June 2, 1999

SLIPPING CALCIUM HELPS TELL TALE OF THE HEART

BALTIMORE, Md.--A healthy heart rhythm and strong heartbeat may be closely linked with a newly uncovered action of calcium in heart cells, reported University of Maryland Biotechnology Institute (UMBI) scientist W. Jonathan Lederer in a recent edition of the journal Science.

The discovery may lead to improved medications and be beneficial to millions suffering cardiovascular and neurological diseases, said Lederer, although he cautioned that "much more research is needed by our team and others."

Last year, a report in Science by Lederer and colleagues for the first time indicated that calcium could sneak through heart cell membranes by an unexpected route. "It sent a shock wave throughout the research community," said Lederer, who is interim Director of UMBI's Medical Biotechnology Center in Baltimore, Md. and professor of physiology, University of Maryland School of Medicine.

The latest Science report offers results of a new and different set of experiments. They confirm the new calcium route, called "slip-mode conductance," according to the researchers, Lederer, L.F. Santana, now at the University of Puerto Rico, and A. M. Gómez, now at the National Institute of Health and Medical Research, Montpellier, France.

Specifically, the Lederer team found that sodium channels in membranes, known only to let sodium through, can be transformed to also let calcium enter the heart cells. The change is caused by activity of nerve cells in the heart, by neurohormones or other internal compounds, or by therapeutic drugs.

"I was shocked to learn that the cardiac sodium-channel conductance becomes slippery,' letting calcium pass through the cell membrane when the channel is exposed to adrenaline, the common neurohormone," said Lederer. He said the new Science paper provides "compelling evidence in support of our initial proposal" and surprising new findings on the function of the sodium channel in heart.

With state-of-the-art micro-imaging equipment, the scientists studied live rat heart cells, one at a time, using high-tech tools for electrical measurements across the cell.

Nearly 20 years ago, Lederer began studying the role of calcium in the heartbeat, which depends on sodium, calcium and potassium channels in its cell membranes as well as other special membrane proteins. Calcium is important in "signaling" because very little free calcium is inside the heart cells, but 10,000 times more is outside cells, said Lederer. The significance is that normally the heart contracts because calcium enters the heart cell to trigger the contraction, about once a second in each and every heart cell.

In 1993 Lederer discovered calcium " sparks," elementary calcium signaling components in heart, skeletal and smooth muscle. Coworkers in his lab and collaborators at other institutions identified the sparks in a series of Science and Nature papers between 1993 and 1996.

The discovery of slip-mode conductance of the cardiac sodium channel reveals a way in which calcium sparks can be activated, according to Lederer and colleagues. They are less active in those who suffer disease such as congestive hart failure.

The experiments by Lederer and his team showed that the therapeutic agent digitalis activates slip mode--calcium movement through sodium channels. Also, Lederer said the discovery of slip-mode conductance provides "completely new molecular targets for drug discovery. It also provides a new method by which pharmaceutical companies can investigate cardiovascular drugs. The National Institutes of Health has provided funding for Lederer to conduct such investigations.

The April 30 Science On-Line report is part of a debate titled, "Whether Slip-Mode Conductance' occurs." The research was supported in part by the NIH's National Heart, Lung and Blood Institute and the University of Maryland Directed Research Initiative Funds. Lead scientists on the new work were J.S. Cruz of UMBI and L.F. Santana of the University of Puerto Rico. Scientists from Columbia University, and the University of Michigan also collaborated.