L1 - SLEEP: P- HYPOTHESIS OF SLEEP. Ode et al. 2020. Frontiers Psychol Flashcards
1
Q
P-dependent control of the sleep-wake cycle - intro
A
- researchers are conducting genetic studies to identify candidate genes in the molecular signalling pathway responsible for sleep homeostasis control in mammals
- want to find genetic manipualtiosn that alter animal’s baseline sleep duration, SWA, and response to sleep deprivation –> validating whether candidate gene product controls sleep involves confirming changes in activity of candidate protein in sleep-wake cycle or sleep-deprived state
- recent studies highlight the importance of kinases in inducing sleep; investigations also focus in the P state of kinases along w/ sleep-wake cycle
2
Q
CAMKIIa/b (calcium/calmodulin dependent protein kinase)
A
- identified as a sleep-promoting kinase through reverse genetic screening in mice using CRISPR/Cas9
- KO of CAMKIIa/b in embryos = significant decrease in sleep duration –> suggests role in promoting sleep, but specific role needs further clarification
- both isoforms are expressed in neurons & atrocytes
- CAMKII has a unique self-regulatory mechanism involving auto-P at T286/287 which keeps the kinase active even in the absence of calcium/ calmodulin
- studies show increased P at T286/287 after sleep deprivation or during awake/dark phase, suggesting upregulation of CAMKII activity during increases sleep need conditions
- CAMKII is known for its crucial role in synaptic plasticity, with auto-P at multiple residues regulating synaptic strength; the specific roles of these auto-P events in regulating sleep duration remains unknown
3
Q
SIK3 (salt-inducible kinase 3)
A
- sleep promoting kinase in mammals –> discovered through large scale forward genetic screening, identifying the “sleepy” mutant w/ prolonged NREMS, due to exon skipping of SIK3 (suggested its a gain of function mutation in SIK3)
- SIK3 activity is regulated by P –> CRISPR-mediated mutagenesis confirmed role of this P-site (particularly S551) in promoting NREMS
- similar mutations in other SIK family proteins also promoted NREMS, suggesting a conserved role in sleep regulation across species; however, the exact role of S551 remains unclear
- C. elegans & drosophila support the sleep-promoting role of SIK3, further highlighting its evolutionary conservation
- however, further studies, incl SIK3 KO are needed to clarify the role of SIK3 and its P-dependent regulation in sleep duration
4
Q
ERK (extracellular-signal-regulated kinase)
A
- sleep-promoting kinase, initially observed in drosophila, where active form of ERK increases sleep duration, and ERK inhibition reduces sleep
- embryonic mice KO & conditional KO of ERK2 in cortical neurons, both lead to decreased NREMS
- administration of ERK inhibitors also decreases NREMS
- P ERK1/2 levels are higher in arousal state than NREMS
5
Q
the P hypothesis
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- kinase-centric view of sleep need –> suggesting that protein activities modified by P serve as a molecular signature of sleep need
- overall, sleep-promoting kinases serve as key molecules linking cellular signalling pathways to the induction of sleep
- the regulation of different timescales in sleep control presents a challenge, as P occurs rapidly, but accumulation of sleep happens more slowly
- multi-site P, a core mechanism of ERK & SIK3, may encode slower dynamics by creating time delays and altering protein structures
- circadian clock proteins like PER & FRQ undergo progessive multisite P within a 24-hr period, suggesting that P dynamics can act as a timer for biological processes
- in the context of sleep control, identifying critical substrate proteins & P residues for sleep-promoting kinases is crucial
- the kinases likely affect neuronal firing patterns, possibly through modulating ion channels & pumps in the cortex
- they may directly influence neuronal excitability by modulating enzymatic & cellular transport systems that control neurotransmitter levels
6
Q
conclusion - P hypothesis
A
- CAMKII, SIK3, ERK, have been identified as sleep-inducing kinases through genetic analyses
- phosphoproteomic investigations have revealed that the P status of synaptic proteins is strongly influenced by the sleep-wake cycle
- P hypothesis proposes that protein P plays a key role in sleep regulation
- while primarily investigated in mouse models, the conservation of protein P across species suggests that this hypothesis may apply to sleep regulation in other organisms incl. humans