The GSK3-Rev-erb pathway that controls the internal clock. Rev-erb is a key component of the clock that exists in most cells of the body. It inhibits the clock gene Bmal1, which in turn increases Rev-erb, such that within a normal 24-hour circadian cycle the levels of Rev-erb and Bmal oscillate within the cell. Lithium inhibits GSK3, which is an enzyme known to regulate circadian rhythm by a previously unknown mechanism. The present study shows that GSK3 normally blocks destruction of the Rev-erb protein. By inhibiting GSK3, lithium tags Rev-erb for destruction, which leads to the activation of clock genes such as bmal1 and gets the clock going.

Image Credit: Mitch Lazar, MD, PhD, University of Pennsylania School of Medicine