Inhibition of excitatory neuronal cell death by cell-permeable calcineurin autoinhibitory peptide.
In glutamate-mediated excitatory neuronal cell death, immunosuppressants (FK506, Cys-A) are powerful agents that protect neurons from apoptosis. Immunosuppressants inhibit two types of enzyme, calcium/calmodulin-dependent protein phosphatase (calcineurin: CaN), and peptidyl-prolyl cis-trans-isomerase (PPIase) activity such as the FKBP family. In this study, we used a protein transduction approach to determine the functional role of CaN and to produce a potential therapeutic agent for glutamate-mediated neuronal cell death. We created a novel cell-permeable CaN autoinhibitory peptide using the 11 arginine protein transduction domain. This peptide was highly efficient at transducing into primary culture neurons, potently inhibited CaN phosphatase activities, and inhibited glutamate-mediated neuronal cell death. These results showed that CaN plays an important role in excitatory neuronal cell death and cell-permeable CaN autoinhibitory peptide could be a new drug to protect neurons from excitatory neuronal death.
Terada
Hiroaki
H
Department of Physiology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Matsushita
Masayuki
M
Lu
Yun-Fei
YF
Shirai
Takeshi
T
Li
Sheng-Tian
ST
Tomizawa
Kazuhito
K
Moriwaki
Akiyoshi
A
Nishio
Shinsaku
S
Date
Isao
I
Ohmoto
Takashi
T
Matsui
Hideki
H
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D065095:Calcineurin Inhibitors; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000633:toxicity; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000166:cytology; D008164:Luminescent Proteins / Q000235:genetics; D050778:NFATC Transcription Factors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D009687:Nuclear Proteins; D010455:Peptides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D050778:NFATC Transcription Factors; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid