The long-term goal of this research is to understand the molecular action and resistance mechanisms of two important classes of insecticides, pyrethroids and sodium channel blocker insecticides (SCBIs). Strategies for the control of arthropod pests of major public health concerns continue to rely heavily on the use of relatively safe insecticides. Currently, pyrethroids are the only class of insecticides used in insecticide treated nets (ITNs) for malaria control, due to their fast acting, high efficacy, and relative low toxicity to humans. However, a major threat to the sustained use of pyrethroids is the development of resistance. Indoxacarb and its active metabolite (DCJW), the first member of a new class of SCBIs, also meets vector control criteria, and could be an alternative insecticide to pyrethroids. Both pyrethroids and indoxacarb target voltage-gated sodium channels;however, the modes of their action are not well understood at the molecular level, which presents a major obstacle to the characterization of mechanisms of resistance.
The specific aims of this renewal proposal are: 1) Characterization of the molecular basis of pyrethroid action and resistance, and 2) Identification of the receptor site and molecular action of indoxacarb/DCJW on sodium channels. A combination of molecular, electrophysiological, and computer modeling methods will be used to test novel hypotheses, with the final goal of defining the molecular identities of the elusive pyrethroid and indoxacarb receptor sites on the insect sodium channel. New knowledge gained from this fundamental research will have significant impact on future development of effective monitoring and management strategies for controlling major human health-threatening arthropod pests.

Public Health Relevance

This application describes basic research to understand how pyrethroid and indoxacarb insecticides interact with the voltage-gated sodium channel at the molecular level and how insect pests develop resistance to these insecticides. The knowledge gained from this research will have important implications for the development of strategies to control arthropod vectors that transmit important human diseases including malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM057440-13A1
Application #
8371255
Study Section
Vector Biology Study Section (VB)
Program Officer
Nie, Zhongzhen
Project Start
1999-01-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$355,614
Indirect Cost
$120,614
Name
Michigan State University
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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) 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
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
Jiang, Dingxin; Du, Yuzhe; Nomura, Yoshiko et al. (2015) Mutations in the transmembrane helix S6 of domain IV confer cockroach sodium channel resistance to sodium channel blocker insecticides and local anesthetics. Insect Biochem Mol Biol 66:88-95
Wang, Lingxin; Du, Yuzhe; Nomura, Yoshiko et al. (2015) Distinct modulating effects of TipE-homologs 2-4 on Drosophila sodium channel splice variants. Insect Biochem Mol Biol 60:24-32
Wang, Lingxin; Nomura, Yoshiko; Du, Yuzhe et al. (2015) A mutation in the intracellular loop III/IV of mosquito sodium channel synergizes the effect of mutations in helix IIS6 on pyrethroid resistance. Mol Pharmacol 87:421-9
Du, Yuzhe; Nomura, Yoshiko; Zhorov, Boris S et al. (2015) Rotational Symmetry of Two Pyrethroid Receptor Sites in the Mosquito Sodium Channel. Mol Pharmacol 88:273-80
Rinkevich, Frank D; Du, Yuzhe; Tolinski, Josh et al. (2015) Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids. Neurotoxicology 47:99-106
Dong, Ke; Du, Yuzhe; Rinkevich, Frank et al. (2014) Molecular biology of insect sodium channels and pyrethroid resistance. Insect Biochem Mol Biol 50:1-17
Gao, R; Du, Y; Wang, L et al. (2014) Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels. Neuroscience 268:297-308

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