The extracellular signal-regulated kinase cascade suppresses amyloid beta protein-induced promotion of glutamate clearance in cultured rat cortical astrocytes.
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.
Abe
Kazuho
K
Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, 142-8501, Tokyo, Japan. abe@hoshi.ac.jp
Misawa
Miwa
M
D000249:Adenosine Monophosphate / Q000032:analysis; D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000737:chemistry; D005419:Flavonoids / Q000494:pharmacology; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats
D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; D011500:Protein Synthesis Inhibitors; C113580:U 0126; D018698:Glutamic Acid; D000249:Adenosine Monophosphate; D003513:Cycloheximide; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one