Abstract
Gymnodimines and spirolides are cyclic imine phycotoxins and known antagonists of nicotinic acetylcholine receptors (nAChRs). We investigated the effect of gymnodimine A (GYM A) and 13-desmethyl spirolide C (SPX 1) from Alexandrium ostenfeldii on rat pheochromocytoma (PC12) cells by monitoring intracellular calcium levels ([Ca]i). Using whole cells, the presence of 0.5 µM of GYM A or SPX 1 induced an increase in [Ca]i mediated by acetylcholine receptors (AChRs) and inhibited further activation of AChRs by acetylcholine (ACh). To differentiate the effects of GYM A or SPX 1, the toxins were applied to cells with pharmacologically isolated nAChRs and muscarinic AChRs (mAChRs) as mediated by the addition of atropine and tubocurarine, respectively. GYM A and SPX 1 activated nAChRs and inhibited the further activation of nAChRs by ACh, indicating that both toxins mimicked the activity of ACh. Regarding mAChRs, a differential response was observed between the two toxins. Only GYM A activated mAChRs, resulting in elevated [Ca]i, but both toxins prevented a subsequent activation by ACh. The absence of the triketal ring system in GYM A may provide the basis for a selective activation of mAChRs. GYM A and SPX 1 induced no changes in [Ca]i when nAChRs and mAChRs were inhibited simultaneously, indicating that both toxins target AChRs.
Highlights
The frequency and widespread occurrence of marine biotoxins associated with microalgae has increased over the years [1]
gymnodimine A (GYM A) activated muscarinic AChRs (mAChRs), resulting in elevated [Ca]i, but both toxins prevented a subsequent activation by ACh
The absence of the triketal ring system in GYM A may provide the basis for a selective activation of mAChRs
Summary
The frequency and widespread occurrence of marine biotoxins associated with microalgae has increased over the years [1]. Among the emerging classes of lipophilic marine toxins are the macrocyclic imine compounds such as prorocentrolides, spiro-prorocentrimine, gymnodimines, spirolides, pinnatoxins, and portimine [2]. Spirolides, one of the classes of cyclic imine, are produced by Alexandrium ostenfeldii [3]. To this day, they have not been found in any other microalgal species. The presence of structurally related gymnodimines and spirolides in a single microalgal species suggests that both toxins share a common biosynthetic pathway. In addition to the cyclic imine moiety, the butenolide side chain is identical for gymnodimines and spirolides, indicating a common function in both toxin types [10]
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