TY - JOUR
T1 - A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice
AU - Honda, Takato
AU - Fujiyama, Tomoyuki
AU - Miyoshi, Chika
AU - Ikkyu, Aya
AU - Hotta-Hirashima, Noriko
AU - Kanno, Satomi
AU - Mizuno, Seiya
AU - Sugiyama, Fumihiro
AU - Takahashi, Satoru
AU - Funato, Hiromasa
AU - Yanagisawa, Masashiyanagisawa
N1 - Publisher Copyright:
© 2018 Proceedings of the National Academy of Sciences of the United States of America. All rights reserved.
PY - 2018/10/9
Y1 - 2018/10/9
N2 - 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.
AB - 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.
KW - Behavioral genetics
KW - Electroencephalography
KW - Electromyography
KW - Protein kinase
KW - Sleep debt
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U2 - 10.1073/pnas.1810823115
DO - 10.1073/pnas.1810823115
M3 - Article
C2 - 30254177
AN - SCOPUS:85054771281
SN - 0027-8424
VL - 115
SP - 10458
EP - 10463
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -