Research breakthroughs often come from tiny things with big impact. And in Dr. S.R. Wayne Chen’s case, we’re talking about the miniscule ryanodine receptor’s significance in changing the lives of heart failure patients worldwide. While it’s the largest ion channel that has ever been discovered, it’s still only 29 nanometres-squared and 20 nanometres thick.
Chen, PhD, is the Heart and Stroke Foundation/Libin Cardiovascular Institute Professor in Cardiovascular Research at the University of Calgary. His research is supported by Alberta Innovates Health Solutions, Canadian Institutes of Health, Heart and Stroke Foundation and National Institutes of Health and looks at cellular mechanisms of how calcium is handled by cardiac cells. Calcium-mediated arrhythmias like ventricular arrhythmia all have a common thread: calcium dis-regulation. Muscles contract because of the release of calcium from internal stores. The protein that’s responsible for the release of calcium is called the cardiac ryanodine receptor (RyR2), or the calcium release channel, which acts like a safety valve that prevents calcium overload.
“This is a very important protein because naturally occurring mutations in this gene have been linked to many cardiac diseases,” says Chen, pointing to sudden cardiac death, ventricular arrhythmia, ventricular fibrillation, atrial fibrillation and more.
“The problem with mutations in the ryanodine receptor is that it lowers the threshold for the calcium release, leading to another phenomenon called spontaneous calcium release.” If these events occur when they shouldn’t, you get random contractions, one of the major triggers of ventricular arrhythmias.
Chen led a breakthrough paper published in the journal Nature Medicine (July 2011) which was the result of a seven year-long collaboration with 28 other researchers including Dr. Anne Gillis and Dr. Hank Duff. The study showed that carvedilol, a common medication used to treat heart arrhythmias, suppressed spontaneous calcium release
using this mechanism (RyR2). Previously, it was not fully understood how exactly the drug worked.
This finding means that Chen is now conducting further research into developing new compounds and more effective
anti-arrhythmic drugs without the side effects. Carvedilol use can have side effects including bradycardia (a slow heart rate) and hypotension (drastically low blood pressure).
Though researchers are still exploring how the spontaneous calcium release occurs, Chen says, “We discovered that the ryanodine receptor may contain a calcium sensor that recognizes the concentration of calcium within the internal store. When the calcium is too high, the sensor opens the channel. That’s the most exciting part: how it occurs.”
Understanding the applications of the sensor can provide further insight into cardiac function and it may provide all the major clues to other phenomena, such as fertilization, that also requires spontaneous calcium release.
Calcium may also play a part in the pathogenesis of dementias and diseases like Parkinsons, so this sensor is crucial. Chen currently runs two labs where he is pursuing this line of research. At the Libin Institute’s King Family Laboratory, he supervises nine individuals. In Chicago, he oversees three other researchers at Rush University Medical Center in the Department of Biophysics and Physiology.