Research Project
Grant-in-Aid for Scientific Research (C)
Although possible involvement of redox signals, such as nitric oxide (NO) and reactive oxygen species (ROS), in brain functions are suggested in recent studies, the molecular mechanism and functional role of redox modification has yet to be determined. In the present study, we conducted knock-in (KI) mice expressing type 1 ryanodine receptor, a Ca2+ release channel, with Cys-to-Ala mutation. In this mice, NO-dependent S-nitrosylation of RyR1 was inhibited. In addition, cerebellar synaptic plasticity as well as cerebellar-dependent motor learning were also impaired. There results demonstrated that essential role of S-nitrosylation of RyR1 in learning and memory. Furthermore, pretreatment of the cerebellar slices with ROS abolished S-nitrosylation of RyR1 and the resultant activation of the receptor. Taken together, the study proceeds our understanding of biological significance and mode of action of redox signals in brain.
一酸化窒素(NO)や活性酸素(ROS)などのレドックスシグナルは、従来、生活習慣病や老化の主要因の一つとされ、悪玉的役割が注目されてきた。本研究ではNOによるCa2+放出チャネルの化学修飾(S-ニトロシル化)の小脳依存的運動学習への関与が解明され、レドックスシグナルの脳における善玉的作用が示された。これは悪玉因子とされていたレドックスシグナルが善玉的役割をも有することを示す、新規概念の提唱へと繋がる。また、従来よりROSによる生体機能阻害が知られていたが、その分子機構は多くの点で不明であった。今回、ROSによるS-ニトロシル化阻害を介した生体機能阻害が示され、老化の分子機構の一端が解明された。
All 2019 2018 2017 2016 2015
All Journal Article (13 results) (of which Int'l Joint Research: 2 results, Peer Reviewed: 12 results, Open Access: 6 results, Acknowledgement Compliant: 3 results) Presentation (13 results) (of which Int'l Joint Research: 2 results, Invited: 4 results) Book (7 results)
Science signaling
Volume: 12 Issue: 576 Pages: 4847-4847
10.1126/scisignal.aaw4847
Folia Pharmacologica Japonica
Volume: 152 Issue: 5 Pages: 227-232
10.1254/fpj.152.227
130007503088
Volume: 152 Issue: 2 Pages: 84-89
10.1254/fpj.152.84
130007432230
日本薬理学雑誌
Volume: 印刷中
Volume: 150 Pages: 217-217
Volume: 150 Issue: 5 Pages: 234-239
10.1254/fpj.150.234
130006198417
science signaling
Volume: 9 Issue: 428
10.1126/scisignal.aad9055
Scientific Reports
Volume: 6 Issue: 1
10.1038/srep27511
EBioMedicine.
Volume: 11 Pages: 253-261
10.1016/j.ebiom.2016.08.020
International Journal of Molecular Sciences
Volume: 17 Issue: 10 Pages: 1652-1652
10.3390/ijms17101652
120005997697
Volume: 147 Issue: 4 Pages: 194-199
10.1254/fpj.147.194
130005143841
Volume: 147 Issue: 4 Pages: 200-205
10.1254/fpj.147.200
130005143839
FEBS Lett.
Volume: in press Issue: 10 Pages: 1095-1104
10.1016/j.febslet.2015.03.028