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J Neurochem ; 107(4): 952-63, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18990115

ABSTRACT

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 alpha7 nAChR expressed in Xenopus oocytes. Competition-binding assays confirmed that GYM-A is a powerful ligand interacting with muscle-type nAChR, heteropentameric alpha3beta2, alpha4beta2, and chimeric alpha7-5HT(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.


Subject(s)
Heterocyclic Compounds, 3-Ring/pharmacology , Hydrocarbons, Cyclic/pharmacology , Imines/pharmacology , Muscle Cells/drug effects , Neuromuscular Junction/drug effects , Receptors, Nicotinic/metabolism , Acetylcholine/pharmacology , Animals , Behavior, Animal/drug effects , Bivalvia/chemistry , Bungarotoxins/metabolism , Cells, Cultured , Chromatography, High Pressure Liquid/methods , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation/methods , Gene Expression/drug effects , Heterocyclic Compounds, 3-Ring/analysis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/classification , Humans , Hydrocarbons, Cyclic/analysis , Hydrocarbons, Cyclic/chemistry , Hydrocarbons, Cyclic/classification , Imines/analysis , Imines/chemistry , Imines/classification , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Mice , Mice, Inbred C57BL , Muscle Cells/metabolism , Neuromuscular Junction/physiology , Neuromuscular Junction/radiation effects , Oocytes , Patch-Clamp Techniques , Protein Binding/drug effects , Synaptic Transmission/drug effects , Xenopus laevis , alpha7 Nicotinic Acetylcholine Receptor
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