Overexpression of PDZ1 domain prevents apoptosis of rat hippocampal neurons induced by kainic acid.
In our previous studies, Tat-GluR6-9c (a glutamate receptor 6 C-terminus peptide fused the TAT protein transduction sequence) not only inhibited the activation of MLK3 (mixed lineage kinase 3) and JNK (c-Jun N-terminal kinase) via the GluR6.PSD-95 (postsynaptic density protein 95).MLK3 signaling module but also diminished neuronal death induced by kainic acid or transient cerebral ischemia in rat hippocampus. Here, we investigate whether overexpression of the PDZ1 domain of PSD-95 protein could suppress the binding of GluR6 with PSD-95 and the activation of MLK3, MKK7 (mitogen-activated kinase kinase 7) and JNK1/2, and rescused neuronal cell death induced by kainic acid. Our results showed that overexpression of the PDZ1 domain of PSD-95 protein could prevent nuclear accumulation and abrogate neuronal cell death in SD (Sprague-Dawley) rat hippocampal neuronal cells. Further studies indicated that overexpression of PDZ1 could inhibit the enhancement of binding of GluR6 to PSD-95 and prevent the activation of MLK3, MKK7 and JNK1/2 induced by kainic acid. Taken together, 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.
Hu
Shu-Qun
SQ
Atherosclerosis Research Center, Nanjing Medical University, Nanjing 210029, China.
Zong
Yan-Yan
YY
Fan
Le-Ming
LM
Zhang
Guang-Yi
GY
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D054731:PDZ Domains / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D018690:Excitatory Amino Acid Agonists; D049452:Green Fluorescent Proteins; D007608:Kainic Acid; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D048055:Mitogen-Activated Protein Kinase 8; D018094:Receptors, Metabotropic Glutamate; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C102719:metabotropic glutamate receptor 7