Vol. 292, Issue 2, 725-730, February 2000

Bisprasin, a Novel Ca²⁺ Releaser with Caffeine-Like Properties from a Marine Sponge, Dysidea spp., Acts on Ca²⁺-Induced Ca²⁺ Release Channels of Skeletal Muscle Sarcoplasmic Reticulum¹

Atsuko Suzuki, Kimihiro Matsunaga, Heejae Shin, Jioji Tabudrav, Yoshikazu Shizuri and Yasushi Ohizumi

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan (A.S., K.M., Y.O.); and Marine Biotechnology Institute, Co., Ltd., Shimizu, Shizuoka, Japan (H.S., J.T., Y.S.).

Bisprasin, a unique bromotyrosine derivative containing a disulfide linkage, was isolated from a marine sponge of Dysidea spp. This compound caused a concentration-dependent (from 10 to 30 µM) increase in the ⁴⁵Ca²⁺ release from the heavy fraction of skeletal muscle sarcoplasmic reticulum (HSR) of rabbit skeletal muscle in the same way as does caffeine. The 50% effective concentrations of bisprasin and caffeine were approximately 18 µM and 1.2 mM, respectively, indicating that the ⁴⁵Ca²⁺-releasing activity of bisprasin was approximately 70 times more potent than that of caffeine in HSR. The bell-shaped profile of Ca²⁺ dependence for bisprasin was almost the same as that for caffeine. Typical blockers of Ca²⁺-induced Ca²⁺ release channels, such as Mg²⁺, procaine, and ruthenium red, inhibited markedly bisprasin- and caffeine-induced ⁴⁵Ca²⁺ release from HSR. This compound, like caffeine, significantly enhanced [³H]ryanodine binding to HSR. Scatchard analysis of [³H]ryanodine binding to HSR revealed that bisprasin and caffeine decreased the K_D value without affecting the B_max value, suggesting that both the drugs facilitate the opening of ryanodine receptor channels. The bisprasin- and caffeine-induced increases in [³H]ryanodine binding were further enhanced by adenosine-5'-(,-methylene)triphosphate. These results suggest that the pharmacological properties of bisprasin are almost similar to those of caffeine, except for its 70-fold higher potency. Here, we present the first report on the pharmacological properties of bisprasin, which, like caffeine, induces Ca²⁺ release from skeletal muscle SR mediated through the ryanodine receptor.