title: The Neurotoxic Effect of 13,19-Didesmethyl and 13-Desmethyl Spirolide C Phycotoxins Is Mainly Mediated by Nicotinic Rather Than Muscarinic Acetylcholine Receptors.
abstract: Spirolides are a large family of lipophilic marine toxins produced by dinoflagellates that have been detected in contaminated shellfish. Among them, 13,19-didesmethyl and 13-desmethyl spirolide C phycotoxins are widely distributed and their mode of action needs to be clearly defined. In order to further characterize the pharmacological profiles of these phycotoxins on various nicotinic acetylcholine receptor (nAChR) subtypes and to examine whether they act on muscarinic receptors (mAChRs), functional electrophysiological studies and competition binding experiments have been performed. While 13-desmethyl spirolide C interacted efficiently with sub-nanomolar affinities and low selectivity with muscular and neuronal nAChRs, 13,19-didesmethyl spirolide C was more selective of muscular and homopentameric α7 receptors and recognized only weakly neuronal heteropentameric receptors, especially the α4β2 subtype. Thus, the presence of an additional methyl group on the tetrahydropyran ring significantly modified the pharmacological profile of 13-desmethyl spirolide C by notably increasing its affinity on certain neuronal nAChRs. Structural explanations of this selectivity difference are proposed, based on molecular docking experiments modeling different spirolide-receptor complexes. In addition, the 2 spirolides interacted only with low micromolar affinities with the 5 mAChRs, highlighting that the toxicity of the spirolide C analogs is mainly due to their high inhibition potency on various peripheral and central nAChRs and not to their low ability to interact with mAChR subtypes.
authors.affiliation: *CNRS, Institut des Neurosciences Paris-Saclay, UMR 9197, Gif sur Yvette, France; CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Toxines Récepteurs et Canaux, Gif sur Yvette, France; and.
authors.forename: Romulo
authors.initials: R
authors.lastname: Aráoz
authors.affiliation: *CNRS, Institut des Neurosciences Paris-Saclay, UMR 9197, Gif sur Yvette, France;
authors.forename: Gilles
authors.initials: G
authors.lastname: Ouanounou
authors.affiliation: CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Gif sur Yvette, France.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Iorga
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Toxines Récepteurs et Canaux, Gif sur Yvette, France; and.
authors.forename: Amélie
authors.initials: A
authors.lastname: Goudet
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Toxines Récepteurs et Canaux, Gif sur Yvette, France; and.
authors.forename: Doria
authors.initials: D
authors.lastname: Alili
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Toxines Récepteurs et Canaux, Gif sur Yvette, France; and.
authors.forename: Muriel
authors.initials: M
authors.lastname: Amar
authors.affiliation: *CNRS, Institut des Neurosciences Paris-Saclay, UMR 9197, Gif sur Yvette, France; CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Toxines Récepteurs et Canaux, Gif sur Yvette, France; and.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Benoit
authors.affiliation: *CNRS, Institut des Neurosciences Paris-Saclay, UMR 9197, Gif sur Yvette, France; CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Toxines Récepteurs et Canaux, Gif sur Yvette, France; and.
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.affiliation: *CNRS, Institut des Neurosciences Paris-Saclay, UMR 9197, Gif sur Yvette, France; denis.servent@cea.fr.
authors.forename: Denis
authors.initials: D
authors.lastname: Servent
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007537:Isometric Contraction / Q000187:drug effects; D008387:Marine Toxins / Q000633:toxicity*; D051379:Mice; D062105:Molecular Docking Simulation; D032342:Muscle Cells / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects
chemical_list: C544516:13,19-didesmethyl spirolide C; C517170:13-desmethylspirolide C; D008387:Marine Toxins; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2
keywords: Xenopus oocytes; Xenopus skeletal myocytes, acetylcholine; marine phycotoxins; muscarinic acetylcholine receptors; neuromuscular junction; nicotinic acetylcholine receptors; spirolides