Gambierol enhances evoked quantal transmitter release and blocks a potassium current in motor nerve terminals of the mouse neuromuscular junction

Jordi Molgó (1, 2, 3, 4) , Sébastien Schlumberger (2) , Makoto Sasaki (5) , Haruhiko Fuwa (5) , Carmen M. Louzao (6) , Luis M Botana (6) , Denis Servent (1, 3, 4) , Evelyne Benoit (1, 2, 3, 4)

1 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
2 NeuroPSI - Institut des Neurosciences Paris-Saclay
3 SIMOPRO
4 MTS - Médicaments et Technologies pour la Santé
5 Department of Biomolecular Sciences, Graduate School of Life Sciences
6 Departamento de Farmacología, Facultad de Veterinaria

In recent years, a great interest was developed to synthetize biologically-active natural products of marine origin. This is due to both their complex molecular structures and chemical diversity, and also to their unique biological activities. Among ladder-shaped toxins, gambierol, originally isolated from cultured Gambierdiscus toxicus dinoflagellate cells, together with ciguatoxins, has been successfully synthesized permitting detailed analyses of its mode and mechanism of action. Gambierol and analogs are known to inhibit some voltage-gated K+ (Kv) channel subtypes in various cell types. The aim of the present study was (i) to investigate whether gambierol has an action on quantal transmitter release evoked by nerve impulses and (ii) to determine whether Kv channels in motor nerve terminals of the mammalian neuromuscular junction are sensitive to the toxin action. Using electrophysiological techniques, the results obtained show that gambierol (2-20 nM) had no significant action on the resting membrane potential of mouse hemidiaphragm muscle fibers. In addition, spontaneous quantal transmitter release, measured by recording spontaneous miniature endplate potential frequency, remained unaffected by gambierol in resting neuromuscular junction. Gambierol (2 nM) increased about eight-fold the mean quantal content of evoked endplate potentials, as determined at individual junctions of the phrenic-hemidiaphragm preparation equilibrated in a low-Ca2+ and high-Mg2+ medium. The ability of gambierol to enhance quantal transmitter release was related to the reduction of a fast K+ current in nerve terminals. Overall, the present results show for the first time that gambierol enhances evoked quantal transmitter release in response to nerve stimuli, suggesting that it can be used to reverse pre- or post-synaptic neuromuscular blockade.

Mots clés: Gambierol; marine biotoxin; nerve terminal; quantal transmitter release; potassium current

Domaines: Neurosciences [q-bio.NC]; Toxicologie

Jordi Molgó, Sébastien Schlumberger, Makoto Sasaki, Haruhiko Fuwa, Carmen M. Louzao, et al.. Gambierol enhances evoked quantal transmitter release and blocks a potassium current in motor nerve terminals of the mouse neuromuscular junction. Hess P. (Ed.), International Society for the Study of Harmful Algae (ISSHA) and Institut Francais de Recherche pour l'Exploitation de la Mer (Ifremer), in cooperation with the Intergovernmental Oceanographic Commission of the United Nations Educational, Scientific and Cultural Organization (IOC UNESCO). Harmful Algae 2018 – From ecosystems to socio-ecosystems, pp.147-150, 2020. ⟨hal-02934507⟩