Elucidation of pyrethroid receptor sites in insect voltage-gated sodium channels

Recipient Organization
MICHIGAN STATE UNIV
(N/A)
EAST LANSING,MI 48824

Performing Department
Entomology

Non Technical Summary
Pyrethroids are a large of synthetic insecticides that are widely used to control various agricultural pest and human disease vectors. They are synthetic analogues of naturally occurring pyrethrum from the flower extracts of Chrysanthemum species. Because of their fast-acting and highly insecticidal activities combined with low mammalian toxicity, pyrethroid insecticides are an integral component of pest management programs to reduce global crop production losses. Unfortunately, the effectiveness of insecticide-based control is facing serious threats as insects develop widespread resistance to these insecticides. Pyrethroids act on sodium channels to exert insecticidal action. Mutations in sodium channels are associated with pyrethroid resistance in many arthropod pests. However, the mechanism of action of pyrethroids and resistance are not well understood at the molecular level. The proposed work is to better understand the molecular mechanisms ofpyrethroid resistance by taking a combination of molecular, electrophysiological, and computer modeling approaches. New knowledge gained from this fundamental research will have significant impact on resistance monitoring, implementation of integrated resistance management strategies, and future development of new chemistries to overcome resistance.

Animal Health Component

10%

Research Effort Categories

Basic

90%

Applied

10%

Developmental

(N/A)

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
314	5220	1150	100%

Knowledge Area
314 - Toxic Chemicals, Poisonous Plants, Naturally Occurring Toxins, and Other Hazards Affecting Animals;

Subject Of Investigation
5220 - Pesticides;

Field Of Science
1150 - Toxicology;

Keywords

pyrethroids

sodium channels

insecticide resistance

Goals / Objectives
The long-term goal of this research is to leverage the availability of sodium channel structures to achieve understanding of sodium channel interactions with pyrethroids at the atomic level. A combination of molecular biology, electrophysiology, pharmacology and structural biology methodologies will be used to pursue the following two specific objectives.Objective 1. Functional characterization of new pyrethroid-resistance-associated sodium channel mutations in Xenopus oocytesObjective 2. Elucidation of the molecular basis of differential actions of Type I and Type II pyrethroids on insect sodium channels

Project Methods
We will functionally characterize insect sodium channels and assessthe role of sodium channelmutations in conferring pyrethroid resistance using the Xenopus oocyte functional expression system. Graduate students will learn site-directed mutagensis andelectrophysiological techniques and carry out experiments to identifymutations in insect sodium channels that reduce or enhance the binding and action of pyrethroids.

Progress 07/01/19 to 10/31/20

Outputs
Target Audience:Target audience included researchers and students in the areas of toxicology and pharamcology, also farmers/growers andextension agents who are interested in pesticide use and pest resistance management Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? We generated many insect sodium channel mutants by site-directed mutagenesis. These mutants are currently being tested in a functional assay to determine the sensitivity of these mutants to pyrethroid insecticides.

Publications

Type: Journal Articles Status: Published Year Published: 2020 Citation: Chen, M., Du, Y., Zhorov, B.S., and Dong, K. (2020) Chronology of sodium channel mutations associated with pyrethroid resistance in Aedes aegypti. Arch. Insect Biochem. Physiol. 104: e21686.

Progress 07/01/19 to 09/30/19

Outputs
Target Audience:Toxicologists, neuroscientists and insect pest management professionals. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals?New sodium channel mutants carrying pyrethroid-resistance-associated mutationswill be functionally examined for their sensitivity to pyrethroids in Xenopus oocytes. Once the mutations are confirmed tobe critial for the binding and action of pyrethroids, we willconduct computational analysis to determine how these mutations affect the interaction of pyrethroids with sodium channels.

Impacts
What was accomplished under these goals? We are making sodium channel constructs that carry several new pyrethroid-resistance-associated mutations.

Publications