Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock

Science. 2006 Feb 17;311(5763):1002-5. doi: 10.1126/science.1121613.

Abstract

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 GSK3beta phosphorylates and stabilizes the orphan nuclear receptor Rev-erbalpha, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erbalpha and activation of clock gene Bmal1. A form of Rev-erbalpha that is insensitive to lithium interferes with the expression of circadian genes. Control of Rev-erbalpha protein stability is thus a critical component of the peripheral clock and a biological target of lithium therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ARNTL Transcription Factors
  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biological Clocks / physiology*
  • Cell Line
  • Cell Line, Tumor
  • Circadian Rhythm / physiology*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Lithium Chloride / pharmacology*
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Proteasome Inhibitors
  • Receptors, Cytoplasmic and Nuclear
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Proteasome Endopeptidase Complex
  • Lithium Chloride