Proteins that control sleep and wakefulness transitions

Professor Hiroki Ueda, Assistant Professor Daisuke Tone, and Koji Ode of the University of Tokyo demonstrated that CaMKIIβ(¹⁾ is a protein kinase mainly expressed in neurons that participates in prolonging sleep time
by promoting sleep onset and inhibiting wakefulness.

Several recent studies have shown that protein phosphorylation ⁽²⁾ is important
for sleep regulation.
In 2016, the group reported that CaMKIIα and CaMKIIβ are protein kinases that promote sleep, proposed that protein phosphorylation may be a molecular driver of sleepiness, and proposed the "sleep phosphorylation hypothesis"
.
CaMKIIα and CaMKIIβ are abundantly expressed in brain nerve cells and play an important role
in functions such as memory.
But the role and conditions of CaMKIIα and CaMKIIβ in sleep control are unclear
.

As we all know, CaMKIIβ has multiple phosphorylation sites, and its function is regulated by the phosphorylation state of its phosphorylation sites ^(3).
As a result, our group produced a series of CaMKIIβ mutants
.
To this end, mutant residues mimicking phosphorylation state are introduced at each site, and mice are used to comprehensively study the relationship between
CaMKIIβ phosphorylation state and sleep regulation.
The researchers found that in a specific phosphorylated state, CaMKIIβ facilitated the transition
from a waking state to a sleep state.
Furthermore, when CaMKIIβ is introduced into a second or third similar phosphorylated variant in this specific phosphorylated state, the transition from sleep to wakefulness is inhibited
.

In the current study, they found that CaMKIIβ plays a role at each step in the multi-step process of extending sleep duration (inducing and maintaining sleep), depending on its phosphorylation status
.
Many existing hypnotics act on the steps
of inducing sleep.
The study shed some light on the mechanisms of sleep induction and maintenance and provided clues to consider more ideal sleep control methods to maintain sleep, which has been difficult
.

The result is part of
the JST Advanced Technology Exploratory Research (ERATO) of the Ueda Biological Timing Program.
In this project, JST developed an approach based on "systems biology that contributes to human understanding," using sleep-wake rhythms as a model
.
The aim is to obtain information about "biological timing," extending from molecules to individuals, in terms
of the human sleep-wake cycle.

< glossary ><>

(1) CaMKII

Ca2⁺/calmodulin-dependent protein kinase II
.
It is abundant in nerve cells and is bound
by calcium-activated ²⁺/calmodulin.
α, β, δ and γ isoforms are known, and these subunits form 12-polymer
.
In addition to phosphorylating other proteins as kinases, they also regulate the activity
of nerve cells by forming complexes with various proteins.
Phosphorylation is known to occur, specifically on
serine, threonine, and tyrosine residues in the 20 amino acids that make up proteins.
Among them, CaMKII phosphorylation
occurs at serine and threonine.

(2) Phosphorylation

In the body, proteins are produced as genes are transcribed and translated, and can subsequently undergo chemical modifications
that regulate their function.
Among them, phosphorylation is a post-translational modification
that occurs in most proteins.

(3) Self-phosphorylation

Kinases phosphorylate other proteins, but they may also phosphorylate and modify themselves
.
This is called autophosphorylation
.
This is a convenient feedback control mechanism because the function of the kinase itself can be controlled
by the action of the kinase.
There are several sites in CaMKIIβ that are modified by autophosphorylation
.