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      S165F mutation of junctophilin 2 affects Ca2+ signalling in skeletal muscle.

      Biochemical Journal

      metabolism, Animals, TRPC Cation Channels, Signal Transduction, Sarcoplasmic Reticulum, Ryanodine Receptor Calcium Release Channel, Protein Kinase C, Phosphorylation, pharmacology, Phosphodiesterase Inhibitors, genetics, Mutation, Muscle, Skeletal, Muscle Fibers, Skeletal, Mice, Membrane Proteins, Immunoprecipitation, Immunoblotting, Humans, Cytosol, Cells, Cultured, physiology, Calcium Signaling, Caffeine

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          Abstract

          JPs (junctophilins) contribute to the formation of junctional membrane complexes in muscle cells by physically linking the t-tubule (transverse-tubule) and SR (sarcoplasmic reticulum) membranes. In humans with HCM (hypertrophic cardiomyopathy), mutations in JP2 are linked to altered Ca2+ signalling in cardiomyocytes; however, the effects of these mutations on skeletal muscle function have not been examined. In the present study, we investigated the role of the dominant-negative JP2-S165F mutation (which is associated with human HCM) in skeletal muscle. Consistent with the hypertrophy observed in human cardiac muscle, overexpression of JP2-S165F in primary mouse skeletal myotubes led to a significant increase in myotube diameter and resting cytosolic Ca2+ concentration. Single myotube Ca2+ imaging experiments showed reductions in both the excitation-contraction coupling gain and RyR (ryanodine receptor) 1-mediated Ca2+ release from the SR. Immunoprecipitation assays revealed defects in the PKC (protein kinase C)-mediated phosphorylation of the JP2-S165F mutant protein at Ser165 and in binding of JP2-S165F to the Ca2+ channel TRPC3 (transient receptor potential cation canonical-type channel 3) on the t-tubule membrane. Therefore both the hypertrophy and altered intracellular Ca2+ signalling in the JP2-S165F-expressing skeletal myotubes can be linked to altered phosphorylation of JP2 and/or altered cross-talk among Ca2+ channels on the t-tubule and SR membranes.

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          Journal
          20095964
          10.1042/BJ20091225

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