology
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Phosphorylation
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Protein Synthesis Inhibitors / pharmacology
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Rats
Substances
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Amino Acid Transport System X-AG
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Amyloid beta-Peptides
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Antioxidants
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Butadienes
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Enzyme Inhibitors
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Flavonoids
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Nitriles
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Protein Synthesis Inhibitors
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U 0126
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Glutamic Acid
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Adenosine Monophosphate
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Cycloheximide
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Mitogen-Activated Protein Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one