Induction of calcium release from sarcoplasmic reticulum of skeletal muscle by xanthone and norathyriol

1 Effects of xanthone and its derivative, 1,3,6,7-tetrahydroxyxanthone (norathyriol), on Ca²⁺ release and ryanodine binding were studied in isolated sarcoplasmic reticulum (SR) vesicles from rabbit skeletal muscle. 2 Both xanthone and norathyriol dose-dependently induced Ca²⁺ release from the actively loaded SR vesicles which was blocked by ruthenium red, a specific Ca²⁺ release inhibitor, and Mg²⁺. 3 Xanthone and norathyriol also dose-dependently increased apparent [³H]-ryanodine binding. Norathyriol, but not xanthone, produced a synergistic effect on binding activation when added concurrently with caffeine. 4 In the presence of Mg²⁺, which inhibits ryanodine binding, both caffeine and norathyriol, but not xanthone, could restore the binding to the level observed in the absence of Mg²⁺. 5 Xanthone activated the Ca²⁺-ATPase activity of isolated SR vesicles dose-dependently reaching 70% activation at 300 μM. 6 When tested in mouse diaphragm, norathyriol potentiated the muscle contraction followed by twitch depression and contracture in either a Ca²⁺-free bathing solution or one containing 2.5 mM Ca²⁺. These norathyriol-induced effects on muscle were inhibited by pretreatment with ruthenium red or ryanodine. 7 These data suggest that xanthone and norathyriol can induce Ca²⁺ release from the SR of skeletal muscle through a direct interaction with the Ca²⁺ release channel, also known as the ryanodine receptor.