SPECIFIC MODIFICATION OF SKELETAL MUSCLE RYANODINE RECEPTOR ACTIVITY

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The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a second type of calcium channel, to regulate the changes in the concentrations of calcium ions within the cell, which are essential for a variety of processes including cardiac contraction, vascular constriction, neuronal activity and immune responses. Despite its importance, little is known about the regulation of the RyR channel opening during contraction in skeletal muscle or the mechanisms of ion movement through its pore. It is often difficult to define the specific role of RyRs in intact tissues because of the lack of specific probes for the channel. The RyR is an obvious target for therapeutic drugs to modify muscle contraction, but has not been used as such because of the lack of specific and reversible drugs. Muscle performance is reduced, and fatigue is rapid, in neuromuscular disease. Performance can be improved by variety of drugs like anabolic steroids which unfortunately have additional adverse actions. The aims of the project are (a) to discover more about the regulation of, and ion conduction pathway through, the skeletal muscle RyR channel, (b) to identify compounds that can be used as specific probes for RyR activity and (c) to identify compounds that might in the future provide the basis for development of the RyR as a therapeutic target.