Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America.
Department of Infectious Diseases and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America.
PLoS Pathog. 2020 Apr 3;16(4):e1008396. doi: 10.1371/journal.ppat.1008396. eCollection 2020 Apr.
Nematode parasites infect approximately 1.5 billion people globally and are a significant public health concern. There is an accepted need for new, more effective anthelmintic drugs. Nicotinic acetylcholine receptors on parasite nerve and somatic muscle are targets of the cholinomimetic anthelmintics, while glutamate-gated chloride channels in the pharynx of the nematode are affected by the avermectins. Here we describe a novel nicotinic acetylcholine receptor on the nematode pharynx that is a potential new drug target. This homomeric receptor is comprised of five non-α EAT-2 subunits and is not sensitive to existing cholinomimetic anthelmintics. We found that EAT-18, a novel auxiliary subunit protein, is essential for functional expression of the receptor. EAT-18 directly interacts with the mature receptor, and different homologs alter the pharmacological properties. Thus we have described not only a novel potential drug target but also a new type of obligate auxiliary protein for nAChRs.
线虫寄生虫感染全球约 15 亿人，是一个重大的公共卫生关注点。人们公认需要新的、更有效的驱虫药物。拟胆碱驱虫药的作用靶点是寄生虫神经和体肌上的烟碱型乙酰胆碱受体，阿维菌素类药物则作用于线虫咽部的谷氨酸门控氯离子通道。本文描述了线虫咽部的一种新型烟碱型乙酰胆碱受体，它可能成为新的药物靶点。这种同型受体由 5 个非-α EAT-2 亚基组成，对现有的拟胆碱驱虫药不敏感。我们发现，新型辅助亚基蛋白 EAT-18 对于受体的功能性表达是必需的。EAT-18 与成熟受体直接相互作用，不同的同源物改变了其药理学特性。因此，我们不仅描述了一个新的潜在药物靶点，还描述了一种新型的烟碱型乙酰胆碱受体必需辅助蛋白。
