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Researchers Discover New Mechanism for Muscle Contraction

Lead Researcher: Andrew Marks

Scientists in the new molecular cardiology program have discovered for the first time that individual calcium channels “talk” with each other to regulate muscle contraction. The process, called coupled gating, shows that the activity of one calcium channel can trigger the activity of its neighboring channels. The discovery may lead to new treatment approaches for diseases of skeletal muscle, such as muscular dystrophy, or of the heart muscle, including heart failure—the leading cause of death in the United States.

“Our new discovery provides a very important next step in understanding how muscle contraction is regulated,” says Dr. Andrew Marks, professor of medicine and of pharmacology and director of the program. The research, reported in the Aug. 6, 1998, issue of Science, suggests that the newly discovered mechanism provides a uniform and highly regulated chemical signal that triggers the contraction and relaxation of muscles.

Muscle cells use calcium to control the contraction and relaxation of muscles. The more calcium that enters the cell through calcium channels in the cell wall the stronger the muscle contraction; conversely, the less calcium, the weaker the contraction.

Contraction occurs as a result of an electrical signal delivered by the nerve acting as a communications network for the brain. The process, called excitation contraction coupling, in which electrical signals are translated into mechanical signals, requires calcium channels to open and close. One of the mysteries Dr. Marks and his team were trying to solve is how thousands of calcium channels in the cell open or close simultaneously.

“If these channels are leaky or if they don’t all open when they are supposed to, then you can get muscle weakness that can cause heart failure,” says Dr. Marks. “Since calcium regulates the strength of the muscle contraction it seemed to us an important logical area to focus our attention. We are at the stage now where we are really just asking the basic questions of how the system works and we also have some evidence that in the failing heart the system is not working normally but until we understand how each component works to regulate the flow of calcium obviously we can’t then ask the question of where the problem is.”

Using electron microscopy, researchers saw that half of the calcium channels were controlled by electrical signals but it was unclear what controlled the other half. Previous theories have involved the idea that a small molecule was infusing throughout the cell to open and close calcium channels. “What we have discovered in this study is that the electrical activation of one single calcium channel can in turn activate its neighbors. Similarly, closing one channel will result in closing its neighbors because the channels actually talk with one another,” says Dr. Marks. “This electrical signal is a much cleaner system and a more direct interaction between the channels.”

Despite all of the advances in molecular biology of the past 20 to 30 years, researchers are still unsure why patients develop heart failure. Most heart failure patients have enlarged hearts that do not contract normally and do not pump blood normally. In the past year, work by the Marks lab and others has shown that cells from hearts with heart failure do not pump calcium normally and researchers don’t know why. More research is needed to understand how each component works to regulate the flow of calcium in the heart. This research was funded by grants from the NIH, the American Heart Association, and the Richard and Lynne Kaiser Family Foundation.

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