Voltage-gated sodium channels (Navs) are targets of a variety of natural neurotoxins and insecticides, including pyrethroids and sodium-channel-blocker insecticides (SCBIs). Pyrethroids are currently one of the most important and effective arsenals against mosquitoes and other arthropod vectors that transmit human diseases. SCBIs belong to a newer class of selective insecticides. A major challenge for effective vector control is global emergence of insecticide resistance. In particular, mutations in Nav genes confer a major form of resistance known as knockdown resistance (kdr). In the absence of 3-D structures of eukaryotic Navs in complex with pyrethroids or SCBIs, major uncertainties remain in understanding their interactions (including the nature of respective receptor sites) and kdr mechanisms. In this grant proposal, we take advantage of recent breakthroughs in the co-PI?s laboratory in the determination of the cryo-EM structures of several eukaryotic Navs. The availability of these Nav structures now promises an unprecedented new level of understanding of Nav interactions with insecticides and other neurotoxins. We propose to determine cryo-EM structures of Navs in complex with pyrethroids, SCBIs and three other neurotoxins and use these structures as a guide to conduct a comprehensive series of mutational, electrophysiological and computational modeling analyses of respective Nav-ligand interactions.
Two specific aims of this renewal proposal are: 1) determine cryo-EM structures of eukaryotic Nav complexes with various pyrethroids to gain insights into the atomic mechanisms of pyrethroids and kdr, and 2) Investigate the mechanisms of Nav interactions with SCBIs (DCJW and metaflumizone), steroidal agonists (BTX and veratridine) and the alkylamide insecticide BTG 502. Results from this research will push our understanding of the molecular actions of pyrethroids, SCBIs and other neurotoxins to a new level, thereby facilitating the development of precision monitoring and management of insecticide resistance worldwide and discovery of new and safe Nav-targeting chemicals to combat global threats from arthropod disease-transmitting vectors.

Public Health Relevance

This application describes basic research to understand how pyrethroids and other sodium channel-targeting insecticides interact with the voltage-gated sodium channel at the atomic level and how insect pests develop resistance to these insecticides. The knowledge gained from this research is critical for management of insecticide resistance and discovery of new and safe Nav-targeting chemicals to combat global threats from human disease-transmitting arthropod species.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Vector Biology Study Section (VB)
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Nie, Zhongzhen
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Duke University
Schools of Arts and Sciences
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Wu, Shaoying; Nomura, Yoshiko; Du, Yuzhe et al. (2017) Molecular basis of selective resistance of the bumblebee BiNav1 sodium channel to tau-fluvalinate. Proc Natl Acad Sci U S A 114:12922-12927
Chen, Mengli; Du, Yuzhe; Nomura, Yoshiko et al. (2017) Mutations of two acidic residues at the cytoplasmic end of segment IIIS6 of an insect sodium channel have distinct effects on pyrethroid resistance. Insect Biochem Mol Biol 82:1-10
Silver, Kristopher; Dong, Ke; Zhorov, Boris S (2017) Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides. Curr Med Chem 24:2912-2924
Chen, Mengli; Du, Yuzhe; Nomura, Yoshiko et al. (2017) Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids. Neurotoxicology 60:197-206
Haddi, Khalid; Tomé, Hudson V V; Du, Yuzhe et al. (2017) Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control. Sci Rep 7:46549
Zhorov, Boris S; Dong, Ke (2017) Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel. Neurotoxicology 60:171-177
Zhang, Yongqiang; Du, Yuzhe; Jiang, Dingxin et al. (2016) The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides. J Biol Chem 291:20113-24
Du, Yuzhe; Nomura, Yoshiko; Zhorov, Boris S et al. (2016) Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti. Insects 7:
Wang, Xing-Liang; Su, Wen; Zhang, Jian-Heng et al. (2016) Two novel sodium channel mutations associated with resistance to indoxacarb and metaflumizone in the diamondback moth, Plutella xylostella. Insect Sci 23:50-8
Du, Yuzhe; Nomura, Yoshiko; Zhorov, Boris S et al. (2016) Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels. J Biol Chem 291:4638-48

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