Clock molecule’s sensitivity to lithium sheds light on bipolar disorder

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.

Media Contact

Karen Kreeger EurekAlert!

Further information:

http://www.uphs.upenn.edu

All news from this category: Life Sciences

Articles and reports from the Life Sciences area deal with applied and basic research into modern biology, chemistry and human medicine.

Valuable information can be found on a range of life sciences fields including bacteriology, biochemistry, bionics, bioinformatics, biophysics, biotechnology, genetics, geobotany, human biology, marine biology, microbiology, molecular biology, cellular biology, zoology, bioinorganic chemistry, microchemistry and environmental chemistry.

Back to the Homepage

Comments (0)

Write comment

Latest posts

Seawater as an electrical cable !?

Wireless power transfers in the ocean For drones that can be stationed underwater for the adoption of ICT in mariculture. Associate professor Masaya Tamura, Kousuke Murai (who has completed the…

Rare quadruple-helix DNA found in living human cells with glowing probes

New probes allow scientists to see four-stranded DNA interacting with molecules inside living human cells, unravelling its role in cellular processes. DNA usually forms the classic double helix shape of…

A rift in the retina may help repair the optic nerve

In experiments in mouse tissues and human cells, Johns Hopkins Medicine researchers say they have found that removing a membrane that lines the back of the eye may improve the…

Partners & Sponsors

By continuing to use the site, you agree to the use of cookies. more information

The cookie settings on this website are set to "allow cookies" to give you the best browsing experience possible. If you continue to use this website without changing your cookie settings or you click "Accept" below then you are consenting to this.

Close