期刊
JOURNAL OF NEUROCHEMISTRY
卷 107, 期 4, 页码 952-963出版社
WILEY
DOI: 10.1111/j.1471-4159.2008.05677.x
关键词
gymnodimine; marine phycotoxins; muscle nicotinic acetylcholine receptor; neuromuscular junction; neuronal nicotinic receptors
资金
- European Program: Food Quality and Safety [FOOD-CT-2004-514055-DETECTOX]
- Agence Nationale de la Recherche [PCV07-194417-NEUROSPIROIMINE]
- Pasteur Institute of Tunisia
- CEA
- DETECTOX
- CNRS
- Cooperation Inter-Universitaire Franco-Tunisienne
- Utique program [08G093]
Gymnodimines (GYMs) are phycotoxins exhibiting unusual structural features including a spirocyclic imine ring system and a trisubstituted tetrahydrofuran embedded within a 16-membered macrocycle. The toxic potential and the mechanism of action of GYM-A, highly purified from contaminated clams, have been assessed. GYM-A in isolated mouse phrenic hemidiaphragm preparations produced a concentration- and time-dependent block of twitch responses evoked by nerve stimulation, without affecting directly elicited muscle twitches, suggesting that it may block the muscle nicotinic acetylcholine (ACh) receptor (nAChR). This was confirmed by the blockade of miniature endplate potentials and the recording of subthreshold endplate potentials in GYM-A paralyzed frog and mouse isolated neuromuscular preparations. Patch-clamp recordings in Xenopus skeletal myocytes revealed that nicotinic currents evoked by constant iontophoretical ACh pulses were blocked by GYM-A in a reversible manner. GYM-A also blocked, in a voltage-independent manner, homomeric human alpha 7 nAChR expressed in Xenopus oocytes. Competition-binding assays confirmed that GYM-A is a powerful ligand interacting with muscle-type nAChR, heteropentameric alpha 3 beta 2, alpha 4 beta 2, and chimeric alpha 7-5HT(3) neuronal nAChRs. Our data show for the first time that GYM-A broadly targets nAChRs with high affinity explaining the basis of its neurotoxicity, and also pave the way for designing specific tests for accurate GYM-A detection in shellfish samples.
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