Abstract
Mosquito-borne diseases such as malaria and dengue fever take a large toll on global health. The primary chemical agents used for controlling mosquitoes are insecticides that target the nervous system. However, the emergence of resistance in mosquito populations is reducing the efficacy of available insecticides. The development of new insecticides is therefore urgent. Here we show that VU573, a small-molecule inhibitor of mammalian inward-rectifying potassium (Kir) channels, inhibits a Kir channel cloned from the renal (Malpighian) tubules of Aedes aegypti (AeKir1). Injection of VU573 into the hemolymph of adult female mosquitoes (Ae. aegypti) disrupts the production and excretion of urine in a manner consistent with channel block of AeKir1 and renders the mosquitoes incapacitated (flightless or dead) within 24 hours. Moreover, the toxicity of VU573 in mosquitoes (Ae. aegypti) is exacerbated when hemolymph potassium levels are elevated, suggesting that Kir channels are essential for maintenance of whole-animal potassium homeostasis. Our study demonstrates that renal failure is a promising mechanism of action for killing mosquitoes, and motivates the discovery of selective small-molecule inhibitors of mosquito Kir channels for use as insecticides.
Highlights
Mosquitoes are vectors of debilitating diseases that take an immense toll on global health
Of the estimated 50–100 million individuals infected with dengue each year, hundreds of thousands require hospitalization and tens of thousands die [2]. These protozoan and viral pathogens are transmitted to humans solely by adult female mosquitoes, which feed on vertebrate blood to obtain nutrients for developing eggs
We tested whether VU573 inhibits the mosquito Kir channel, AeKir1
Summary
Mosquitoes are vectors of debilitating diseases that take an immense toll on global health. To confirm the inhibition of Kir channels by VU573, we used two-electrode voltage clamping to measure the basolateral membrane voltage (Vbl) and input resistance (Rpc) of principal cells of isolated Malpighian tubules [21]. To determine whether the VU573-mediated inhibition of fluid secretion by isolated Malpighian tubules causes renal failure in intact mosquitoes, we measured urine excretion rates using a method modified from the laboratory of Hansen [22].
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