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Open AccessFeature PaperArticle

Synthetic Pinnatoxins A and G Reversibly Block Mouse Skeletal Neuromuscular Transmission In Vivo and In Vitro

1
Commissariat à l’Energie Atomique et aux énergies Alternatives (CEA), Institut des Sciences du Vivant Frédéric Joliot, Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), CEA de Saclay, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France
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Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR 9197 CNRS/Université Paris-Sud, F-91198 Gif-sur-Yvette, France
3
Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles, UPR 2301, Labex LERMIT, F-91198 Gif-sur-Yvette, France
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Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
*
Author to whom correspondence should be addressed.
J.M. dedicates this article to honor Professor Stephen Thesleff from the University of Lund (Sweden) on the occasion of his 95th birthday, for his human qualities and sincere friendship over the last 40 years.
Mar. Drugs 2019, 17(5), 306; https://doi.org/10.3390/md17050306
Received: 7 May 2019 / Revised: 17 May 2019 / Accepted: 21 May 2019 / Published: 24 May 2019
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
Pinnatoxins (PnTXs) A-H constitute an emerging family belonging to the cyclic imine group of phycotoxins. Interest has been focused on these fast-acting and highly-potent toxins because they are widely found in contaminated shellfish. Despite their highly complex molecular structure, PnTXs have been chemically synthetized and demonstrated to act on various nicotinic acetylcholine receptor (nAChR) subtypes. In the present work, PnTX-A, PnTX-G and analogue, obtained by chemical synthesis with a high degree of purity (>98%), have been studied in vivo and in vitro on adult mouse and isolated nerve-muscle preparations expressing the mature muscle-type (α1)2β1δε nAChR. The results show that PnTX-A and G acted on the neuromuscular system of anesthetized mice and blocked the compound muscle action potential (CMAP) in a dose- and time-dependent manner, using a minimally invasive electrophysiological method. The CMAP block produced by both toxins in vivo was reversible within 6–8 h. PnTX-A and G, applied to isolated extensor digitorum longus nerve-muscle preparations, blocked reversibly isometric twitches evoked by nerve stimulation. The action of PnTX-A was reversed by 3,4-diaminopyridine. Both toxins exerted no direct action on muscle fibers, as revealed by direct muscle stimulation. PnTX-A and G blocked synaptic transmission at mouse neuromuscular junctions and PnTX-A amino ketone analogue (containing an open form of the imine ring) had no effect on neuromuscular transmission. These results indicate the importance of the cyclic imine for interacting with the adult mammalian muscle-type nAChR. Modeling and docking studies revealed molecular determinants responsible for the interaction of PnTXs with the muscle-type nAChR. View Full-Text
Keywords: pinnatoxins; marine phycotoxins; mouse neuromuscular system; compound muscle action potential; synaptic potentials; emerging toxins; cyclic imines pinnatoxins; marine phycotoxins; mouse neuromuscular system; compound muscle action potential; synaptic potentials; emerging toxins; cyclic imines
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MDPI and ACS Style

Benoit, E.; Couesnon, A.; Lindovsky, J.; Iorga, B.I.; Aráoz, R.; Servent, D.; Zakarian, A.; Molgó, J. Synthetic Pinnatoxins A and G Reversibly Block Mouse Skeletal Neuromuscular Transmission In Vivo and In Vitro. Mar. Drugs 2019, 17, 306.

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