Tiny Worm Yields Big Clues On Muscle Contraction

A University of Illinois at Chicago neurobiologist working with colleagues from France discovered a new protein required for proper clustering of muscle receptors for the neurotransmitter acetylcholine. The receptors, properly clustered on the muscle membrane where the muscle is wired to the nerve, are necessary for normal muscle contraction. The protein has close counterparts in humans and presents a new target for research in areas as diverse as nicotine cravings and treatment for myasthenia gravis.

The findings are reported in the Sept. 30 issue of Nature by Janet Richmond, assistant professor of biology at UIC, and Christelle Gally, Stefan Eimer and Jean-Louis Bessereau of the Ecole Normale Superieure in Paris.

"We looked at acetylcholine receptors, found at neuromuscular synapses that control muscles throughout our body, causing them to contract," said Richmond. But acetylcholine, a neurotransmitter substance made the body, is not the only chemical signal that the receptors receive. "Certain drugs, such as nicotine, can also act on these receptors," Richmond said. "There's a big interest in understanding more about these receptors for one reason -- there are a lot of people addicted to nicotine."

The worm used in the experiments, a one millimeter-long nematode called Caenorhabditis elegans, is not known to smoke, but has become something of a darling experimental organism among biologists because all of its genes have been identified and many of its proteins are the same as those in other animals, including humans.

The researchers applied a molecular tag to the the worm's acetylcholine receptors, then watched the receptors cluster in regions on muscles where neurons, or nerve cells, communicate with muscles, telling them when to contract. In the process of screening for mutant worms in which the receptors wouldn't cluster in the correct place, the researchers discovered a gene for a novel protein which they called LEV-10.

"This novel protein acts with the acetylcholine receptor on the outside of the muscle membrane, which we didn't necessarily expect," said Richmond. "That's a fairly novel kind of mechanism for targeting receptors. A lot of times receptors are clustered from the inside of the muscle.

"We were able to show that this protein, LEV-10, is absolutely required to get receptors to stay where they need to be," said Richmond. "Nobody has ever studied a protein like this involved in acetylcholine receptor clustering before."

Richmond's contribution to the research centered on a technique she developed to pin down the wiggly, microscopic worms by using a glue-like substance made for human wound sutures. She then carefully dissected the mutant worms, using hand-held glass needles, exposing their muscle tissue. Richmond recorded muscle responses and showed that while the mutant varieties of the worms did have functional acetylcholine receptors, they were scattered about rather than clustered, and so were not performing their job properly.

Richmond says her team hopes these findings yield clues to debilitating muscular diseases such as myasthenia gravis, in which the body is unable to maintain enough acetylcholine receptors to allow normal muscle contraction. It may also suggest new avenues of research into treating nicotine addiction.

"Understanding how receptors are targeted and localized to the membrane is going to be very important. It may eventually help us understand and treat nicotine cravings," said Richmond. "The more we can learn about these receptors, the better."

Richmond's research was supported by a grant from the National Institutes of Health.