The extracellular signal-regulated kinase cascade suppresses amyloid beta protein-induced promotion of glutamate clearance in cultured rat cortical astrocytes

Brain Res. 2003 Jul 25;979(1-2):179-87. doi: 10.1016/s0006-8993(03)02899-3.

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

  • Adenosine Monophosphate / analysis
  • Amino Acid Transport System X-AG / biosynthesis
  • Amino Acid Transport System X-AG / drug effects
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Animals, Newborn
  • Antioxidants / pharmacology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Blotting, Western
  • Butadienes / pharmacology
  • Cells, Cultured
  • Cerebral Cortex / metabolism
  • Cycloheximide / pharmacology
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Inhibitors / pharmacology
  • Extracellular Space / chemistry
  • Flavonoids / pharmacology
  • Glutamic Acid / drug effects
  • Glutamic Acid / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nitriles / pharmacology
  • Phosphorylation
  • Protein Synthesis Inhibitors / pharmacology
  • Rats

Substances

  • Amino Acid Transport System X-AG
  • Amyloid beta-Peptides
  • Antioxidants
  • Butadienes
  • Enzyme Inhibitors
  • Flavonoids
  • Nitriles
  • Protein Synthesis Inhibitors
  • U 0126
  • Glutamic Acid
  • Adenosine Monophosphate
  • Cycloheximide
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one