Columbia University Medical Center

Columbia Researchers Discover New Mechanism For Muscle Contraction

New York, NY August 6, 1998– Scientists at Columbia University College of Physicians & Surgeons 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 Andrew Marks, M.D., professor of medicine and pharmacology at Columbia University College of Physicians & Surgeons and director of the Molecular Cardiology Program at Columbia-Presbyterian Medical Center.

The research, reported in the August 7 issue of Science, suggest 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, and 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 require calcium channels to open and close.

One of the mysteries Dr. Marks’ team was 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 have seen that half of the calcium channels were controlled by electrical signals and 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.” This had never been shown before.

Despite all of the advances in molecular biology of the last 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 don’t pump blood normally. In the last year, work in Dr. Marks’ lab and others have shown that cells from hearts with heart failure do not pump calcium normally and researchers don’t know why. Dr. Marks says more research is needed to understand how each component works to regulate the flow of calcium in heart. The Columbia University molecular cardiology program, established in 1997, is designed to apply all of the modern techniques of molecular and cell biology to what has become fundamentally the most significant cause of death and morbidity in this country — heart disease. The program focuses on two particular problems the molecular biology of heart failure and of sudden cardiac death. This interdisciplinary program involves the departments of medicine, biochemistry and pharmacology.

The research was funded by grants from the National Institutes of Health, the American Heart Association and the Richard and Lynne Kaiser Family Foundation.

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