Regulation
of neuronal signal by protein transduction
Masayuki Matsushita
Department of Physiology, Okayama University Graduate School of Medicine
and Dentistry,
Proteins and peptides have been demonstrated to penetrate across the
plasma membrane of eukaryotic cells by protein transduction domains (PTD). We
show that protein transduction by 11 arginine (11R) is an efficient method of
delivering proteins into the neurons of primary culture and brain slices.
Previously, we showed that PKA inhibitory peptide, fused with 11R and nuclear
localization signal (NLS), delivers the peptide exclusively into the nuclear
compartment of neurons in brain slices. This inhibitory peptide blocked both
CREB phosphorylation and Long-lasting Long-term potentiation (L-LTP) induction
but not Early LTP (E-LTP).In this study, we used 11R protein transduction
domain to create the potential neuroprotective peptides as a therapeutic agent
in excitatory
neuronal cell death.
Of the prime cascade involved in excitatory neuronal death, calcium
signaling throws the NMDA receptor play a critical role. Therefore, we created
the NR2B inhibitor peptide and calcineurin (PP2B) autoinhibitory peptide fused
with 11R. These cell permeable peptides significantly protected culture neuron
from excitatory neuronal cell death. Protein structures of many signaling
molecules will be become available in the near future, so inhibitor peptides of
protein interaction could theoretically be designed.
The cell-permeable inhibitor peptides used in these experiments clearly
shows that a peptide delivery system using poly arginine opens new
possibilities for the development of novel peptide drugs in the form of peptide
therapy.
References
Matsushita, M. et al. A
high-efficiency protein transduction system demonstrating the role of PKA in
long-lasting long-term proteintiation. J.
Neurosci. 21, 6000-6007 (2001).