Depolarization of the transverse tubule (TT) membrane of a skeletal muscle fiber initiates a sequence of steps leading to contractile activation. Later steps involve Ca release from the sarcoplasmic reticulum (SR), elevation Delta Ca of myoplasmic free calcium concentration and CA binding to contractile filaments. The initial voltage-sensitive step in the depolarization-contraction coupling process may be movement of intramembrane charge (Q) within the TT membrane. In order to study the mechanisms involved in control of SR calcium release by Q and other factors, we have developed techniques for simultaneously monitoring both Delta Ca and Q in voltage-clamped cut segments of single skeletal muscle fibers containing the Ca indicator dye antipyrylazo III. Delta Ca records can be used to empirically characterize the systems responsible for removing Ca from the myoplasm. Using this information, the time course of SR calcium release can be calculated from Delta Ca. Calcium release and Q will be monitored for a variety of pulse protocols in order to test whether the two parameters exhibit the appropriate relationships for Q to control SR Ca permeability. Calcium depletion from the SR and a relatively fast inactivation of release that may be calcium dependent will both be characterized. This information will allow calculation of the activation of SR calcium release for comparison with Q. The molecular basis for signal transmission from TT to SR will be investigated. Knowledge about this important step in muscle activation may allow design of more effective or more specific skeletal muscle relaxant drugs and will allow tests for possible modification of this step in various pathological conditions. An inactivation of calcium release by elevated resting myoplasmic calcium levels that might be related to muscle """"""""weakness"""""""" under certain conditions will also be studied.
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