TY - JOUR
T1 - Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need
AU - Park, Minjeong
AU - Miyoshi, Chika
AU - Fujiyama, Tomoyuki
AU - Kakizaki, Miyo
AU - Ikkyu, Aya
AU - Honda, Takato
AU - Choi, Jinhwan
AU - Asano, Fuyuki
AU - Mizuno, Seiya
AU - Takahashi, Satoru
AU - Yanagisawa, Masashi
AU - Funato, Hiromasa
N1 - Funding Information:
We thank all Y/F lab members and IIIS researchers for kind support and discussion. This work was supported by the World Premier International Research Center Initiative from MEXT to MY, (Grant Number 17H06095 to MY, HF; 16K15187, 17H04023, 17H05583, 25460318, 26507003 to HF), MEXT KAKENHI (Grant Number; 23126526, 25126725, 15H05935 to HF). Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from JSPS to MY, Research grant from Uehara Memorial Foundation, Naito Foundation and Astellas Foundation to HF.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Although sleep is one of the most conserved behaviors, the intracellular mechanism regulating sleep/wakefulness remains unknown. We recently identified a protein kinase, SIK3, as a sleep-regulating molecule. Mice that lack a well-conserved protein kinase A (PKA) phosphorylation site, S551, showed longer non-rapid eye movement (NREM) sleep and increased NREMS delta density. S551 of SIK3 is conserved in other members of the SIK family, such as SIK1 (S577) and SIK2 (S587). Here, we examined whether the PKA phosphorylation sites of SIK1 and SIK2 are involved in sleep regulation by generating Sik1S577A and Sik2S587A mice. The homozygous Sik1S577A mice showed a shorter wake time, longer NREMS time, and higher NREMS delta density than the wild-type mice. The heterozygous and homozygous Sik2S587A mice showed increased NREMS delta density. Both the Sik1S577A and Sik2S587A mice exhibited proper homeostatic regulation of sleep need after sleep deprivation. Despite abundant expression of Sik1 in the suprachiasmatic nucleus, the Sik1S577A mice showed normal circadian behavior. Although Sik2 is highly expressed in brown adipose tissue, the male and female Sik2S587A mice that were fed either a chow or high-fat diet showed similar weight gain as the wild-type littermates. These results suggest that PKA-SIK signaling is involved in the regulation of sleep need.
AB - Although sleep is one of the most conserved behaviors, the intracellular mechanism regulating sleep/wakefulness remains unknown. We recently identified a protein kinase, SIK3, as a sleep-regulating molecule. Mice that lack a well-conserved protein kinase A (PKA) phosphorylation site, S551, showed longer non-rapid eye movement (NREM) sleep and increased NREMS delta density. S551 of SIK3 is conserved in other members of the SIK family, such as SIK1 (S577) and SIK2 (S587). Here, we examined whether the PKA phosphorylation sites of SIK1 and SIK2 are involved in sleep regulation by generating Sik1S577A and Sik2S587A mice. The homozygous Sik1S577A mice showed a shorter wake time, longer NREMS time, and higher NREMS delta density than the wild-type mice. The heterozygous and homozygous Sik2S587A mice showed increased NREMS delta density. Both the Sik1S577A and Sik2S587A mice exhibited proper homeostatic regulation of sleep need after sleep deprivation. Despite abundant expression of Sik1 in the suprachiasmatic nucleus, the Sik1S577A mice showed normal circadian behavior. Although Sik2 is highly expressed in brown adipose tissue, the male and female Sik2S587A mice that were fed either a chow or high-fat diet showed similar weight gain as the wild-type littermates. These results suggest that PKA-SIK signaling is involved in the regulation of sleep need.
UR - http://www.scopus.com/inward/record.url?scp=85085335388&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085335388&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-65647-0
DO - 10.1038/s41598-020-65647-0
M3 - Article
C2 - 32457359
AN - SCOPUS:85085335388
SN - 2045-2322
VL - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 8676
ER -