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

Significance The neural substrate for “sleepiness,” as well as the molecular mechanisms determining daily sleep amounts, remain mysterious. Here, we found that a single amino acid, S551, of the protein kinase SIK3 has a crucial role in the regulation of sleep need and daily nonrapid-eye movement sleep amounts. Importantly, S551 in SIK3 is evolutionally conserved as a PKA phosphorylation site from nematodes and fruit flies to mice and humans. These findings implicate SIK3 in the molecular basis of homeostatic sleep/wake regulation. 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.