Circadian rhythms enable all living beings to coordinate with the daily cycle, but how the body clock keeps accurate time, or how its malfunction affects people with sleep disorders, is not fully understood. Now, scientists say that a molecular “phosphoswitch” may provide the key.
Researchers led by Dr. David Virshup, of Duke-NUS Graduate Medical School Singapore (Duke-NUS), and Daniel Forger, PhD, from the University of Michigan at Ann Arbor, say discovery of the switch could lead to more effective treatment of circadian rhythm disorders caused by jet lag, shift work or metabolic disorders.
The findings are published in the journal Molecular Cell.
Normally, the circadian body clock is synchronized with the rising and setting of the sun, ensuring that we sleep at night.
The clock’s relative insensitivity to minor temperature changes prevent it from running too fast or too slow when temperatures change. How the clock compensates for changes in temperature and maintains its speed is a mystery.
In recent decades, scientists have found that one of the proteins critical for determining the timing of the clock, and of sleep, is Period2 (PER2).
The findings suggest that a molecular switch balances the activity of PER2, keeping its daily accumulation and degradation on schedule. The findings clarify how the clock adapts to diverse conditions such as temperature and metabolic changes.
- To avoid sleep problems, go to bed and get up at the same time each day
- Remove all gadgets from the sleeping environment, and only use your bed for sleeping
- Sleep in a dark, quiet room which is neither too hot nor too cold.
The stability of PER2 depends on a process called phosphorylation, in which enzymes called kinases add a phosphate group to PER2 at two key sites to influence PER2’s function.
The level of PER2 rises and falls in a circadian pattern to control the sleep-wake cycle and other rhythmic behaviors. Phosphorylation acts as a switch that causes PER2 either to increase in stability or to degrade.
It was previously believed that PER2 degraded exponentially, but the team noticed three stages of degradation: an initial rapid decay, followed by a plateau-like slow decay, and then a more rapid decay at the end.
Based on this finding, they developed a mathematical model of the circadian clock. The model predicted that the initial and final stages of rapid decay are caused by phosphorylation at one of the binding sites, while the second stage of plateau-like decay is driven by phosphorylation at the other site.
The phosphoswitch appears to be sensitive to temperature fluctuations and metabolic signals, and so it fine-tunes clock speed as needed. Sometimes the clock compensates or overcompensates for shifts in temperature. A malfunction in the phosphoswitch could lead to certain sleep disorders.
Usually, the rate of a biochemical reaction increases as the temperature rises, which means the speed of the body clock should increase if the temperature rises.
However, the phosphoswitch seems to ensure that degradation of PER2 is slower at higher temperatures, therefore maintaining the speed of the body clock.
The new insight provides a molecular explanation for the symptoms of familial advanced sleep-phase disorder (FASP), a disorder that causes people to sleep and wake much earlier than normal due to abnormalities in the daily rhythmic fluctuations in PER2 levels.
Previous research has shown that FASP is caused by a PER2 mutation that prevents phosphorylation by an unknown priming kinase at the FASP site. The new findings mean that this mutation would cause less PER2 to enter the second slow stage of decay, resulting in more rapid degradation of this protein and an acceleration of the circadian clock.
Dr. Virshup says:
“This study sheds light on one of the biggest mysteries of the circadian clock in the last 60 years, and has helped to explain some of the basic mechanisms that govern the timing of the clock. By using both biochemical analysis and mathematical modeling, we demonstrated how the core circadian clock keeps to a 24-hour cycle despite temperature changes and metabolic changes.”
The findings could lead to new treatment strategies for a range of circadian clock-related conditions. The phosphoswitch provides a potential drug target to influence the behavior of the circadian clock and counter the effects of jet lag, shift work and, perhaps, seasonal affective disorder.
The research also provides a mathematical model that accurately predicts the behavior of the clock under different circumstances. This will be useful in determining when drugs should be administered to modify circadian rhythms to maximize effectiveness.
The researchers would like future studies to use the new math model to predict the clock’s response to drugs that modify rhythms.
The next step for the team is to test their predictions in an animal model. They plan to explore more about how phosphatases, an enzyme found in the body, and other kinases that may be important in regulating the circadian clock. Their current hypothesis is that the interplay of these systems will regulate the sleep and wake cycle.
Dr. Virshup hopes the research will lead to “the development of novel drugs that would broaden the current treatment options of melatonin, light, and behavioral therapy, which do not always effectively treat symptoms in patients.”
Medical News Today recently reported on how caffeine can affect the body clock by delaying a rise in the level of the hormone melatonin.