3,4-Diaminopyridine antagonizes the block of muscle nicotinic acetylcholine receptor caused by cyclic imine toxins at isolated mouse diaphragm preparations - Archive ouverte HAL Accéder directement au contenu
Poster De Conférence Année : 2023

3,4-Diaminopyridine antagonizes the block of muscle nicotinic acetylcholine receptor caused by cyclic imine toxins at isolated mouse diaphragm preparations

Nicolas Lamassiaude
  • Fonction : Collaborateur
  • PersonId : 1093805
Évelyne Benoit
Rómulo Aráoz

Résumé

Cyclic imine toxins (CiTXs) are a family of worldwide-distributed marine macrocyclic phycotoxins comprising different groups of lipophilic compounds: gymnodimines (GYMs), spirolides, pinnatoxins (PnTXs), pteriatoxins (PteTXs), portimines, prorocentrolides and spiroprorocentrimine. CiTXs and the acyl derivative products of shellfish metabolism contaminate and bioaccumulate in filter-feeding bivalves, edible mollusks and other marine invertebrates and thus, represent a risk for shellfish consumers and a menace for wildlife conservation. All CiTXs studied interact and block, with different affinities, embryonic (α12βγδ) and mature (α12βεδ) nicotinic acetylcholine receptors (nAChRs) expressed in skeletal muscles. 3,4-Diaminopyridine (3,4-DAP) is a well-known K+-channel blocker that prolongs the presynaptic action potential and indirectly enhances the entry of Ca2+ into nerve terminals and, thereby, increases quantal ACh release at the neuromuscular junction. 3,4-DAP is used effectively to treat muscular weakness in various human myasthenic syndromes. The aim of this work was to determine whether 3,4-DAP, which increases quantal ACh release, is able to reverse the action of CiTXs on skeletal muscle expressing α12βεδ nAChRs. The use of isolated mouse phrenic-nerve-hemi-diaphragm muscle preparations enabled monitoring nerve-evoked isometric muscle contraction in the presence of GYM-A, PnTX-A, PnTX-G and PteTX-A and, afterwards, the action of 3,4-DAP (10-100 μM) in the continuous presence of the respective CiTXs. The results show that 3,4-DAP improves neuromuscular function in a time- and concentration-dependent manner and, at the highest concentration used (100 μM), completely reverses the neuromuscular block caused by the CiTX studied. These results support the view that GYM-A, PnTX-A, PnTX-G and PteTX-A are competitive and reversible inhibitors of muscle-type α12βεδ nAChRs. In fact, CiTXs can be typified as competing with the binding of ACh (the natural ligand) to the nAChR. The ability of 3,4-DAP to antagonize the action of CiTXs is related to the increased release of ACh that is able to displace the respective CiTX from their nAChR binding sites.
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Dates et versions

hal-04474247 , version 1 (23-02-2024)

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  • HAL Id : hal-04474247 , version 1

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Nicolas Lamassiaude, Évelyne Benoit, Rómulo Aráoz, Armen Zakarian, Denis Servent, et al.. 3,4-Diaminopyridine antagonizes the block of muscle nicotinic acetylcholine receptor caused by cyclic imine toxins at isolated mouse diaphragm preparations. RT29 – 29th Meeting of the French Society of Toxinology – Toxins: From the Wild to the Lab, Nov 2023, Paris, France. ⟨hal-04474247⟩
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