Biophysics of the Excitation-Contraction Coupling process in Skeletal Muscle. Research in our laboratory aims to unveil the detailed mechanisms of excitation-contraction (EC) coupling in vertebrate skeletal muscle and their pathological alterations in diseases. To this end, the laboratory uses a combination of advanced optical and electrophysiological approaches. The group has shown, with a localized detection method and pulse laser imaging that one of the earliest manifestations of the EC coupling process in skeletal muscle is a massive local increase of the intracellular Ca2+ concentration in microscopic regions of the muscle fibers where the sarcoplasmic reticulum (SR) apposes the T-tubule (triadic junction). It has also been recently found that these Ca2+ microdomains in mammalian muscle fibers are doubled peaked, as expected from the existence of two triadic junctions per sarcomere. The large, rapidly dissipating, Ca2+ gradients are not restricted to action potential-evoked Ca2+ release in muscle fibers; they also occur as a triggering mechanism in synaptic transmission and other neurosecretory processes. Novel approaches in imaging, flash-photolysis, and de-novo expression of recombinant membrane proteins are currently under development. These methodologies will allow the group to obtain new insights on the role of the membrane potential in initiating the cascade of events that lead to EC coupling in skeletal muscle fibers.