Abstract
Glutamate induces gene transcription in numerous physiological and pathological conditions. Among the glutamate-responsive transcription factors, NF-kappaB has been mainly implicated in neuronal survival and death. Recent data also suggest a role of NF-kappaB in neural development and memory formation. In non-neuronal cells, degradation of the inhibitor IkappaBalpha represents a key step in NF-kappaB activation. However, little is known of how glutamate activates NF-kappaB in neurons. To investigate the signalling cascade involved we used primary murine cerebellar granule cells. Glutamate induced a rapid reduction of IkappaBalpha levels and nuclear translocation of the NF-kappaB subunit p65. The glutamate-induced reduction of IkappaBalpha levels was blocked by the N-methyl-d-aspartate inhibitor MK801. Specific inhibitors of the proteasome, caspase 3, and the phosphoinositide 3-kinase had no effect on glutamate-induced IkappaBalpha degradation. However, inhibition of the glutamate-activated Ca2+-dependent protease calpain by calpeptin completely blocked IkappaBalpha degradation and reduced the nuclear translocation of p65. Calpeptin also partially blocked glutamate-induced cell death. Our data indicate that the Ca2+-dependent protease calpain is involved in the NF-kappaB activation in neurons in response to N-methyl-d-aspartate receptor occupancy by glutamate. NF-kappaB activation by calpain may mediate the long-term effects of glutamate on neuron survival or memory formation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Animals, Newborn
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Calpain / antagonists & inhibitors
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Calpain / metabolism*
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Cell Death / drug effects
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Cell Death / physiology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cerebellar Cortex / cytology
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Cerebellar Cortex / drug effects
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Cerebellar Cortex / metabolism
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Dipeptides / pharmacology
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Glutamic Acid / metabolism*
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Glutamic Acid / pharmacology
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I-kappa B Proteins / drug effects
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I-kappa B Proteins / metabolism
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Immunohistochemistry
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Memory / physiology
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Mice
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Nervous System / cytology
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Nervous System / growth & development
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Nervous System / metabolism
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Neurons / drug effects
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Neurons / metabolism*
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Protein Subunits / drug effects
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Protein Subunits / metabolism
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Receptors, N-Methyl-D-Aspartate / drug effects
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Receptors, N-Methyl-D-Aspartate / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
Substances
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Dipeptides
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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I-kappa B Proteins
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NF-kappa B
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Nfkbia protein, mouse
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Protein Subunits
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Receptors, N-Methyl-D-Aspartate
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NF-KappaB Inhibitor alpha
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calpeptin
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Glutamic Acid
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Calpain