STRUCTURAL AND FUNCTIONAL INTERACTIONS BETWEEN THE II-III LOOP OF THE SKELETAL DHPR AND THE RYANODINE RECEPTOR

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The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from internal stores. Ryanodine receptor (RyR) calcium channels, either alone or in combination with a different internal calcium channel, regulate calcium release in each of these diverse functions. The essential nature of RyRs is underlined by death at or before birth when RyR expression is defective. Genetic defects in the RyR cause cardiac arrhythmias, malignant hyperthermia and central core disease. RyR function is compromised in heart failure and fatigue. The key role of RyRs makes them a potential therapeutic target, but they are not used as such because of the limited knowledge of the nature and structure of their regulatory sites. Electrical signals from the brain are able to release calcium from internal stores in muscle and initiate muscle contraction by virtue of a physical interaction between two calcium channel proteins, a surface membrane channel and the RyR. The molecular basis of this protein-protein interaction is is not understood and is a subject of this proposal. We will (a) solve the structure of one part of the surface channel that is known to contribute to the protein-protein interaction with the RyR, (b) determine the amino acid residues that interact with each other and (c) evaluate the functional consequences of the the binding of proteins. Understanding more about RyR regulation will pave the way for rational drug design and the eventual use of the RyR as a therapeutic target.