Archive for Sunday, March 30, 2003

Mysterious ladies’ becoming less so

March 30, 2003


Thirty years ago, scientists identified the sites in the brain where heroin and opium get processed.

Those sites are called receptors.

Soon after discovering the opiate receptors, scientists realized that the brain makes its own form of heroin -- for example, the endorphins that calm you down after a workout.

That calm, along with everything else we sense, feel and think in our lives, results from an endless succession of chemical kisses.

Scientists have found about two dozen chemical messengers so far. A puff of one leaves a brain cell, travels across a tiny gap and kisses a receptor that's shaped to receive it on the next cell.

Sometimes, a kiss is just a kiss -- but not always. Too much of the brain chemical dopamine, for example, causes schizophrenia. Too little serotonin produces depression.

And sometimes people mess up their own receptors. The alcohol in a stiff drink plays kissy face with glutamate receptors. This means that this chemical, which is important to memory, can't reach its receptor.

That's why longtime alcoholics experience blackouts.

Eli Michaelis has spent a scientific lifetime thinking about the architecture of the brain's four or five classes of glutamate receptors.

Glutamate is one of the two most important brain chemicals, says Michaelis, Kansas University professor of pharmacology and toxicology.

It fires up nerve cells all over the brain. Yet like other chemical messengers, it has both sunny and dark sides.

In strokes, for example, oxygen starvation in the brain leads to a massive glutamate release. A stroke victim suffers a natural glutamate overdose, and a slew of brain cells die.

One pharmaceutical approach to the problem is to design drugs that will occupy glutamate receptors when people have a stroke so that glutamate can't activate those receptors.

But there's a complication. Not all the glutamate receptors may be responsible for cell death.

Michaelis' team and a Japanese group have both spent years studying what, for a long time, they took to be the same glutamate receptor.

Now it seems they may actually have been dealing with two receptors. The Japanese group's is made of similar copies of one protein.

Michaelis' is made of four different proteins.

He and his team have cloned the genes responsible for the production of the four proteins. He's submitted details of the cloning of the fourth and final gene for review by editors of a journal published by the European Molecular Biology Society.

He's not 100 percent sure that his four-protein molecule is a glutamate receptor. But if it is, his thought is that the Japanese group's receptor works when glutamate flow is normal, his when glutamate floods the system.

He theorizes that his receptor may exist to kill the cell in response to glutamate overdose.

In 1964, a chemist named D.K. de Jongh wrote, "To most modern pharmacologists, the receptor is like a beautiful but remote lady."

That language now seems antique -- like something from an old Humphrey Bogart movie. The statement is also far less true than it once was.

"The mysterious ladies," Michaelis says, "are becoming less mysterious."

-- Roger Martin is a research writer and editor for the Kansas University Center for Research and editor of Explore, KU's research magazine Web site, which can be found at Martin's e-mail address is

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