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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaloids / pharmacology*
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Animals
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Antineoplastic Agents / pharmacology*
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Astrocytes / chemistry
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Astrocytes / drug effects
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Astrocytes / metabolism
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Biological Transport / drug effects
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Bradykinin / pharmacology
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Caffeine / pharmacology
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Calcium / metabolism
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Calcium Channels / chemistry*
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Calcium Channels / metabolism
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Central Nervous System Stimulants / pharmacology
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Cytosol / chemistry
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Cytosol / metabolism
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Dose-Response Relationship, Drug
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Inositol 1,4,5-Trisphosphate / metabolism
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Inositol 1,4,5-Trisphosphate Receptors
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Ionomycin / pharmacology
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Ionophores / pharmacology
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Macrocyclic Compounds
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Membrane Proteins / physiology
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Neurons / chemistry
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Neurons / drug effects*
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Neurons / metabolism
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Oxazoles / pharmacology
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PC12 Cells
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Porifera / chemistry*
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Quinolizines / pharmacology*
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Rabbits
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Rats
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Receptors, Cytoplasmic and Nuclear / chemistry*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Ryanodine / pharmacology
Substances
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Alkaloids
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Antineoplastic Agents
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Calcium Channels
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Central Nervous System Stimulants
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Inositol 1,4,5-Trisphosphate Receptors
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Ionophores
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Macrocyclic Compounds
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Membrane Proteins
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Oxazoles
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Quinolizines
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Receptors, Cytoplasmic and Nuclear
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xestospongin A
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xestospongin D
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demethylxestospongine B
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Ryanodine
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Caffeine
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Ionomycin
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Inositol 1,4,5-Trisphosphate
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xestospongin B
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Bradykinin
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Calcium