NEW YORK (Reuters Health) - A leak in an intracellular calcium channel has been shown to trigger potentially fatal arrhythmias in patients with heart failure and other cardiac conditions. Now, new research indicates that treatment with an agent that fixes this leak can prevent cardiac arrhythmias in mice predisposed to such disturbances.
In the sarcoplasmic reticulum, there is a channel that mediates calcium release. Under normal circumstances, a protein called calstabin2 binds to the channel, stabilizing it and preventing calcium from leaking out. In patients with heart failure, however, the channel is phosphorylated, leading to decreased affinity for calstabin2 and, as a result, calcium leak.
Using a murine model of cardiac arrhythmia, Dr. Andrew R. Marks, from Columbia University in New York, and colleagues examined the efficacy and mechanism of action of JTV519, an agent that has been shown to reduce calcium leak from the sarcoplasmic reticulum.
As reported in the April 9th issue of Science, the authors found that JTV519 enhanced the binding of calstabin2 to the calcium channel, thereby stabilizing the closed state of the channel. This resulted in decreased calcium leak and protected against arrhythmias.
“JTV519 has actually already been tested in humans for another indication 5 years ago,” Dr. Marks told Reuters Health. “We’ve made derivatives of JTV519 that are 200-fold more potent than the parent compound and we think we have some very exciting lead compounds.”
“Right now, we are working as quickly as possible to develop these agents for clinical use,” Dr. Marks said. “Optimistically, we could be doing clinical studies within a year.”
Source: Science 2004;304:292-296. [ Google search on this article ]
MeSH Headings:Ion Channels: Membrane Glycoproteins: Membrane Proteins: Calcium ChannelsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.