Journal
TOXINS
Volume 8, Issue 9, Pages -Publisher
MDPI AG
DOI: 10.3390/toxins8090249
Keywords
dinoflagellate toxin; spirolides; nicotinic acetylcholine receptors; neuromuscular transmission; Xenopus oocytes; nicotinic currents; competition-binding assays; molecular docking
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Funding
- Agence Nationale de la Recherche (France) [ANR-12-ASTR-0037-AQUANEUROTOX]
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The cyclic imine toxin 20-methyl spirolide G (20-meSPX-G), produced by the toxigenic dinoflagellate Alexandrium ostenfeldii/Alexandrium peruvianum, has been previously reported to contaminate shellfish in various European coastal locations, as revealed by mouse toxicity bioassay. The aim of the present study was to determine its toxicological profile and its molecular target selectivity. 20-meSPX-G blocked nerve-evoked isometric contractions in isolated mouse neuromuscular preparations, while it had no action on contractions elicited by direct electrical stimulation, and reduced reversibly nerve-evoked compound muscle action potential amplitudes in anesthetized mice. Voltage-clamp recordings in Xenopus oocytes revealed that 20-meSPX-G potently inhibited currents evoked by ACh on Torpedo muscle-type and human 7 nicotinic acetylcholine receptors (nAChR), whereas lower potency was observed in human 42 nAChR. Competition-binding assays showed that 20-meSPX-G fully displaced [H-3]epibatidine binding to HEK-293 cells expressing the human 32 (Ki = 0.040 nM), whereas a 90-fold lower affinity was detected in human 42 nAChR. The spirolide displaced [I-125]-bungarotoxin binding to Torpedo membranes (Ki = 0.028 nM) and in HEK-293 cells expressing chick chimeric 7-5HT(3) nAChR (Ki = 0.11 nM). In conclusion, this is the first study to demonstrate that 20-meSPX-G is a potent antagonist of nAChRs, and its subtype selectivity is discussed on the basis of molecular docking models.
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