Nuclear Receptor Rev-erbα Is a Critical Lithium-Sensitive Component of the Circadian Clock

  title={Nuclear Receptor Rev-erb$\alpha$ Is a Critical Lithium-Sensitive Component of the Circadian Clock},
  author={Lei Yin and Jing Wang and Peter S Klein and Mitchell A. Lazar},
  pages={1002 - 1005}
Lithium is commonly used to treat bipolar disorder, which is associated with altered circadian rhythm. Lithium is a potent inhibitor of glycogen synthase kinase 3 (GSK3), which regulates circadian rhythm in several organisms. In experiments with cultured cells, we show here that GSK3β phosphorylates and stabilizes the orphan nuclear receptor Rev-erbα, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erbα and activation of… 
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Nuclear receptor Rev-erbα: up, down, and all around
Lithium differentially affects clock gene expression in serum-shocked NIH-3T3 cells
It is found that lithium significantly increased the expression of Per2 and Cry1, whereas Per3, Cry2, Bmal1, E4BP4 and Rev-Erb-α expression was reduced, and lithium prolonged the period of Per1 and Per2.
Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function.
These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.
Rev-erbalpha2 mRNA encodes a stable protein with a potential role in circadian clock regulation.
It is proposed that the relative expression levels of the two REV-ERBalpha variants fine-tune the circadian period length by regulating REV-, rev-erbalpha1 and alpha2 half-life.


The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.
It is shown that Rev-erbalpha dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human.
Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase‐3 protein expression in the mouse suprachiasmatic nuclei
It is suggested that GSK‐3 plays a role in regulating the period of the mammalian circadian pacemaker by finding an association between the effect of lithium and theperiod of circadian oscillation as well as the level of G SK‐3 protein expression after lithium treatment.
Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila
It is demonstrated that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies, and lithium partially rescues the shortening of circadian period when the GSK-3β gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK -3β as a component in lithium's effect on the circadian oscillator.
Role of the CLOCK protein in the mammalian circadian mechanism.
CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.
Molecular analysis of mammalian circadian rhythms.
Greater understanding of the cellular and molecular mechanisms of the SCN clockwork provides opportunities for pharmacological manipulation of circadian timing.
Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim.
The Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless, and PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box.
CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP.
Evidence is presented that circadian Dbp transcription requires the basic helix-loop-helix-PAS protein CLOCK, an essential component of the negative-feedback circuitry generating circadian oscillations in mammals and fruit flies.
Interacting molecular loops in the mammalian circadian clock.
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