Gambierol Potently Increases Evoked Quantal Transmitter Release and Reverses Pre- and Post-Synaptic Blockade at Vertebrate Neuromuscular Junctions

Jordi Molgó, Sébastien Schlumberger, Makoto Sasaki, Haruhiko Fuwa, M. Carmen Louzao, Luis M. Botana, Denis Servent, Evelyne Benoit

Research output: Contribution to journalArticlepeer-review

Abstract

Gambierol is a marine polycyclic ether toxin, first isolated from cultured Gambierdiscus toxicus dinoflagellates collected in French Polynesia. The chemical synthesis of gambierol permitted the analyses of its mode of action which includes the selective inhibition of voltage-gated K+ (KV) channels. In the present study we investigated the action of synthetic gambierol at vertebrate neuromuscular junctions using conventional techniques. Gambierol was studied on neuromuscular junctions in which muscle nicotinic ACh receptors have been blocked with d-tubocurarine (postsynaptic block), or in junctions in which quantal ACh release has been greatly reduced by a low Ca2+–high Mg2+ medium or by botulinum neurotoxin type-A (BoNT/A) (presynaptic block). Results show that nanomolar concentrations of gambierol inhibited the fast K+ current and prolonged the duration of the presynaptic action potential in motor nerve terminals, as revealed by presynaptic focal current recordings, increased stimulus-evoked quantal content in junctions blocked by high Mg2+–low Ca2+ medium, and by BoNT/A, reversed the postsynaptic block produced by d-tubocurarine and increased the transient Ca2+ signals in response to nerve-stimulation (1–10 Hz) in nerve terminals loaded with fluo-3/AM. The results suggest that gambierol, which on equimolar basis is more potent than 3,4-diaminopyridine, can have potential application in pathologies in which it is necessary to antagonize pre- or post-synaptic neuromuscular block, or both. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Original languageEnglish
Pages (from-to)106-116
Number of pages11
JournalNeuroscience
Volume439
DOIs
Publication statusPublished - 2020 Jul 15

Keywords

  • Ca transients
  • botulinum type A neurotoxin
  • marine biotoxin
  • nerve terminal
  • potassium current
  • quantal transmitter release

ASJC Scopus subject areas

  • Neuroscience(all)

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