March 20, 1997 in Nation/World

Scientists Find ‘Lock’ In Brain Elusive Substance Is Important Part Of How Brains Work

Washington Post
 

Swiss scientists have isolated one of the most important and elusive substances in the brain, an advance that could lead to new drugs for problems from cerebral palsy to spinal cord injuries, as well as provide new insights into memory and learning.

Researchers at the pharmaceutical company Novartis Pharma Ag in Basel, Switzerland, isolated the GABA-B receptor, a molecule distributed throughout the brain that is necessary for the key chemical messenger GABA to work.

“You’re talking about one of the most important receptors in the brain,” said John Henry Morrison, a neurobiologist at the Mount Sinai School of Medicine in New York. “It’s a major step forward.”

Receptors are molecules on brain cells that allow chemical messengers, called neurotransmitters, to turn the cells on and off, which is how information is communicated. The neurotransmitter is like a “key,” and the receptor is like a “lock,” with each neurotransmitter able to turn on or turn off only cells fitted with the corresponding receptor “lock.”

GABA, which stands for gamma aminobutyric acid, is an “inhibitory” neurotransmitter, meaning it inhibits, or turns off, cells. Without such neurotransmitters, brain cells would fire uncontrollably, such as in an epileptic seizure.

In fact, drugs that stimulate GABA receptors are used to control epilepsy. Tranquilizers known as benzodiazepines, such as Valium, work by stimulating GABA receptors. Part of alcohol’s effect is related to GABA.

There are two known receptors for GABA: GABA-A and GABA-B. GABA-A was isolated a decade ago, triggering a rush of new research. “When the first GABA receptor was cloned, it had enormous implications,” Morrison said. “I can’t think of anything more influential in the last 10 years.”

Despite many years of trying, however, scientists had been frustrated in their attempts to isolate and study GABA-B.

Researchers at Novartis finally succeeded by systematically searching for the molecule using rat and monkey cells and special radioactive probes until they eventually isolated the receptor.

“Since it is a major neurotransmitter in the brain, it has great potential for therapeutic intervention,” said lead researcher Bernhard Bettler, who reports the advance in Thursday’s issue of the journal Nature. “What we did was open the door.”

Scientists now will try to determine the receptor’s exact chemical makeup and structure. Once that has been determined, researchers hope they can then develop drugs that exclusively either activate or block the receptor.

That could lead to better drugs for cerebral palsy, multiple sclerosis and certain spinal cord injuries, where uncontrollable muscle movement - spasticity - is a problem, said Philip H. Sheridan of the National Institute of Neurological Disorders and Stroke.

Research also has suggested that GABA-B may play an important role in learning and memory.


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