Novel targets for treating heart and muscle disease: stabilizing ryanodine receptors and preventing intracellular calcium leak.
Ryanodine receptors (RyRs) function as intracellular Ca(2+) release channels on the endoplasmic and sarcoplasmic reticulum membranes. In striated muscles, Ca(2+) 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 Ca(2+) leak. In heart failure, for instance, the RyR complex becomes altered, resulting in chronic channel dysfunction and chronic sarcoplasmic reticulum Ca(2+) leak. Recently, the efficacy of novel Ca(2+) release channel-stabilizing drugs has been demonstrated in cardiac and skeletal muscle disease models.
Lehnart
Stephan E
SE
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. sel2004@columbia.edu
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016503:Drug Delivery Systems; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006331:Heart Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D009135:Muscular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium