The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Toxicology and Applied Pharmacology Année : 2012

The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors.

Résumé

APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC(50)=0.74 μM), without affecting directly-elicited twitch tension up to 2.72 μM. The compound (0.007-3.40 μM) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 μM, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC(50)=0.36 μM) without significant change in the resting membrane potential of the muscle fibers up to 3.40 μM. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (α1(2)β1γδ) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC(50)=0.0005 μM), indicating a higher affinity of the compound for Torpedo (α1(2)β1γδ) than for the mouse (α1(2)β1γε) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction.

Dates et versions

hal-00781193 , version 1 (25-01-2013)

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Citer

Marjana Grandič, Rómulo Aráoz, Jordi Molgó, Tom Turk, Kristina Sepčić, et al.. The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors.. Toxicology and Applied Pharmacology, 2012, 265 (2), pp.221-8. ⟨10.1016/j.taap.2012.09.024⟩. ⟨hal-00781193⟩

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