Abstract
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.
Highlights
Pinnatoxins (PnTXs) A–D were originally identified in the digestive glands of the bivalve mollusksPinna attenuata and Pinna muricata following food poisoning outbreaks that were linked to these shellfish in China and Japan [1,2,3,4]
Our results show that synaptic transmission is strongly impaired by both PnTX-A and G, Overall,that ourboth results show that block, synaptic is strongly impaired by and and suggest phycotoxins in atransmission reversible manner, the interaction of both
PnTX-A and G blocked, in a reversible manner, nerve-evoked muscle contraction in the mouse peroneal nerve-extensor digitorum longus (EDL) muscle preparation without affecting directly-elicited twitch or tetanic contractions. This is consistent with previous work done with other cyclic imine toxins like GYM-A [38], 13-SPX-C, and 13,19-didesmethyl spirolide C [39]
Summary
Pinnatoxins (PnTXs) A–D were originally identified in the digestive glands of the bivalve mollusksPinna attenuata and Pinna muricata following food poisoning outbreaks that were linked to these shellfish in China and Japan [1,2,3,4]. Pinna muricata following food poisoning outbreaks that were linked to in the French named Vulcanodinium rugosum discovered in water samples of Mediterranean lagoons these shellfish in China and Japan [1,2,3,4]. It is still unclear whether PnTXs were the cause of coast [11]. Isolated and dinoflagellate structurally characterized extracts of Pacific oysters (Crassostrea gigas) and razorfish (Pinna was first reported in France in 2011from [12], but retro-analysis of contaminated shellfish samples revealed bicolor) from South Australia [5,6]. There is evidence that the harmful reported positive for PnTXs, the discovery of a peridinoid dinoflagellate producing
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