Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in 
the rapid release of Ca(2+) from the sarcoplasmic reticulum and muscle 
contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) 
increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine 
derivative JTV519, and the more specific derivative S107 
(2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to 
improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, 
we report a high degree of nonspecific and specific low affinity [(3)H]S107 
binding to SR vesicles. SR vesicles enriched in RyR1 bound ∼48 [(3)H]S107 per 
RyR1 tetramer with EC(50) ∼52 µM and Hillslope ∼2. The effects of S107 and 
FKBP12 on RyR1 were examined under conditions that altered the redox state of 
RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of 
reduced glutathione and the NO-donor NOC12, with no effect in the presence of 
oxidized glutathione. Addition of 0.15 µM FKBP12 to SR vesicles prevented FKBP12 
dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 
dissociation was observed in skeletal muscle homogenates that contained 0.43 µM 
myoplasmic FKBP12 and was attenuated by S107. In single channel measurements 
with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented 
the FKBP12-mediated decrease in channel activity. The data suggest that S107 can 
reverse the harmful effects of redox active species on SR Ca(2+) release in 
skeletal muscle by binding to RyR1 low affinity sites.