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National Institute of Environmental Health Sciences

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Publication Detail

Title: Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor.

Authors: Gafni, J; Munsch, J A; Lam, T H; Catlin, M C; Costa, L G; Molinski, T F; Pessah, I N

Published In Neuron, (1997 Sep)

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.

PubMed ID: 9331361 Exiting the NIEHS site

MeSH Terms: Alkaloids/pharmacology*; Animals; Antineoplastic Agents/pharmacology*; Astrocytes/chemistry; Astrocytes/drug effects; Astrocytes/metabolism; Biological Transport/drug effects; Bradykinin/pharmacology; Caffeine/pharmacology; Calcium Channels/chemistry*; Calcium Channels/metabolism; Calcium/metabolism; Central Nervous System Stimulants/pharmacology; Cytosol/chemistry; Cytosol/metabolism; Dose-Response Relationship, Drug; Inositol 1,4,5-Trisphosphate Receptors; Inositol 1,4,5-Trisphosphate/metabolism; Ionomycin/pharmacology; Ionophores/pharmacology; Macrocyclic Compounds; Membrane Proteins/physiology; Neurons/chemistry; Neurons/drug effects*; Neurons/metabolism; Oxazoles/pharmacology; PC12 Cells; Porifera/chemistry*; Quinolizines/pharmacology*; Rabbits; Rats; Receptors, Cytoplasmic and Nuclear/chemistry*; Receptors, Cytoplasmic and Nuclear/metabolism; Ryanodine/pharmacology

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