In striated muscle cells, the transverse tubular (TT) invagination of plasma membrane contacts the terminal cisternae of sarcoplasmic reticulum (S.R) to form a restricted triad junction structure, thereby providing the structural framework for orthograde regulation of intracellular Ca release and retrograde regulation of extracellular Ca entry. While the molecular machinery directly responsible for the voltage- sensing mechanism and the Ca release pathway has been studied in detail, little is known about the intermediate components that mediate this bi-directional Ca signaling process in skeletal and cardiac muscle cells. We have recently discovered a novel muscle-specific protein named MG53 that contains a TRIM motif at the amino-terminus and a SPRY domain at the carboxyl-terminus. Unlike other TRIM family proteins, MG53 is exclusively expressed in cardiac and skeletal muscle fibers. Immunofluorescent staining and electron microscopy localization identify MG53 predominately at the peri-sarcolemma region, in addition to intracellular vesicles. Live cell imaging reveals that cells overexpressing MG53 exhibit elevated membrane trafficking and fusion events. Biochemical assays demonstrate that MG53 can interact with the dihydropyridine receptor located on TT membrane, as well as with the ryanodine receptor located on SR membrane. Built on these observations, the present project will test the central hypothesis that """"""""the TRIM and SPRY motifs of MG53 can participate in the bi-directional Ca signaling process in muscle cells, through direct interaction with Ca regulatory proteins and/or modulation of membrane trafficking and triad-junction architecture in skeletal muscle"""""""". Specifically, our experiments will address two questions: 1) What roles do the TRIM and SPRY motifs of MG53 play in integrating the various dynamic processes of voltage-induced Ca release and Ca-induced Ca release in skeletal muscle (Aim 1)? 2) Does MG53 regulate store-operated Ca entry (SOCE) by direct interaction with the SOCE macromolecular complex, or by altering membrane trafficking to affect SOCE function (Aim 2)? Answers to the above questions should provide new insights into the cellular and molecular mechanisms that control Ca signaling in muscle function in both healthy and diseased states, as well as potential therapeutic purpose for targeting MG53 in muscle dysfunction involving compromised membrane integrity or Ca signaling events.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-B (91))
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Przywara, Dennis
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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