The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1

Abstract

Mounting evidence suggests that PERIOD (PER) proteins play a central role in setting the speed (period) and phase of the circadian clock. Pharmacological and genetic studies have shown that changes in PER phosphorylation kinetics are associated with changes in circadian rhythm period and phase, which can lead to sleep disorders such as Familial Advanced Sleep Phase Syndrome in humans. We and others have shown that casein kinase 1δ and ε (CK1δ/ε) are essential PER kinases, but it is clear that additional, unknown mechanisms are also crucial for regulating the kinetics of PER phosphorylation. Here we report that circadian periodicity is determined primarily through PER phosphorylation kinetics set by the balance between CK1δ/ε and protein phosphatase 1 (PP1). In CK1δ/ε-deficient cells, PER phosphorylation is severely compromised and nonrhythmic, and the PER proteins are constitutively cytoplasmic. However, when PP1 is disrupted, PER phosphorylation is dramatically accelerated; the same effect is not seen when PP2A is disrupted. Our work demonstrates that the speed and rhythmicity of PER phosphorylation are controlled by the balance between CK1δ/ε and PP1, which in turn determines the period of the circadian oscillator. Thus, our findings provide clear insights into the molecular basis of how the period and phase of our daily rhythms are determined.dynamic regulation of phosphorylation | stoichiometry | period determination

Circadian Typology: A Comprehensive Review

“…For PER3, these polymorphisms are hypothesised to affect the promoter-driven gene expression levels of PER3 , or are hypothesised to alter the phosphorylation state of the PER3 protein by removal of potential Casein Kinase I (CKI) phosphorylation sites (Archer et al, 2003;Ebisawa et al, 2001). The latter is important because studies have shown that changes to the phosphorylation levels of PER protein can change circadian period (Lee et al, 2011). In addition, familial mutations in PER2 (Toh et al, 2001) and CKI (Xu et al, 2005) have been linked with advanced sleep phase disorder (ASPD) where it has been shown that greatly advanced circadian rhythms and sleep timing are due to changes in phosphorylation of PER protein.…”

A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention

“…1). Per1 must be phosphorylated by CK1-␦/ε to enter the nucleus (20). We (30,31) have previously shown that pharmacological inhibition of CK1-␦/ε using PF-670462 recapitulated the effects of Per1 knockdown, including increased levels of Cry2, decreased ␣-ENaC mRNA and protein expression, and, importantly, decreased ENaC channel activity.…”

The intricate dance of post-translational modifications in the rhythm of life

“…Transitions between the phosphorylated and dephosphorylated states can thus be important switches regulating biological activities (for example, switching transcription from on to off). In mammals, phosphoprotein phosphatase 1 (PPP1) dephosphorylates PER proteins, thereby antagonizing CKI-mediated PER degradation 15,51,52 (Fig. 2, state 2 to state 1).…”