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