Distinct phosphorylation states of mammalian CaMKIIβ control the induction and maintenance of sleep

The reduced sleep duration previously observed in Camk2b knockout mice revealed a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII)beta as a sleep-promoting kinase. However, the underlying mechanism by which CaMKII beta supports sleep regulation is largely unknown. Here, we demonstrate that activation or inhibition of CaMKII beta can increase or decrease sleep duration in mice by almost 2-fold, supporting the role of CaMKII beta as a core sleep regulator in mammals. Importantly, we show that this sleep regulation depends on the kinase activity of CaMKII beta. A CaMKII beta 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 CaMKII beta differently control sleep induction and maintenance processes, leading us to propose a phosphorylation hypothesis of sleep for the molecular control of sleep in mammals.

Automated summary

This study reveals the important role of CaMKII beta kinase in sleep regulation. Activation or inhibition of this kinase can increase or decrease the duration of sleep in mice. Furthermore, the phosphorylation states of CaMKII beta differently control sleep induction and maintenance processes.