Grant: Operating Grant

In the human body, electricity controls life. Electrical signals are generated by the combined work of many different proteins, called ion channels. Each of these ion channels plays a unique role in the heart normal function. Since contractions are controlled by the influx of calcium cations (positively charged molecules), the calcium channel is very important in the heart function. The L-type calcium channel opens and closes in response to changes in electrical activity in cardiac muscle. It is very important that calcium ions enter the cell for the cardiac muscle to contract but the amount of calcium ions has to be exquisitely determined. Too many calcium ions or too few calcium ions will cause important disturbances, called arrhythmias, in the heart electrical activity. We made it our lifelong goal to understand the molecular mechanisms that link the heart electrical activity and the activity (opening and closing) of the calcium channel. Tremendous progress has been made over the last 20 years. We are now able to modify the molecular structure of proteins such as the L-type calcium channels using standard molecular biology techniques and to test the function of the modified proteins using classical electrophysiological methods (whereby we measure the currents generated by the ion channels). We are also able to track the movement of these proteins within cells by tagging the channel proteins with fluorescent labels. By comparing the changes in the electrical pattern and the change in the level of fluorescence between the normal and the modified protein, we are able to identify portions of the protein that are important for its function. We hope that the knowledge we will gain by understanding these fundamental mechanisms will provide additional therapeutic avenues to treat heart failure and lethal arrhythmias.