Phosphorylation Hypothesis of Sleep

Abstract

Sleep is a fundamental property conserved across species. The homeostatic induction of sleep indicates the presence of a mechanism that is progressively activated by the awake state and that induces sleep. Several lines of evidence support that such function, namely, sleep need, lies in the neuronal assemblies rather than specific brain regions and circuits. However, the molecular mechanism underlying the dynamics of sleep need is still unclear. This review aims to summarize recent studies mainly in rodents indicating that protein phosphorylation, especially at the synapses, could be the molecular entity associated with sleep need. Genetic studies in rodents have identified a set of kinases that promote sleep. The activity of sleep-promoting kinases appears to be elevated during the awake phase and in sleep deprivation. Furthermore, the proteomic analysis demonstrated that the phosphorylation status of synaptic protein is controlled by the sleep-wake cycle. Therefore, a plausible scenario may be that the awake-dependent activation of kinases modifies the phosphorylation status of synaptic proteins to promote sleep. We also discuss the possible importance of multisite phosphorylation on macromolecular protein complexes to achieve the slow dynamics and physiological functions of sleep in mammals.

Keywords: CaMKII; NREM sleep; kinase; phosphorylation; proteomics.

FIGURE 1

Genetic and phosphoproteomics approach to investigate the role of protein phosphorylation in the regulation of sleep. Genetic manipulation to either increase or decrease the kinase activity tests the causal effect of kinase activity on the animals’ sleep control. It would be valuable to evaluate whether the up- and downregulation of the same kinase activity affects the animals’ sleep phenotype bidirectionally. Although such kinase activity is not fully established, this criterion would discriminate whether the kinase activity serves as an external input to the core homeostatic process or if the kinase is involved in the core component of sleep homeostasis. Phosphoproteomics analysis provides complementary information to evaluate whether the kinases’ activity correlates with the expected sleep pressure in vivo. Note that this figure depicts the case of sleep-promoting kinases; when the kinases serve as a wake-promoting factor, the relationship between enzyme activity and sleep phenotype would be the opposite direction (i.e., loss of wake-promoting kinase would result in the increased sleep duration).

FIGURE 2

Posttranscriptional, posttranslational, and protein phosphorylation shape the daily rhythmicity of protein action. Daily rhythmicity of mRNA and protein abundance is created not only by the timing of transcription initiation but also through multiple layers of posttranscriptional and posttranslational regulation. The continuous elevation of sleep pressure predominantly attenuates the rhythmicity observed in protein and phospho-protein abundance at the synapse.

FIGURE 3

Phosphorylation hypothesis of molecular sleepiness. Sleep-promoting kinases may play important roles in integrating several signals that affect sleep-wake dynamics. The activities of sleep-promoting kinases, in turn, may affect sleep-wake dynamics as well as physiological functions associated with neural activity.

FIGURE 4

Three properties that the central factor responsible for sleep homeostasis should have. If sleep-promoting kinases compose a core mechanism of sleep homeostasis, first, the dynamics of kinase activity would correspond to the level of sleep need. Second, the kinase activity would be directly or indirectly regulated by circadian clocks as an interface of sleep homeostasis and circadian clocks. Third, the kinase activities may mediate various external signals to affect the arousal state of animals.