Syngenta, Jealott's Hill Research Centre, Bracknell, Berkshire, UK.
Institute for Molecular Bioscience, the University of Queensland, Brisbane, Queensland, Australia.
FEBS Lett. 2019 Jun;593(12):1336-1350. doi: 10.1002/1873-3468.13435. Epub 2019 May 31.
The insecticidal effects of ω-hexatoxin-Hv1a, κ-hexatoxin-Hv1c and ω/κ-hexatoxin-Hv1h are currently attributed to action at calcium and potassium channels. By characterizing the binding of these toxins to neuronal membranes, we show that they have more potent effects as positive allosteric modulators (PAMs) of insect nicotinic acetylcholine receptors (nAChRs), consistent with their neuroexcitatory toxicology. Alanine scanning analysis of ω-hexatoxin-Hv1a reveals a structure-activity relationship for binding that mirrors that for insecticidal activity. Spinosyn A does not compete with ω-hexatoxin-Hv-1a for binding, and we show that these two PAMs have distinct pharmacology of binding indicating that they act at different receptor populations. These toxins represent valuable tools for the characterization of insect nAChRs and for the development of more selective agrochemicals.
ω-六桶毒素-Hv1a、κ-六桶毒素-Hv1c 和 ω/κ-六桶毒素-Hv1h 的杀虫作用目前归因于对钙和钾通道的作用。通过对这些毒素与神经元膜的结合进行表征，我们表明它们作为昆虫烟碱型乙酰胆碱受体 (nAChR) 的正变构调节剂 (PAM) 具有更强的作用，这与它们的神经兴奋毒性一致。ω-六桶毒素-Hv1a 的丙氨酸扫描分析揭示了与杀虫活性相似的结合结构-活性关系。斯皮诺菌素 A 不与 ω-六桶毒素-Hv-1a 竞争结合，我们表明这两种 PAM 具有不同的结合药理学，表明它们作用于不同的受体群体。这些毒素为昆虫 nAChR 的表征和更具选择性的农用化学品的开发提供了有价值的工具。
