Resetting the Biological Clock

Wind me up. A protein called MOP4 helps the brain tell the body what time it is.

Researchers have discovered a new way in which the brain coordinates the body's daily rhythm. A receptor in blood vessel walls responds to a protein that helps tell an animal what time it is. By fiddling with the receptor, researchers can shift the internal clock in a mouse or in human cells.

Inside each person ticks a biological clock that sets a daily rhythm, regulating bodily processes such as blood pressure, temperature, and sleep-wake cycles. A structure in the brain called the suprachiasmatic nucleus regulates these rhythms, but molecules in other tissues may strengthen or dampen the signals sent by the brain. This control is carried out by proteins that bind DNA, turning genes on or off throughout the day.

Cardiovascular scientists Garret FitzGerald and Peter McNamara of the University of Pennsylvania weren't studying circadian clock regulation, but they discovered something unexpected while searching for proteins that interact with hormone receptors in human vascular cells. The receptors latched onto a protein called MOP4, a close relative of a protein called CLOCK that helps regulate genes related to circadian rhythms. What's more, the hormones that normally bind to the receptors appear to regulate how tightly MOP4 clings to the receptor--when the hormones are present, MOP4 sticks to the receptor about 15 times more tightly.

Intrigued, FitzGerald and his colleagues tested whether the receptor and MOP4 could bind to DNA. They discovered that MOP4 binds to DNA better without the receptor and hormones. When they injected mice with a substance that ties up the hormones, they shifted the animals' internal clock by about 4 hours--the same effect they observed in human blood vessel cells grown in the lab.

"It's a very provocative paper," says neurobiologist Steven Reppert of the University of Massachusetts Medical School in Worcester. The finding may help identify novel ways to reset the central clock in the brain, perhaps leading to better remedies for jet lag.

Related sites

Garret FitzGerald's Web page
Steven Reppert's Web page
The Center for Biological Timing

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