Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
PLoS Pathog. 2019 Jan 29;15(1):e1007570. doi: 10.1371/journal.ppat.1007570. eCollection 2019 Jan.
Glutamate-gated chloride channel receptors (GluClRs) mediate inhibitory neurotransmission at invertebrate synapses and are primary targets of parasites that impact drastically on agriculture and human health. Ivermectin (IVM) is a broad-spectrum pesticide that binds and potentiates GluClR activity. Resistance to IVM is a major economic and health concern, but the molecular and synaptic mechanisms of resistance are ill-defined. Here we focus on GluClRs of the agricultural endoparasite, Haemonchus contortus. We demonstrate that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times. We further demonstrate that IVM greatly enhances the active durations of single receptors. These effects are greatly attenuated when endogenous IVM-insensitive subunits are incorporated into GluClRs, suggesting a mechanism of IVM resistance that does not affect glutamate sensitivity. We discovered functional groups of IVM that contribute to tuning its potency at different isoforms and show that the dominant mode of access of IVM is via the cell membrane to the receptor.
谷氨酸门控氯离子通道受体 (GluClRs) 在无脊椎动物突触中介导抑制性神经传递，是影响农业和人类健康的寄生虫的主要靶点。伊维菌素 (IVM) 是一种广谱杀虫剂，可结合并增强 GluClR 的活性。对 IVM 的耐药性是一个主要的经济和健康问题，但耐药性的分子和突触机制尚未明确。在这里，我们专注于农业寄生线虫旋毛虫的 GluClRs。我们证明 IVM 通过诱导持续 15 分钟的紧张电流、增强突触后电流峰值幅度和衰减时间来增强抑制性输入。我们进一步证明 IVM 大大增加了单个受体的活性持续时间。当内源性对 IVM 不敏感的亚基被整合到 GluClRs 中时，这些作用会大大减弱，这表明 IVM 耐药性的机制不会影响谷氨酸的敏感性。我们发现了 IVM 的功能基团，这些基团有助于调节其在不同亚型中的效力，并表明 IVM 的主要进入方式是通过细胞膜进入受体。
