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- W2078118378 abstract "S100A1 and calmodulin (CaM) modulate skeletal muscle Ca2+ signaling. Recently, isothermal titration calorimetry demonstrated that CaM binds to three regions within the ryanodine receptor type-1 (RyR1) sequence: CAMBD1, residues 1975-1999; CaMBD2, residues 3614-3640; CAMBD3, residues 4295-4325 (Lau K, et al., 2014). We previously studied the binding to and modulation of RyR1 by CaM and S100A1 via CaMBD2, showing that skeletal muscle fibers from S100A1 knock out (S100A1KO) mice or RyR1-L3625D (RyR1D) mice (having disrupted CaM and S100A1 binding to CaMBD2), exhibit impaired RyR1 regulation. Here we propose and test the hypothesis that S100A1 also modulates fiber activation via sites other than CaMBD2. Double mutant mice were generated by crossbreeding homozygous RyR1D and S100A1KO mice to obtain homozygous double mutant RyR1D-S100A1KO mice, which were viable and appeared normal. Homozygous RyR1D mice were used as controls to eliminate any effect of binding at CaMBD2. In vivo stimulation of tibialis anterior muscles in anesthetized mice showed that maximal specific force was reduced in RyR1D-S100A1KO compared with RyR1D muscles (RyR1D Po= 5.15 ± .09 g/mg, RyR1D-S100A1KO Po= 4.05 ± .09 g/mg; p < 0.05). Using high-speed confocal microscopy of Ca2+ indicator rhod-2, we show that RyR1D-S100A1KO flexor digitorum brevis muscle fibers exhibit increased global myoplasmic Ca2+ transients following field stimulation. We also found no differences in myoplasmic resting Ca2+ between RyR1D and RyR1D-S100A1KO. Our results indicate that RyR1D-S100A1KO muscles have increased SR Ca2+ release, however exhibit reduced force generation. These results suggest that S100A1, similar to CaM, binds to different regions within the RyR1, but also indicates that S100A1 could bind to other target proteins (i.e., contractile apparatus). Where and how exactly S100A1 exerts these additional effects is currently unknown. Support: NIH R37-AR055099 and R01-AR059179." @default.
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- W2078118378 date "2015-01-01" @default.
- W2078118378 modified "2023-09-28" @default.
- W2078118378 title "Characterization of Dual Mutant RyR1D-S100A1KO Mice with Disrupted CaM and S100A1 Binding to CaMBD2 and Lacking S100A1 Expression" @default.
- W2078118378 doi "https://doi.org/10.1016/j.bpj.2014.11.1487" @default.
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