Identification the signaling pathway of a novel sleep regulatory molecule SIK3 protein kinase

• Project/Area Number: 17K15592
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: University of Tsukuba
• Principal Investigator: Ma Jing 筑波大学, 国際統合睡眠医科学研究機構, 研究員 (70793222)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Sleepy / sleep need / sleep / SNIPPs / single prolonged stress / mPFC / PTSD / immunoprecipitation / mass spectrometric / sleep/wakefulness / signal transduction / protein kinase / phosphoproteome / 睡眠覚醒 / 細胞内シグナル伝達系 / リン酸化酵素

Outline of Final Research Achievements

We performed quantitative phosphoproteomic studies of whole mouse brains from two models of sleep/wake perturbation. A combined proteome and phosphoproteome data for 9,410 mouse proteins and 62,384 phosphopeptides were examined. Comparison of two models identifies 80 mostly synaptic Sleep-Need-Index-PhosphoProteins (SNIPPs), whose phosphorylation states closely parallel changes of sleep need. Mutant SLEEPY/SIK3 kinase preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation state of SNIPPs and slow wave activity (SWA) during non-rapid-eye-movement sleep (NREMS), the best known measurable index of sleep need, in both Sleepy and sleep-deprived wild-type mice. Our results suggest that SNIPPs accumulate/dissipate phosphorylation as the molecular substrate of sleep need.

Academic Significance and Societal Importance of the Research Achievements

For the first time, our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and the phosphorylation dephosphorylation cycle of SNIPPs represent a major regulatory mechanism underlies sleep wake homeostasis.

Research Products

• [Journal Article] Hyper-activation of mPFC Underlies Traumatic Stress-Induced Sleep-Wake EEG Disturbances (2020)
  • Author(s): Tingting Lou, Jing Ma, Zhiqiang Wang, Yuka Terakoshi, Chia-Ying Lee, Greg Asher, Liqin Cao, Zhiyu Chen, Katsuyasu Sakurai, Qinghua Liu
  • Journal Title: Frontiers in Neuroscience Volume: In press
  • Peer Reviewed
• [Journal Article] Quantitative phosphoproteomic analysis of the molecular substrates of sleep need (2018)
  • Author(s): Z. Wang, J. Ma, C. Miyoshi, Y. Li, M Sato, Y. Ogawa, T. Lou, C. Ma, X. Gao, C. Lee, T. Fujiyama, X. Yang, S. Zhou, N. Hotta-Hirashima, D. Klewe-Nebenus, A. Ikkyu, M. Kakizaki, S. Kanno, L. Cao, S. Takahashi, J. Peng, Y. Yu, H. Funato, M. Yanagisawa, Q. Liu
  • Journal Title: Nature Volume: 558 Issue: 7710 Pages: 435-439
  • DOI: 10.1038/s41586-018-0218-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantitative phosphoproteomic analysis of the molecular substrates of sleep need (2018)
  • Author(s): Zhiqiang Wang, Jing Ma, Chika Miyoshi, etc.
  • Journal Title: Nature Volume: 印刷中
  • Int'l Joint Research