Molgó Jordi, Schlumberger Sébastien, Sasaki Makoto, Fuwa Haruhiko, Louzao M Carmen, Botana Luis M, Servent Denis, Benoit Evelyne
CEA, Institut des sciences du vivant Frédéric Joliot, Service d'Ingénierie Moléculaire des Protéines, Université Paris-Saclay, bâtiment 152, 91191 Gif sur Yvette, France; Institut des Neurosciences Paris-Saclay, UMR 9197 CNRS / Université Paris-Sud, CNRS, Gif sur Yvette, France.
Institut des Neurosciences Paris-Saclay, UMR 9197 CNRS / Université Paris-Sud, CNRS, Gif sur Yvette, France.
Neuroscience. 2020 Jul 15;439:106-116. doi: 10.1016/j.neuroscience.2019.06.024. Epub 2019 Jun 28.
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 (K) 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 Ca-high Mg 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 Mg-low Ca medium, and by BoNT/A, reversed the postsynaptic block produced by d-tubocurarine and increased the transient Ca 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.
冈比毒素是一种海洋多环醚毒素，最初从法属波利尼西亚采集的养殖有毒冈比甲藻中分离得到。冈比毒素的化学合成使得对其作用方式的分析成为可能，其作用方式包括对电压门控钾（K）通道的选择性抑制。在本研究中，我们使用传统技术研究了合成冈比毒素在脊椎动物神经肌肉接头处的作用。我们在以下两种神经肌肉接头上研究了冈比毒素的作用：一种是肌肉烟碱型乙酰胆碱受体已被筒箭毒碱阻断的接头（突触后阻断），另一种是通过低钙高镁培养基或A型肉毒杆菌神经毒素（BoNT/A）使量子乙酰胆碱释放大幅减少的接头（突触前阻断）。结果表明，纳摩尔浓度的冈比毒素可抑制快速钾电流，并延长运动神经末梢突触前动作电位的持续时间，这通过突触前局部电流记录得以揭示；增加高镁低钙培养基和BoNT/A阻断的接头中刺激诱发的量子含量；逆转筒箭毒碱产生的突触后阻断；并增加在加载了氟-3/AM的神经末梢中对神经刺激（1-10赫兹）的瞬时钙信号。结果表明，在等摩尔基础上比3,4-二氨基吡啶更有效的冈比毒素，在需要拮抗突触前或突触后神经肌肉阻断或两者的病理情况下可能具有潜在应用价值。本文是名为：纪念里卡多·米莱迪——二十至二十一世纪杰出神经科学家的特刊的一部分。
