Abongwa Melanie, Baber Katherine E, Martin Richard J, Robertson Alan P
Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
Invert Neurosci. 2016 Dec;16(4):10. doi: 10.1007/s10158-016-0193-4. Epub 2016 Dec 19.
Nematode parasite infections pose a significant threat in human and veterinary medicine. At least a third of the world's population is at risk from nematode parasite infections. These infections not only cause health problems, but also cause loss of livestock production and hence, economic losses. Anthelmintic drugs are the mainstay by which control of nematode parasite infections is achieved. Many of the currently available anthelmintics act on nicotinic acetylcholine receptors (nAChRs). However, the detailed mode of action (MOA) of these anthelmintics is not clearly understood. Elucidation of the MOA of anthelmintics is highly desirable; an in-depth knowledge of the MOA will better inform on mechanisms of resistance development and on ways to slow down or overcome resistance. The cholinomimetic anthelmintic, morantel, has a complex MOA involving the activation and block of levamisole-sensitive single nAChR channels (L-type nAChR or L-nAChR). More recently, morantel has been demonstrated to activate Haemonchus contortus and Parascaris equorum ACR-26/ACR-27 nAChRs expressed in Xenopus laevis oocytes. Previous studies in our laboratory, however, have shown morantel does not activate the nicotine-sensitive nAChR (N-type nAChR or N-nAChR), Ascaris suum ACR-16 (Asu-ACR-16). In this study, we used two-electrode voltage-clamp (TEVC) electrophysiology to investigate the inhibitory effects of morantel, on expressed Asu-ACR-16 nAChRs in X. laevis oocytes. Our results show that morantel acts as a non-competitive antagonist on Asu-ACR-16. This non-competitive antagonism by morantel was further demonstrated to be voltage-sensitive. We conclude based on our findings that morantel is a non-competitive voltage-sensitive open channel blocker of Asu-ACR-16.
线虫寄生虫感染在人类医学和兽医学中构成重大威胁。世界上至少三分之一的人口面临线虫寄生虫感染的风险。这些感染不仅会引发健康问题，还会导致牲畜生产损失，进而造成经济损失。驱虫药物是实现线虫寄生虫感染控制的主要手段。目前许多可用的驱虫药作用于烟碱型乙酰胆碱受体（nAChRs）。然而，这些驱虫药的详细作用模式（MOA）尚不清楚。阐明驱虫药的作用模式非常必要；深入了解作用模式将更好地为耐药性产生机制以及减缓或克服耐药性的方法提供信息。拟胆碱驱虫药噻嘧啶具有复杂的作用模式，涉及对左旋咪唑敏感的单nAChR通道（L型nAChR或L-nAChR）的激活和阻断。最近，已证明噻嘧啶可激活在非洲爪蟾卵母细胞中表达的捻转血矛线虫和马副蛔虫ACR-26/ACR-27 nAChRs。然而，我们实验室之前的研究表明，噻嘧啶不会激活对尼古丁敏感的nAChR（N型nAChR或N-nAChR），即猪蛔虫ACR-16（Asu-ACR-16）。在本研究中，我们使用双电极电压钳（TEVC）电生理学来研究噻嘧啶对非洲爪蟾卵母细胞中表达的Asu-ACR-16 nAChRs的抑制作用。我们的结果表明，噻嘧啶对Asu-ACR-16起非竞争性拮抗剂的作用。噻嘧啶的这种非竞争性拮抗作用进一步被证明是电压敏感的。基于我们的研究结果，我们得出结论，噻嘧啶是Asu-ACR-16的非竞争性电压敏感开放通道阻滞剂。
