Researchers Discover How Melatonin Production is Switched Off

Researchers have long known that melatonin--a key hormone that regulates the body's circadian clock--rapidly disappears from the blood after exposure to bright light.

Now, a team of scientists at the National Institute of Child Health and Human Development (NICHD), has discovered what causes melatonin to disappear from the brain and circulatory system. The finding has important implications for the eventual design of a treatment to alleviate jet lag and assist shift workers in adjusting to erratic schedules. The study appears in the February 27th issue of Science.

"When you expose animals to light, their melatonin levels plummet--it's as if a switch has been thrown," said David Klein, PhD, a researcher in NICHD's Laboratory of Developmental Neurobiology. "The big step forward is that we've discovered the molecular basis of the switch."

Briefly, Dr. Klein explained, melatonin is made in the pineal gland of the brain from another chemical, serotonin, with the help of two enzymes: arylalkylamine N-acetyl transferase (AA-NAT) and hydroxyindole-O-methyl transferase (HIOMT). AA-NAT appears to be the "melatonin rhythm enzyme," because a large increase in the activity of AA-NAT is responsible for the high levels of melatonin found in the brain and in the bloodstream at night. Similarly, low levels of melatonin formed during the day reflect low levels of this enzyme. This difference in day and night levels of melatonin is important for setting the body's circadian clock.

About two years ago, Dr. Klein and his coworkers isolated the gene for AA-NAT and determined its protein sequence. From the protein sequence, they realized that the enzyme contained sites that would permit it to be rapidly destroyed.

In the current paper, Dr. Klein and his group showed that light stops the enzyme from making melatonin by switching off neural stimulation of the pineal gland--which manufactures melatonin. This triggers a set of processes which results in the enzyme being destroyed. Destruction involves the funneling of the enzyme into a barrel-shaped cellular structure known as a proteasome, which breaks the enzyme apart.

"This destruction is incredibly rapid," Dr. Klein said. "It is remarkable because it appears that out of the hundreds of cytoplasmic proteins, AA-NAT gets tagged for destruction within seconds and then gets sucked down this cellular garbage disposal."

In recent years, scientists have increasingly recognized the importance of the proteasomes in controlling proteins by degrading them. This is the first known example of the proteasome’s involvement in regulating an enzyme in the vertebrate brain.

Dr. Klein said that recognizing the role of the AA-NAT and the proteasome may lead to the eventual design of drugs that can switch melatonin off and could conceivably increase alertness. Perhaps such a drug could be given during the hours when a person needed to remain awake and melatonin could be given when the person needed to sleep.

Klein also indicated that this discovery opens up a new line of brain research on control of neural processing by selective proteolysis of key regulatory proteins.

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