Xestoquinone, isolated from sea sponge, causes Ca(2+) release through sulfhydryl modification from skeletal muscle sarcoplasmic reticulum.
Xestoquinone (XQN) (3 x 10(-7) to 3 x 10(-3) M), isolated from the sea sponge Xestospongia sapra, induced a concentration-dependent Ca(2+) release from the heavy fraction of fragmented sarcoplasmic reticulum (HSR) of rabbit skeletal muscle with an EC(50) value of approximately 30 microM. On the basis of the EC(50), XQN is 10 times more potent than caffeine. Dithiothreitol completely blocked XQN-induced Ca(2+) release from HSR without affecting that induced by caffeine. Caffeine-induced Ca(2+) release was reduced markedly by Mg(2+), procaine, and ruthenium red, agents that are known to block release of Ca(2+) from sarcoplasmic reticulum, whereas that induced by XQN was not inhibited. The bell-shaped profile of Ca(2+) dependence for XQN was significantly shifted upward in a wider range of pCa (between 7 and 3), whereas that for caffeine was shifted to the left in a narrower range of pCa (between 8 and 7). The maximum response to caffeine in (45)Ca(2+) release was not affected by 9-methyl-7-bromoeudistomin D, whereas the response was further increased by XQN. XQN caused a concentration-dependent decrease in [(3)H]ryanodine binding to HSR. This effect of XQN also was abolished in the presence of dithiothreitol. Scatchard analysis revealed that the mode of inhibition by XQN was noncompetitive in [(3)H]ryanodine binding to HSR. These results indicate that sulfhydryl groups are involved in both the XQN effect on ryanodine binding and on Ca(2+) release.
Ito
M
M
Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Japan.
Hirata
Y
Y
Nakamura
H
H
Ohizumi
Y
Y
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002316:Cardiotonic Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology*; D066298:In Vitro Techniques; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry*; D011809:Quinones / Q000302:isolation & purification* / Q000494:pharmacology*; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013439:Sulfhydryl Reagents / Q000494:pharmacology*
D002132:Calcium Radioisotopes; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011809:Quinones; D013439:Sulfhydryl Reagents; D012433:Ryanodine; D002110:Caffeine; C068501:xestoquinone; D002118:Calcium; D004229:Dithiothreitol