Gpr176 – The key to developing drugs targeting the circadian clock

sunflower_circadian

Sunflower Heliotropism – The sunflower tracks the sun during the day, and uses circadian rhythm to “anticipate” the sunrise the following morning, moving to face east without external cues. 

The circadian rhythm of life is any biological process that takes approximately 24 hours to complete naturally. It is observed in controlling behavior and physiological processes in plants, animals, fungi and cyanobacteria.

The first recorded study of the circadian oscillation was based on the movement of the leaves of the plant Mimosa pudica by French scientist Jean-Jacques d’Ortous de Mairan in 1729. He observed that the movement pattern of the leaves followed a 24-hour cycle even when kept in complete darkness!

In the human body, the circadian rhythm is maintained by a region in the brain known as the suprachiasmatic nucleus (SCN). Impairment of the SCN has been linked to a wide-variety of diseases such as sleep-wake disorder, obesity, diabetes and hypertension. Furthermore, the effectiveness and toxicity of drugs are regulated by the circadian rhythms as well.

To treat any disease, drugs are created with a chemical composition that can bind with proteins on cell surfaces to effect a change in cell behavior. G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors found in the human body. The GPCRs act as channels for information sharing between the cell nucleus and surrounding light energy, sugars, lipids, proteins and peptides, thereby  helping to regulate bodily functions.

Conclusively, most pharmaceutical drugs developed try to pattern themselves to be received by “orphan” GPCRs, GPCRs that seem to be free of purpose in binding with external stimuli. However, as some GPCRs are present in cells of most tissues and organs, it is difficult to prepare drugs that target only problem areas without affecting the surrounding tissues. To do so, it is vital to identify clusters of orphan GPCRs prevalent in different regions of the body.

To address this need in identifying unique GPCRs located in the SCN, scientists from Kyoto University, Japan conducted an experiment where they

  1. identified orphan GPCRs that had a rich presence in the SCN
  2. generated mutant animals deficient in the candidate GPCR
  3. observed if the absent GPCRs affected the circadian rhythm of the animals
Screen Shot 2016-04-24 at 4.05.28 AM

Gpr176; Source: Nature Communications

“This finding suggests that Gpr176 is a desirable drug target because of its specific location and function,” says Hitoshi Okamura, one of the researchers in the study. “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 has no known natural ligands, small molecules acting as ligands could be developed as potential drug candidates to treat diseases related to the circadian clock.

The research paper was published in Nature Communications in February 2016.

Source: Kyoto University.

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