Abstract
Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6.PSD-95.MLK3 signaling module and subsequent JNK activation. In our previous studies, we demonstrated the neuroprotective role of a GluR6 c-terminus containing peptide against KA or cerebral ischemia-induced excitotoxicity in vitro and in vivo. Here, we first report that overexpression of the PDZ1 domain of PSD-95 protein exerts a protective role against neuronal death induced by cerebral ischemia-reperfusion in vivo and can prevent neuronal cell death induced by oxygen-glucose deprivation. Further studies show that overexpression of PDZ1 can perturb the interaction of GluR6 with PSD-95 and suppress the assembly of the GluR6.PSD-95.MLK3 signaling module and therefore inhibit JNK activation. Thus, it not only inhibits phosphorylation of c-Jun and down-regulates Fas ligand expression but also inhibits phosphorylation of 14-3-3 and decreases Bax translocation to mitochondria, decreases the release of cytochrome c, and decreases caspase-3 activation. Overall, the essential role of the PDZ1 domain of PSD-95 in apoptotic cell death in neurons provides an experimental foundation for gene therapy of neurodegenerative diseases with overexpression of the PDZ1 domain.
Copyright 2009 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Blotting, Western
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Cell Death / genetics
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Cell Fractionation
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Cell Line
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Cells, Cultured
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Cytochromes c / metabolism
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Disks Large Homolog 4 Protein
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GluK2 Kainate Receptor
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Glucose / deficiency
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Hippocampus / metabolism*
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Hippocampus / pathology
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Humans
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Hypoxia / genetics
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Hypoxia / metabolism
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Immunohistochemistry
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In Situ Nick-End Labeling
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mitochondria / genetics
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Mitochondria / metabolism
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Neurons / metabolism*
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Neurons / pathology
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Phosphorylation / genetics
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Protein Transport / genetics
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Rats
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Rats, Sprague-Dawley
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Receptors, Kainic Acid / metabolism
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Reperfusion Injury / genetics
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Reperfusion Injury / metabolism*
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Reperfusion Injury / pathology
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Signal Transduction / physiology
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Subcellular Fractions / metabolism
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Subcellular Fractions / pathology
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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DLG4 protein, human
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Disks Large Homolog 4 Protein
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, Kainic Acid
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bcl-2-Associated X Protein
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Cytochromes c
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JNK Mitogen-Activated Protein Kinases
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Glucose