Grant: Project Grant

The human heart continuously beat over a person's lifetime at a regular pace (more than 2 billion heartbeats in a 70-year lifespan). For the heart to function properly, its upper (atria) and lower (ventricle) chambers must fill with and pump blood in an organized manner. This is achieved through an intricate network of electrical signals. Electrical signals are propagated through specialized proteins called ion channels. Each ion channel must fulfill a very specific function to ensure that the electrical impulse is transmitted normally. By bringing in the cell the calcium ions necessary for the heart contraction (beating), the L-type calcium channel is one of most important proteins for the heart function. Change in the function of the channel will affect the amount of calcium ions coming in the cell. Excess calcium ions in the cell trigger a series of maladaptive reactions that could ultimately result in fatal heart failure. It is therefore paramount to understand how calcium ions transit through the ion channel. L-type calcium channels are made from multiple proteins or subunits that ensure the controlled passage of calcium ions from the circulation to the cardiac cell. This project investigates the role of the "Cavalpha2delta1" subunit in bringing in calcium in the cell. Too many calcium ions will kill the cell and not enough calcium ions will make beating impossible. We are identifying the hotspots of the "Cavalpha2delta1" protein that are critical for incoming calcium ions under normal physiological conditions. We are further investigating the variations in the expression of "Cavalpha2delta1" in pathological settings, using rat models of heart failure. We use molecular tools that label regions of "Cavalpha2delta1" and we track their role by measuring the electrical activity of the protein. This knowledge will provide valuable insight into future gene and pharmacological therapies to target the active sites and design improved calcium channel blockers.