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

作用于控制昆虫和线虫运动的神经肌肉传递的化学品提供了成功的害虫管理。在这种方法的持续发展中，一个重要的标准是选择性毒性，这使得处理能够作为有效的害虫控制，同时对无害生物体具有有限的有害影响。常规地，这通过定义在门和种之间选择性地发现的受体类别来解决。我们最近已经建立了胆碱能传递的组织选择性敏感性，其可区分线虫的运动和进食（Gonzalez，提交的J Biol Chem）。这种差异是由于在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。咽部传输依赖于一种研究不足的兴奋性烟碱乙酰胆碱受体EAT-2。该受体是一类由内源性激动剂乙酰胆碱激活的同源寡聚受体。然而，EAT-2在烟碱受体中是独特的，在激动剂结合位点的高度进化保守环C中缺乏签名邻位半胱氨酸。以前认为，这种邻位半胱氨酸是必不可少的乙酰胆碱受体的激活，在同源和异源寡聚体受体。激动剂结合位点的这种特征存在于研究得更少的乙酰胆碱门控氯离子通道中（PLoS Pathog 2020 16（4）：e1008396）。这突出表明，烟碱受体可以提供一个独特的药效团，以提供一个选择性驱虫化学品的路线。重要的是，原型EAT-2控制模式生物C的摄食。线虫，并在包括植物寄生线虫在内的其他线虫中发现。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。学生将探索它们在关键植物寄生线虫中的功能作用，并解决这一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。

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.