Researchers at the University of Pennsylvania School of Medicine discovered that a key receptor protein is a critical component of the internal molecular clock in mammals. What's more, this molecule –called Rev-erb– is sensitive to lithium and may help shed light on circadian rhythm disorders, including bipolar disorder. The findings, which also provide insight into clock-controlled aspects of metabolism, are reported in this week's issue of Science.
"We're interested in the internal control of metabolism because feeding behavior is on a daily cycle, and hormonal activities that regulate this are circadian," says senior author Mitch Lazar, MD, PhD, Director of the Institute for Diabetes, Obesity, and Metabolism at Penn. "Many studies, including those here at Penn, suggest a relationship between the human circadian clock and metabolism. Proteins are the gears of the clock, and not much is known about what regulates protein levels within the cell."
Rev-erb was known to be a key component of the clock that exists in most cells of the body. Rev-erb inhibits clock genes called bmal and clock, but within a normal 24-hour circadian cycle the Rev-erb protein is destroyed within the cell, allowing bmal and other clock proteins to increase. Among other actions, these clock genes cause Rev-erb to increase, which again inhibits bmal and clock. "The time it takes for that to happen determines the length of the cycle–roughly 24 hours–and keeps the clock going," explains Lazar.
Penn colleague and coauthor Peter Klein, MD, PhD, Assistant Professor of Medicine, discovered a few years ago that the drug lithium, used to treat biopolar illness, inhibits GSK3, an enzyme known to regulate circadian rhythm in several animal species. In the present study, the researchers showed that the destruction of Rev-erb, a receptor shown previously by Lazar and others to play a role in maintaining normal metabolism, is prevented by GSK3 in mouse and human cells. "It's like pulling a pin out of the gears of the clock, to allow them to turn in a synchronized manner," says Lazar.
Lithium blocks this action of GSK3, tagging Rev-erb for destruction, which leads to activation of clock genes such as bmal1. "We suggest that just as our cells in the incubator need to have their internal clocks reset, maybe this is what happens in some people with circadian disorders," says Lazar. "One effect of lithium may be to reset clocks that become stuck when Rev-erb levels build up."
These results point to Rev-erb as a lithium-sensitive component of the human clock and therefore a possible target for developing new circadian-disorder drugs. Some patients taking lithium have developed kidney toxicity and other problems. Lazar surmises that new treatments that lead to the destruction of Rev-erb would have the potential of providing another point of entry into the circadian pathway.
Noting that Rev-erb is present in metabolically active tissues, Lazar and his team at the Institute for Diabetes, Obesity, and Metabolism are also interested in the relationship between the control of the circadian clock and metabolic diseases such as obesity and diabetes. "There is a dynamic interplay between circadian rhythms and metabolism," Lazar says. "You don't eat while you are sleeping, and the body needs to take this into account."
Study co-authors are Lei Yin and Jing Wang, both from Penn. The research was funded by the National Institute of Diabetes & Digestive & Kidney Diseases and the National Institute of Mental Health.
This release and a related image can be found at http://www.uphs.upenn.edu/news/
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 called 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 work 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. (Credit: Mitch Lazar, University of Pennsylania School of Medicine)
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