Immuno-proteomic approach to excitation–contraction coupling in skeletal and cardiac muscle: Molecular insights revealed by the mitsugumins

A comprehensive understanding of excitation–contraction (E–C) coupling in skeletal and cardiac muscle requires that all the major components of the Ca2+ release machinery be resolved. We utilized a unique immuno-proteomic approach to generate a monoclonal antibody library that targets proteins localized to the skeletal muscle triad junction, which provides a structural context to allow efficient E–C coupling. Screening of this library has identified several mitsugumins (MG); proteins that can be localized to the triad junction in mammalian skeletal muscle. Many of these proteins, including MG29 and junctophilin, are important components in maintaining the structural integrity of the triad junction. Other triad proteins, such as calumin, play a more direct role in regulation of muscle Ca2+ homeostasis. We have recently identified a family of trimeric intracellular cation-selective (TRIC) channels that allow for K+ movement into the endoplasmic or sarcoplasmic reticulum to counter a portion of the transient negative charge produced by Ca2+ release into the cytosol. Further study of TRIC channel function and other novel mitsugumins will increase our understanding of E–C coupling and Ca2+ homoeostasis in muscle physiology and pathophysiology.