|Julio A. Copello, Ph.D.
Excitation-Contraction Coupling in Cardiac and Skeletal Muscle
In striated muscles, large and transient increase in cytosolic calcium is induced by excitatory processes. Calcium then starts the contractile event as required for the heartbeat and for the skeletal muscle twitch. Our goal is to understand this process of “excitation-contraction (EC) coupling” both in health and diseases. Our methodological approach combines biochemistry, electrophysiology and calcium imaging. In cardiac and skeletal muscle, intracellular reticular meshwork of vesicular and tubular organelles act as calcium intracellular stores (the sarcoplasmic reticulum [SR]). These organelles provide the bulk of calcium required to activate the contractile machinery upon excitation. On the surface of the SR vesicles there are coordinated arrays of calcium channel molecules named ryanodine receptors (RyRs; as they tightly bind the alkaloid ryanodine) or foot structures (as seen by electron microscopy). We study how these intracellular RyRs communicate for synchronous activity as required for rapid mobilization of large amounts of calcium. We also study SR calcium accumulation during ischemia and its rapid and massive mobilization from SR to cytosol during early during reperfusion. This triggers myocardial tissue damage and, in turns, heart failure. Our goals include understanding mechanisms of abnormal calcium management and uncover drugs that prevent SR calcium accumulation during ischemia or massive calcium release in reperfusion. Finally, we also study if abnormalities in calcium signaling play a role in cancer cell resistance to chemotherapy.