Eat-2-ing away: acetylcholine receptor binding subunits lacking vicinal cysteines, a new pharmacophore for mitigation of plant parasitic infection.

Eat-2-ingaway：缺乏邻位半胱氨酸的乙酰胆碱受体结合亚基，这是一种减轻植物寄生虫感染的新药效团。

• 批准号: 2597113
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2597113
• 关键词: Eat; ing; away; acetylcholine; receptor

Chemicals acting on neuromuscular transmission that control insects and nematode movement have provided successful pest management. An important criterion in ongoing development of this approach is selective toxicityThis allows treatments to act as potent pest control while having limited deleterious effect on non-harmful organisms. Conventionally, this is addressed by defining receptor classes selectively found between phyla and species. We have recently established a tissue selective sensitivity in the cholinergic transmission that pharmacologically discriminates between locomotion and feeding in nematodes (Gonzalez, J Biol Chem in submission). This difference is due to the distinct nature of the major acetylcholine receptors underpinning cholinergic transmission at these neuromuscular junctions. Pharyngeal transmission is dependent on an under investigated excitatory nicotinic acetylcholine receptor called EAT-2. This receptor is among an emerging class of homo-oligomeric receptors activated by the endogenous agonist acetylcholine. However, EAT-2 is unique amongst nicotinic receptors in lacking the signature vicinal cysteine in the highly evolutionary conserved loop C of the agonist binding site. It was previously assumed that this vicinal cysteine was essential for acetylcholine receptor activation in both homo and hetero-oligomeric receptors. This feature of the agonist binding site exists in the even more poorly investigated acetylcholine gated chloride channels (PLoS Pathog 2020 16(4):e1008396). This highlights that nicotinic receptors can present a distinct pharmacophore to provide a route to selective anthelmintic chemicals. Importantly, the prototype EAT-2 controls feeding in the model organism C. elegans and is found in other nematodes including the plant parasitic nematodes. The proposal will seek to identify selective pharmacology of EAT-2 and other non-vicinal acetylcholine receptors. The student will probe their functional role in key plant parasitic nematodes and address if this under investigated determinant of the neuromuscular function can act as credible target for the chemical mitigation of nematode pests.

作用于控制昆虫和线虫运动的神经肌肉传递的化学物质已经提供了成功的害虫防治。这种方法持续发展的一个重要标准是选择性毒性，这使得治疗能够起到有效的害虫控制作用，同时对无害生物体产生有限的有害影响。传统上，这是通过定义在门和物种之间选择性发现的受体类别来解决的。我们最近在胆碱能传递中建立了组织选择性敏感性，可以从药理学上区分线虫的运动和摄食（Gonzalez，J Biol Chem 已提交）。这种差异是由于这些神经肌肉接头处支撑胆碱能传递的主要乙酰胆碱受体的不同性质造成的。咽部传输依赖于一种尚未被研究的兴奋性烟碱乙酰胆碱受体，称为 EAT-2。该受体是由内源性激动剂乙酰胆碱激活的新兴一类同源寡聚受体之一。然而，EAT-2 在烟碱受体中是独一无二的，因为在激动剂结合位点的高度进化保守的环 C 中缺乏标志性的邻位半胱氨酸。先前认为该邻近半胱氨酸对于同源和异源寡聚受体中的乙酰胆碱受体激活都是必需的。激动剂结合位点的这一特征存在于研究更差的乙酰胆碱门控氯离子通道中 (PLoS Pathog 2020 16(4):e1008396)。这强调烟碱受体可以呈现独特的药效团，为选择性驱虫化学物质提供途径。重要的是，原型 EAT-2 控制着模式生物秀丽隐杆线虫的摄食，并且在包括植物寄生线虫在内的其他线虫中也有发现。该提案将寻求确定 EAT-2 和其他非邻位乙酰胆碱受体的选择性药理学。学生将探讨它们在关键植物寄生线虫中的功能作用，并探讨正在研究的神经肌肉功能决定因素是否可以作为线虫害虫化学缓解的可靠目标。