Researchers at the University of Maryland may have succeeded where the alchemists of old failed. Rather than turning base metals into gold, they have found a way to turn sodium channels into calcium channels. The finding could prove more valuable than gold to the millions of people who suffer from cardiovascular and neurological diseases.
W.J. Lederer, MD, PhD, A.M. Gomez, PhD, and L.F. Santana,PhD, report on their findings in the February 13 issue of the journal Science. Lederer is professor of physiology at the University of Maryland School of Medicine and head of the Department of Molecular Biology and Biophysics at the University of Maryland Medical Biotechnology Center in Baltimore. Gomez and Santana are senior post-doctoral fellows.
The researchers discovered that common neurotransmitters like adrenalin and drugs like digitalis can transmute sodium channels into calcium channels.
Sodium channels are proteins that regulate the electrical activity of virtually every excitable cell in the body, including those in the heart and brain. Any cell that has an electrical signal that changes quickly is excitable. Heart and other muscle cells, neurons or nerve cells and sensory cells in the eye and ear all are excitable cells.
Calcium channels affect how cells work by letting calcium in. Calcium is the trigger that controls heartbeat, the transduction of sound into hearing and the translation of light into vision. It also is thought to underlie the encoding of memory in the brain.
"We found that the sodium channel can be stimulated to do something new and different by a neurotransmitter like adrenaline. It can be induced to conduct calcium," Lederer says. "A sodium channel that conducts calcium under normal conditions is without precedent."
"What's more," he adds, "when the sodium channel conducts calcium in heart muscle, it significantly increases contraction. This is not academic minutia; this is truly revolutionary."
Calcium movement through sodium channels is a new cell-signaling pathway, says Lederer. "Under the control of nerve activity and circulating hormones, this system can be turned on and off. Although the work was done in heart cells, the sodium channel is one of the most constant proteins in biology, and these results may apply to all excitable cells."
Since calcium causes contraction in the heart, this finding could explain how traditional remedies such as digitalis work for conditions like heart failure. More importantly, Lederer says, the discovery provides completely novel targets for drug discovery and molecular medicine. Not only could the Maryland researchers' findings lead to development of more effective drugs to treat heart failure, they could have broad applications in developing drug therapies for a variety of nerve, brain and muscle conditions.
Lederer named the new signaling pathway "slip-mode conductance" of the sodium channel. He is widely known for his discovery of calcium "sparks" that occur inside excitable cells and can account for the normal heartbeat, cardiac arrhythmias, contraction of skeletal muscle, and control of vascular tone. Later this month he will receive the prestigious Cole Prize of the Biophysical Society for his work on calcium sparks.
The slip-mode conductance research was supported in part by the National Institutes of Health's National Heart, Lung and Blood Institute and the University of Maryland Directed Research Initiative Funds, with equipment furnished by the Medical Biotechnology Center of the University of Maryland Biotechnology Institute.
The seven schools at the Baltimore campus of the University of Maryland train the majority of the state's health, social work and law professionals. Based on the founding campus of the University System of Maryland, those schools are: medicine, law, nursing, pharmacy, social work, dental, and graduate programs.
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