Distinct phosphorylation states of mammalian CaMKIIβ control the induction and maintenance of sleep

PLoS Biol. 2022 Oct 4;20(10):e3001813. doi: 10.1371/journal.pbio.3001813. eCollection 2022 Oct.


The reduced sleep duration previously observed in Camk2b knockout mice revealed a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII)β as a sleep-promoting kinase. However, the underlying mechanism by which CaMKIIβ supports sleep regulation is largely unknown. Here, we demonstrate that activation or inhibition of CaMKIIβ can increase or decrease sleep duration in mice by almost 2-fold, supporting the role of CaMKIIβ as a core sleep regulator in mammals. Importantly, we show that this sleep regulation depends on the kinase activity of CaMKIIβ. A CaMKIIβ mutant mimicking the constitutive-active (auto)phosphorylation state promotes the transition from awake state to sleep state, while mutants mimicking subsequent multisite (auto)phosphorylation states suppress the transition from sleep state to awake state. These results suggest that the phosphorylation states of CaMKIIβ differently control sleep induction and maintenance processes, leading us to propose a "phosphorylation hypothesis of sleep" for the molecular control of sleep in mammals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium* / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2* / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2* / metabolism
  • Mammals / metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Sleep


  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium

Grants and funding

This work was supported by grants from the Brain/MINDS JP20dm0207049, Science and Technology Platform Program for Advanced Biological Medicine JP21am0401011, AMED-CREST 18gm0610006h0006 (to H.R.U.) (Japan Agency for Medical Research and Development: https://www.amed.go.jp/en/index.html), Grant-in-Aid for Scientific Research (S) JP18H05270 (JSPS KAKENHI) (to H.R.U.) and Scientific Research (C) JP20K06576 (JSPS KAKENHI) (to K.L.O.), Grant-in-Aid for Early-Career Scientists JP19K16115 (JSPS KAKENHI) (to D.T.) (Japan Society for the Promotion of Science: https://www.jsps.go.jp/english/index.html), HFSP Research Grant Program RGP0019/2018 (Human Frontier Science Program: https://www.hfsp.org/) (to H.R.U.), ERATO JPMJER2001 (Japan Science and Technology Agency: https://www.jst.go.jp/EN/) (to H.R.U.), MEXT Quantum Leap Flagship Program (MEXT QLEAP) JPMXS012033064 (Japan Science and Technology Agency: https://www.jst.go.jp/stpp/q-leap/en/index.html) (to H.R.U.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.