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Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10458-10463. doi: 10.1073/pnas.1810823115. Epub 2018 Sep 25.

A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice.

Author information

1
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 305-8575 Tsukuba, Japan.
2
PhD Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 305-8575 Tsukuba, Japan.
3
Laboratory Animal Resource Center, University of Tsukuba, 305-8575 Tsukuba, Japan.
4
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 305-8575 Tsukuba, Japan; funato.hiromasa.km@u.tsukuba.ac.jp yanagisawa.masa.fu@u.tsukuba.ac.jp.
5
Department of Anatomy, Faculty of Medicine, Toho University, 143-8540 Tokyo, Japan.
6
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
7
Life Science Center for Survival Dynamics (TARA), University of Tsukuba, 305-8575 Tsukuba, Japan.

Abstract

Sleep is an evolutionally conserved behavior from vertebrates to invertebrates. The molecular mechanisms that determine daily sleep amounts and the neuronal substrates for homeostatic sleep need remain unknown. Through a large-scale forward genetic screen of sleep behaviors in mice, we previously demonstrated that the Sleepy mutant allele of the Sik3 protein kinase gene markedly increases daily nonrapid-eye movement sleep (NREMS) amounts and sleep need. The Sleepy mutation deletes the in-frame exon 13 encoding a peptide stretch encompassing S551, a known PKA recognition site in SIK3. Here, we demonstrate that single amino acid changes at SIK3 S551 (S551A and S551D) reproduce the hypersomnia phenotype of the Sleepy mutant mice. These mice exhibit increased NREMS amounts and inherently increased sleep need, the latter demonstrated by increased duration of individual NREMS episodes and higher EEG slow-wave activity during NREMS. At the molecular level, deletion or mutation at SIK3 S551 reduces PKA recognition and abolishes 14-3-3 binding. Our results suggest that the evolutionally conserved S551 of SIK3 mediates, together with PKA and 14-3-3, the intracellular signaling crucial for the regulation of daily sleep amounts and sleep need at the organismal level.

KEYWORDS:

behavioral genetics; electroencephalography; electromyography; protein kinase; sleep debt

PMID:
30254177
PMCID:
PMC6187192
[Available on 2019-04-09]
DOI:
10.1073/pnas.1810823115
[Indexed for MEDLINE]

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