The insect nervous system is the target of &gt;85% of insecticides, yet the development of resistance to the majority of these insecticides has highlighted the need for the identification of novel biochemical targets that would mitigate established resistance mechanisms. Inward rectifier potassium (Kir) channels are of growing interest within the field of insecticide science as they have been shown to be critical for proper function of various insect systems. Despite the increased focus to insect Kir channels, the physiological role and toxicological potential of neural Kir channels are poorly understood and thus, we combined chemical and genetic technologies to determine the impact of reduced Kir function to neural activity and insect survivorship. We performed neurophysiological recordings of the excised Drosophila central nervous system (CNS) to test the hypothesis that Kir channels are critical for proper neural transmission in insects. Exposure to 300 nM VU041 increased the spike discharge frequency by 32 ± 6%, a statistically significant increase when compared to baseline spike discharge frequency (P&lt;0.05). At increasing concentrations, VU041 was found to have a depressant effect on the Drosophila CNS activity with an IC50 of 23 μM. To identify the spatial expression patterns of Kir channels in the fly central nervous system, we utilized a specific antibody for Drosophila Kirs and GAL4/UAS techniques to fluorescently label specific glial cell types and central neurons. Fluorescent microscopy clearly shows Kir proteins are localized to glial cells and not central neurons. The localization patterns were validated through voltage-clamp electrophysiology studies that show a large inward K+ conductance in glia cells, but not neurons. Importantly, exposure of Aedes aegypti and Drosophila melanogaster to VU041, an insect specific inhibitor of Kir channels, induced acute toxicity reminiscent of nervous system poisoning. These data suggest neural Kir channels are a putative target site for insecticide development.

Inducing neural failure through chemical inhibition of insect inward rectifier potassium channels

2019 Fall National Meeting

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