# High-resolution insights into insecticide interactions with voltage-gated sodium channels

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $201,766

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 9971064
- **Project number:** 2R01GM057440-17
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** KE DONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $201,766
- **Award type:** 2
- **Project period:** 1999-01-01 → 2020-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971064

## Citation

> US National Institutes of Health, RePORTER application 9971064, High-resolution insights into insecticide interactions with voltage-gated sodium channels (2R01GM057440-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971064. Licensed CC0.

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