Navigation Links
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 pull ing 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.


'"/>

Source:University of Pennsylvania School of Medicine


Related biology news :

1. Effective Cancer Treatments Follow The Clock
2. What Makes The Brain Tick, Tick, Tick: Researchers Gaining New Insights Into Brains Internal Clock
3. Clocking in Pillow Time without the Pillow
4. Childrens taste sensitivity and food choices influenced by taste gene
5. Evolution of taste receptor may have shaped human sensitivity to toxic compounds
6. Assessing the Amazon Rivers sensitivity to deforestation
7. Global warming increases oyster sensitivity to pollution
8. Mutations in the BRAF gene predict sensitivity to a novel class of cancer drugs
9. Increased sensitivity to nerve signals keeps diabetes at bay
10. With record resolution and sensitivity, tool images how life organizes in a cell membrane
11. Restoring tamoxifen sensitivity in resistant breast cancer cells
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:6/30/2017)... ARLINGTON, Va. , June 30, 2017 /PRNewswire-USNewswire/ ... a leading developer and supplier of face and ... the ATA Featured Product provider program. ... created an innovative way to monitor a driver,s ... benefit greatly from being able to detect fatigue ...
(Date:5/16/2017)... --  Bridge Patient Portal , an enterprise patient ... Systems , an electronic medical record solutions developer ... a partnership to build an interface between the ... products, including Centricity Practice Solution (CPS), Centricity Business ... integrations will allow healthcare delivery networks using GE ...
(Date:4/17/2017)... MELBOURNE, Florida , April 17, 2017 ... security technology company, announces the filing of its 2016 Annual Report ... Securities and Exchange Commission. ... Report on Form 10-K is available in the Investor Relations section ... well as on the SEC,s website at http://www.sec.gov . ...
Breaking Biology News(10 mins):
(Date:10/7/2017)... ... October 06, 2017 , ... ... advanced instruments and applications consulting for microscopy and surface analysis, Nanoscience Instruments ... consulting, Nanoscience Analytical offers a broad range of contract analysis services for ...
(Date:10/7/2017)... 6, 2017  The 2017 Nobel Prize in ... Jacques Dubochet, Joachim Frank and ... cryo-electron microscopy (cryo-EM) have helped to broaden ... biology community. The winners worked with systems manufactured ... produce highly resolved, three-dimensional images of protein structures ...
(Date:10/6/2017)... ... October 06, 2017 , ... ... discussion and webinar on INSIGhT, the first-ever adaptive clinical trial for glioblastoma (GBM). ... Institute. The event is free and open to the public, but registration is ...
(Date:10/5/2017)... ... , ... Understanding the microbiome, the millions of bacteria that live in our ... My Future, the newest exhibit on display at the University City Science Center’s Esther ... the lens of the gut microbiome. , Gut Love opens October 12, 2017, ...
Breaking Biology Technology: