XESTOSPONGINS - POTENT MEMBRANE-PERMEABLE BLOCKERS OF THE INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR

Xestospongins (Xe's) A, C, D, araguspongine B, and demethylxestospongi n B, a group of macrocyclic bis-1-oxaquinolizidines isolated from the Australian sponge, Xestospongia species, are shown to be potent blocke rs of IP3-mediated Ca2+ release from endoplasmic reticulum vesicles of rabbit cerebellum. XeC blocks IP3-induced Ca2+ release (IC50 = 358 nM ) without interacting with the IP3-binding site, suggesting a mechanis m that is independent of the IP3 effector site. Analysis of Pheochormo cytoma cells and primary astrocytes loaded with Ca2+-sensitive dye rev eals that XeC selectively blocks bradykinin-and carbamylcholine-induce d Ca2+ efflux from endoplasmic reticulum stores. Xe's represent a new class of potent, membrane permeable IP3 receptor blockers exhibiting a high selectivity over ryanodine receptors. Xe's are a valuable tool f or investigating the structure and function of IP3 receptors and Ca2signaling in neuronal and nonneuronal cells.