Kyoto University lays groundwork for circadian clock drug design
The human body's internal clock regulates sleep and wake periods throughout the day. It is controlled by a part of the brain called the "suprachiasmatic nucleus" (SCN), which responds to light and dark signals. Malfunction of this circadian clock has been linked to a host of diseases, such as sleeping disorders, obesity, diabetes, and cancer, which makes the clock an attractive target for drug development.
Previous studies have identified potential therapies targeting components of the circadian clock, but similar components can also be found in different parts of the body, meaning that the specificity and efficacy of the drug candidates has been limited.
More than a third of currently available drugs target the function of a group of proteins known as G-protein-coupled receptors (GPCRs), which make up the body's largest family of cell surface receptors involved in a broad range of physiological functions.
Kyoto University researchers used this knowledge to speculate on the value of 'orphan' GPRCs in the SCN. These GPRCs have structures similar to the other identified family members, but their functions and binding partners remained unknown, meaning they could possibly serve as important circadian system modulators.
The researchers analyzed all known orphan GPCR genes in the SCN, and identified three SCN-enriched areas. They then bred mice that lack the respective genes to determine the function of the corresponding GPCRs. In a surprising breakthrough, they discovered that Gpr176, one of these orphans, is responsible for regulating the pace of the circadian clock. Notably, Grp176 is expressed mainly in the brain, with most being found in the SCN.
"This finding suggests that Gpr176 is a desirable drug target because of its specific location and function," says Hitoshi Okamura. "Gpr176 is expressed strongly only in the SCN; if we specifically target Gpr176 we may be able to avoid side effects on peripheral organs."
Since Gpr176 and the other orphan GPRCs have no known natural ligands, small molecules that act as ligands could be developed as potential drug candidates for treating a variety of diseases associated with the circadian clock.
Kyoto University lays groundwork for circadian clock drug design
Paper Information
[DOI] https://doi.org/10.1038/ncomms10583
[KURENAI Access URL] http://hdl.handle.net/2433/204599
Masao Doi, Iori Murai, Sumihiro Kunisue, Genzui Setsu, Naohiro Uchio, Rina Tanaka, Sakurako Kobayashi, Hiroyuki Shimatani, Hida Hayashi, Hsu-Wen Chao, Yuuki Nakagawa, Yukari Takahashi, Yunhong Hotta, Jun-ichirou Yasunaga, Masao Matsuoka, Michael H. Hastings, Hiroshi Kiyonari & Hitoshi Okamura
"Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour"
Nature Communications , 17 February 2016
