Abstract
Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system. Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented. Although application of kainic acid imposed the same level of noxious stress, the phosphorylation of c-Jun and the transcriptional activity of the AP-1 transcription factor complex were markedly reduced in the mutant mice. These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis*
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Drug Resistance
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Excitatory Amino Acid Agonists / toxicity*
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Gene Expression / drug effects
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Gene Targeting
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Glutamic Acid / metabolism
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Hippocampus / drug effects
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Hippocampus / enzymology*
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Hippocampus / pathology
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Kainic Acid / toxicity*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinases*
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Neurons / drug effects
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Neurons / enzymology
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Neurons / metabolism
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Phosphorylation
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Protein Kinases / deficiency
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Protein Kinases / genetics
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Protein-Tyrosine Kinases / deficiency
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology*
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Seizures / chemically induced
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Signal Transduction
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Transcription Factor AP-1 / metabolism
Substances
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Excitatory Amino Acid Agonists
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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Transcription Factor AP-1
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Glutamic Acid
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Protein Kinases
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Mitogen-Activated Protein Kinase 10
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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Kainic Acid