Distinct phosphorylation states of mammalian CaMKIIβ control the induction and maintenance of sleep
Daisuke Tone, Koji L. Ode, Qianhui Zhang, Hiroshi Fujishima, Rikuhiro G. Yamada, Yoshiki Nagashima, Katsuhiko Matsumoto, Zhiqing Wen, Shota Yoshida, Tomoki T. Mitani, Yuki Arisato, Rei-ichiro Ohno, Maki Ukai‐Tadenuma, Junko Yoshida Garçon, Mari Kaneko, Shoi Shi, Hideki Ukai, Kazunari Miyamichi, Takashi Okada, Kenta Sumiyama, Hiroshi Kiyonari, Hiroki R. Ueda
Abstract
The reduced sleep duration previously observed in Camk2b knockout mice revealed a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII)β as a sleep-promoting kinase. However, the underlying mechanism by which CaMKIIβ supports sleep regulation is largely unknown. Here, we demonstrate that activation or inhibition of CaMKIIβ can increase or decrease sleep duration in mice by almost 2-fold, supporting the role of CaMKIIβ as a core sleep regulator in mammals. Importantly, we show that this sleep regulation depends on the kinase activity of CaMKIIβ. A CaMKIIβ mutant mimicking the constitutive-active (auto)phosphorylation state promotes the transition from awake state to sleep state, while mutants mimicking subsequent multisite (auto)phosphorylation states suppress the transition from sleep state to awake state. These results suggest that the phosphorylation states of CaMKIIβ differently control sleep induction and maintenance processes, leading us to propose a "phosphorylation hypothesis of sleep" for the molecular control of sleep in mammals.