For muscle contractions to occur, electrical signals will travel from the brain to the muscle via a complex process. Two key players involved in this process are the voltage-gated calcium channel (Cav1.1) and ryanodine receptor 1 (RyR1). Cav1.1 senses the electrical signal and triggers opening of RyR1 to release calcium required for muscle contraction. When they malfunction, it can give rise to several muscle diseases, such as congenital myopathies, periodic paralysis, malignant hyperthermia, and central core disease. The proposed project will use advanced imaging techniques to look at three-dimensional structures of these proteins to understand the process of voltage-sensing. The project will also investigate how disease mutations, endogenous modulators, and pharmacological agents change the structure and function of these proteins. These structural and functional insights will help us understand the cause of these muscle diseases and provide a framework for design of novel therapeutics to prevent and treat them.