title: Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor.
abstract: Xestospongins (Xe's) A, C, D, araguspongine B, and demethylxestospongin B, a group of macrocyclic bis-1-oxaquinolizidines isolated from the Australian sponge, Xestospongia species, are shown to be potent blockers 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 mechanism that is independent of the IP3 effector site. Analysis of Pheochromocytoma cells and primary astrocytes loaded with Ca2+-sensitive dye reveals that XeC selectively blocks bradykinin- and carbamylcholine-induced 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 for investigating the structure and function of IP3 receptors and Ca2+ signaling in neuronal and nonneuronal cells.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gafni
authors.forename: J A
authors.initials: JA
authors.lastname: Munsch
authors.forename: T H
authors.initials: TH
authors.lastname: Lam
authors.forename: M C
authors.initials: MC
authors.lastname: Catlin
authors.forename: L G
authors.initials: LG
authors.lastname: Costa
authors.forename: T F
authors.initials: TF
authors.lastname: Molinski
authors.forename: I N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D047028:Macrocyclic Compounds; D008565:Membrane Proteins / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D016716:PC12 Cells; D011161:Porifera / Q000737:chemistry*; D011807:Quinolizines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D015220:Calcium Channels; D000697:Central Nervous System Stimulants; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007476:Ionophores; D047028:Macrocyclic Compounds; D008565:Membrane Proteins; D010080:Oxazoles; D011807:Quinolizines; D018160:Receptors, Cytoplasmic and Nuclear; C108644:xestospongin A; C108642:xestospongin D; C078550:demethylxestospongine B; D012433:Ryanodine; D002110:Caffeine; D015759:Ionomycin; D015544:Inositol 1,4,5-Trisphosphate; C078549:xestospongin B; D001920:Bradykinin; D002118:Calcium