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

Yin L, Wang J, Klein PS, Lazar MA

Division of Endocrinology, Diabetes, and Metabolism, and University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.

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.

Published 17 February 2006 in Science, 311(5763): 1002-5.
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