title: Inhibitory mechanism of xestospongin-C on contraction and ion channels in the intestinal smooth muscle.
abstract: 1. Xestospongin-C isolated from a marine sponge, Xestospongia sp., has recently been shown to be a membrane-permeable IP(3) 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 microM) inhibited contractions induced by Ca(2+) mobilized from sarcoplasmic reticulum (SR) with IP(3) or carbachol with GTP, but not with caffeine. 3. In intact smooth muscle tissue, xestospongin-C (3-10 microM) inhibited carbachol- and high-K+-induced increases in [Ca(2+)](i) and contractions at sustained phase. 4. It also inhibited voltage-dependent inward Ba(2+) currents in a concentration-dependent manner with an IC(50) of 0.63 microM. Xestospongin-C (3-10 microM) had no effect on carbachol-induced inward Ca(2+) currents via non-selective cation channels; but it did reduce voltage-dependent K+ currents in a concentration-dependent manner with an IC(50) of 0.13 microM. 5. These results suggest that xestospongin-C inhibits the IP(3) receptor but not the ryanodine receptor in smooth muscle SR membrane. In intact smooth muscle cells, however, xestospongin-C appears to inhibit voltage-dependent Ca(2+) and K+ currents at a concentration range similar to that at which it inhibits the IP(3) receptor. Xestospongin-C is a selective blocker of the IP(3) receptor in permeabilised cells but not in cells with intact plasma membrane.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan. aozaki@mail.ecc.u-tokyo.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Yoon-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Seong-Chun
authors.initials: SC
authors.lastname: Kwon
authors.forename: Duck-Sun
authors.initials: DS
authors.lastname: Ahn
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakazawa
authors.forename: Motomasa
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karaki
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D047028:Macrocyclic Compounds; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010080:Oxazoles / Q000302:isolation & purification / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels; D047028:Macrocyclic Compounds; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; C108644:xestospongin A