FK506 (tacrolimus) increases halothane-induced Ca²⁺ release from skeletal muscle sarcoplasmic reticulum

Background: FK506 binding protein is closely associated with the sarcoplasmic reticulum ryanodine receptor-channel and can modulate its function. The ryanodine receptor is stabilized by its association with FK506 binding protein. The immunosuppressant drugs FK506 (tacrolimus) and rapamycin can promote dissociation of FK506 binding protein from the ryanodine receptor 1 and by this mechanism increase sensitivity of ryanodine receptor 1 to agonists such as caffeine. Furthermore, it was shown recently that treatment of normal human skeletal muscle with FK506 and rapamycin increased halothane- induced contracture. The authors investigated the effect of the immunosuppressants FK506 and rapamycin on halothane-induced Ca²⁺ release in skeletal muscle sarcoplasmic reticulum vesicles. Methods: Skeletal muscle terminal cisterns were isolated from New Zealand White rabbits. Ca²⁺ uptake and release was monitored in skeletal muscle sarcoplasmic reticulum vesicles using the fluo-3 fluorescent technique. Western Blot analysis of FK506 binding protein was performed using standard protocol. Results: The authors observed that treatment of skeletal muscle sarcoplasmic reticulum vesicles with FK506 and rapamycin enhances halothane-induced Ca²⁺ release by about five times. Furthermore, the Ca²⁺ release induced by halothane in the presence of FK506 was inhibited by several antagonists of the ryanodine receptor, such as ruthenium red, spermine, and Mg²⁺. Conclusion: Dissociation of FK506 binding protein from its binding site in skeletal muscle sarcoplasmic reticulum vesicles can modulate halothane-induced Ca²⁺ release through the ryanodine receptor. Data are discussed in relation to the role of the FK506 binding protein in modulating the effect of halothane on the ryanodine receptor and the development of malignant hyperthermia phenotype.