Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors.
We present an overview of the toxicological profile of the fast-acting, lipophilic macrocyclic imine toxins, an emerging family of organic compounds associated with algal blooms, shellfish contamination and neurotoxicity. Worldwide, shellfish contamination incidents are expanding; therefore, the significance of these toxins for the shellfish food industry deserves further study. Emphasis is directed to the dinoflagellate species involved in their production, their chemical structures, and their specific mode of interaction with their principal natural molecular targets, the nicotinic acetylcholine receptors, or with the soluble acetylcholine-binding protein, used as a surrogate receptor model. The dinoflagellates Karenia selliformis and Alexandrium ostenfeldii / A. peruvianum have been implicated in the biosynthesis of gymnodimines and spirolides, while Vulcanodinium rugosum is the producer of pinnatoxins and portimine. The cyclic imine toxins are characterized by a macrocyclic skeleton comprising 14-27 carbon atoms, flanked by two conserved moieties, the cyclic imine and the spiroketal ring system. These phycotoxins generally display high affinity and broad specificity for the muscle type and neuronal nicotinic acetylcholine receptors, a feature consistent with their binding site at the receptor subunit interfaces, composed of residues highly conserved among all nAChRs, and explaining the diverse toxicity among animal species. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Commissariat à l'Energie Atomique et aux énergies alternatives (CEA), Institut de Biologie et Technologies de Saclay (IBITECS), Université Paris-Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.|Institut des Neurosciences Paris-Saclay, UMR 9197, Centre National de la Recherche Scientifique (CNRS)/Université Paris-Sud, Gif-sur-Yvette Cedex, France.
Jordi
J
Molgó
Aix-Marseille Université / Centre National de la Recherche Scientifique, Architecture et Fonction des Macromolécules Biologiques laboratory, Marseille, France.
Pascale
P
Marchot
Commissariat à l'Energie Atomique et aux énergies alternatives (CEA), Institut de Biologie et Technologies de Saclay (IBITECS), Université Paris-Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.|Institut des Neurosciences Paris-Saclay, UMR 9197, Centre National de la Recherche Scientifique (CNRS)/Université Paris-Sud, Gif-sur-Yvette Cedex, France.
Rómulo
R
Aráoz
Commissariat à l'Energie Atomique et aux énergies alternatives (CEA), Institut de Biologie et Technologies de Saclay (IBITECS), Université Paris-Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.|Institut des Neurosciences Paris-Saclay, UMR 9197, Centre National de la Recherche Scientifique (CNRS)/Université Paris-Sud, Gif-sur-Yvette Cedex, France.
Evelyne
E
Benoit
Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles, UPR 2301, Labex LERMIT, Gif-sur-Yvette, France.
Bogdan I
BI
Iorga
Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California, USA.
Armen
A
Zakarian
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
Palmer
P
Taylor
Aix-Marseille Université / Centre National de la Recherche Scientifique, Architecture et Fonction des Macromolécules Biologiques laboratory, Marseille, France.
Yves
Y
Bourne
Commissariat à l'Energie Atomique et aux énergies alternatives (CEA), Institut de Biologie et Technologies de Saclay (IBITECS), Université Paris-Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.
Denis
D
Servent
D000109:Acetylcholine / Q000037:antagonists & inhibitors*; D000818:Animals; D004141:Dinoflagellida / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007097:Imines / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism / Q000494:pharmacology*
D007097:Imines; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014118:Toxins, Biological; D000109:Acetylcholine
acetylcholine-binding protein; dinoflagellates; gymnodimines; marine phycotoxins; muscarinic acetylcholine receptor; nicotinic acetylcholine receptor; pinnatoxins; spirolides