Inhibitory mechanism of xestospongin-C on contraction and ion channels in the intestinal smooth muscle

1 Xestospongin-C isolated from a marine sponge, Xestospongia sp., has recently been shown to be a membrane-permeable IP3 receptor inhibitor. In this study we examined the effects of this compound on smooth muscle from guinea-pig ileum. 2 In guinea-pig ileum permeabilized with alpha-toxin, xestospongin-C (3 muM) inhibited contractions induced by Ca2+ mobilized from sarcoplasmic reticulum (SR) with IP3 or carbachol with GTP, but not with caffeine. 3 In intact smooth muscle tissue, xestospongin-C (3 - 10 muM) inhibited carbachol- and high-K+-induced increases in [Ca2+](i) and contractions at sustained phase. 4 It also inhibited voltage-dependent inward Ba2+ currents in a concentration-dependent manner with an IC50 of 0.63 muM. Xestospongin-C (3 - 10 muM) had no effect on carbachol-induced inward Ca2+ currents via non-selective cation channels; but it did reduce voltage-dependent K+ currents in a concentration-dependent manner with an IC50 of 0.13 muM. 5 These results suggest that xestospongin-C inhibits the IP3 receptor but not the ryanodine receptor in smooth muscle SR membrane. In intact smooth muscle cells, however, xestospongin-C appears to inhibit voltage-dependent Ca2+ and K+ currents at a concentration range similar to that at which it inhibits the IP3 receptor. Xestospongin-C is a selective blocker of the IP3 receptor in permeabilised cells but not in cells with intact plasma membrane.