Controlled fl uctuations in intracellular calcium concentrations play an important role in many cellular processes such as muscle contraction, secretion, metabolism, and neuronal function. Ryanodine receptors (RyR) are intracellular ion channels that mediate the release of calcium ions from internal stores and have been suggested as pharmacological targets for heart disease and neurodegenerative diseases. Bastadins are an ever-growing family of marine natural products isolated from sponges. Seemingly subtle differences in their substitution pattern suffi ce to alter the response observed. To characterize bastadin-induced changes in calcium homeostasis we measured, using FLUO-3, a calciumsensitive fl uorescent probe, the ability of bastadin 5 (positive control) and the acyclic analogues 2a, b and 4 to increase the intracellular calcium concentration in cultured rat cerebellar granule cells. We monitored also the infl ux of extracellular calcium to neurons employing 45Ca isotope. The observed effect of the acyclic analogues on calcium accumulation decreased in order: 4>2b>2a. Addition of ryanodine to medium before application of bastadin abolished analyzed effects. This observation indicates that RyR are the primary targets for their pharmacological activity. Thus, the infl ux of extracellular calcium to bastadin-treated neurons appears to be a secondary effect resulting from the release of calcium from the ryanodine-sensitive pool. Constraining the catechol aryl ether moiety of bastadins by incorporation into a macrocyle is not necessary in order to mimic the effects of these marine natural products on neuronal calcium homeostasis. Simple, acyclic analogues that embody the ìwesternî or ìeasternî parts of bastadins were found to evoke comparable responses with bastadin 5.
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