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 Sik1^S577A and Sik2^S587A mice. The homozygous Sik1^S577A mice showed a shorter wake time, longer NREMS time, and higher NREMS delta density than the wild-type mice. The heterozygous and homozygous Sik2^S587A mice showed increased NREMS delta density. Both the Sik1^S577A and Sik2^S587A mice exhibited proper homeostatic regulation of sleep need after sleep deprivation. Despite abundant expression of Sik1 in the suprachiasmatic nucleus, the Sik1^S577A mice showed normal circadian behavior. Although Sik2 is highly expressed in brown adipose tissue, the male and female Sik2^S587A 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.

尽管睡眠是最保守的行为之一，但调节睡眠/觉醒的细胞内机制仍然未知。我们最近确定了一种蛋白激酶SIK3作为睡眠调节分子。缺乏良好保守的蛋白激酶A（PKA）磷酸化位点S551的小鼠表现出更长的非快速眼动（NREM）睡眠，并增加了NREMSδ密度。SIK3的S551在SIK系列的其他成员（例如SIK1（S577）和SIK2（S587））中是保守的。在这里，我们检查了SIK1和SIK2的PKA磷酸化位点是否通过产生Sik1 ^S577A和Sik2 ^S587A小鼠参与睡眠调节。纯合Sik1 ^S577A小鼠表现出比野生型小鼠更短的唤醒时间，更长的NREMS时间和更高的NREMSδ密度。杂合和纯合Sik2 ^S587A小鼠显示出增加的NREMSδ密度。无论是SIK1 ^S577A和SIK2 ^S587A小鼠表现出睡眠剥夺后的睡眠需要适当的稳态调节。尽管Sik1在视交叉上核中大量表达，但Sik1 ^S577A小鼠表现出正常的昼夜节律行为。尽管Sik2在棕色脂肪组织中高度表达，但雄性和雌性Sik2 ^S587A用普通饮食或高脂饮食喂养的小鼠显示出与野生同窝仔猪相似的体重增加。这些结果表明，PKA-SIK信号传导参与睡眠需求的调节。