Skeletal muscle activation (excitation-contraction coupling) involves signal transmission across specialized membrane junctions (triads) that join the transverse tubules (T-system) with the Sarcoplasmic Reticulum. The purpose of this research is to characterize a non-linear potential change that occurs in the T-system membranes, presumably at the triadic junctions. This phenomenon was recently discovered by the P.I. using potentiometric dyes and was shown to reflect a transient electrostatic potential change that occurs upon depolarization and is closely associated with excitation-contraction coupling. The research will examine the relationship of this phenomenon to Q gamma movement, which is now thought to reflect a conformational change on the voltage-sensing molecule in the T-system that mediates junctional transmission. Additionally, it will examine the physiological function of this phenomenon and its relationship to the molecular mechanism of junctional coupling. These questions will be addressed by making detailed comparisons of the non-linear electrostatic potential change, with charge movement. The measurements will be performed using single voltage-clamped muscle fibers stained with potentiometric dyes and mounted in an experimental apparatus that allows simultaneous measurement of T-system optical signals and charge movement. This research can lead to a better understanding of the mechanisms of normal muscle activation. Also, it is broadly relevant to muscular dystrophies that involve an abnormality of excitation-contraction coupling and to the design of therapeutic agents such as the muscle relaxant Dantrolene Na+ that specifically alter this process.
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