Novel targets for treating heart and muscle disease – stabilizing ryanodine receptors and preventing intracellular calcium leak

Ryanodine receptors (RyRs) function as intracellular Ca2+ release channels on the endoplasmic and sarcoplasmic reticulum membranes. In striated muscles, Ca2+ release through RyRs controls muscle excitation–contraction coupling. RyR channel function is regulated by a cytoplasmic scaffold domain that forms a macromolecular signaling complex including calstabin (formerly known as FK506-binding protein), calmodulin, phosphodiesterase, kinase and phosphatase proteins. An increasing number of genetic and acquired diseases has been associated with intracellular Ca2+ leak. In heart failure, for instance, the RyR complex becomes altered, resulting in chronic channel dysfunction and chronic sarcoplasmic reticulum Ca2+ leak. Recently, the efficacy of novel Ca2+ release channel-stabilizing drugs has been demonstrated in cardiac and skeletal muscle disease models.