Voltage-Gated Sodium Channels as Insecticide Targets

Silver, Kristopher; Du, Yuzhe; Nomura, Yasuo; Oliveira, Eugênio E.; Salgado, Vincent L.; Zhorov, Boris S.; Dong, Ke

doi:10.1016/b978-0-12-417010-0.00005-7

Cited by 142 publications

(110 citation statements)

References 156 publications

(291 reference statements)

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“…Type II pyrethroids, like deltamethrin, preferably bind to open sodium channels, whereas type I pyrethroids, like permethrin, can also modify resting or inactivated channels (24). In terms of the chemical structure, DDT is more similar to type I pyrethroids than to type II pyrethroids, and DDT is believed to bind to the closed channel and stabilize the open state upon channel opening (25).…”

Section: Resultsmentioning

confidence: 99%

Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels

Nomura

Zhorov

et al. 2016

Journal of Biological Chemistry

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1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), the first organochlorine insecticide, and pyrethroid insecticides are sodium channel agonists. Although the use of DDT is banned in most of the world due to its detrimental impact on the ecosystem, indoor residual spraying of DDT is still recommended for malaria control in Africa. Development of resistance to DDT and pyrethroids is a serious global obstacle for managing disease vectors. Mapping DDT binding sites is necessary for understanding mechanisms of resistance and modulation of sodium channels by structurally different ligands. The pioneering model of the housefly sodium channel visualized the first receptor for pyrethroids, PyR1, in the II/III domain interface and suggested that DDT binds within PyR1. Previously, we proposed the second pyrethroid receptor, PyR2, at the I/II domain interface. However, whether DDT binds to both pyrethroid receptor sites remains unknown. Here, using computational docking of DDT into the K v 1.2-based mosquito sodium channel model, we predict that two DDT molecules can bind simultaneously within PyR1 and PyR2. The bulky trichloromethyl group of each DDT molecule fits snugly between four helices in the bent domain interface, whereas two p-chlorophenyl rings extend into two wings of the interface. Model-driven mutagenesis and electrophysiological analysis confirmed these propositions and revealed 10 previously unknown DDT-sensing residues within PyR1 and PyR2. Our study proposes a dual DDT-receptor model and provides a structural background for rational development of new insecticides.Voltage-gated sodium channels are transmembrane proteins that are critical for the initiation and propagation of action potentials in neurons and other excitable cells. In response to membrane depolarization, sodium channels open (activate) and allow sodium ions to flow into the cell, causing depolarization of the membrane potential. Activation of sodium channels is responsible for the rapidly rising phase of action potential. A few milliseconds after channel opening, the channel pore is occluded by an inactivation particle in the process known as fast inactivation that plays an important role in the termination of action potentials. Because of their crucial role in regulating membrane excitability, sodium channels are the primary target site of a broad range of neurotoxins, including insecticides.The pore-forming ␣-subunit of the sodium channel consists of four homologous repeat domains (I-IV). Each domain has six transmembrane segments (S1-S6) that are connected by intracellular and extracellular loops (Fig. 1). The S1-S4 segments in each domain serve as the voltage-sensing modules, whereas the S5 and S6 segments from each of the four domains and the four extracellular membranes re-entering S5-S6 loops, known as P-regions, constitute the pore-forming module. In response to membrane depolarization, the S4 segments move in the extracellular direction, initiating conformational changes that lead to the pore opening. Short intracellular linkers L...

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Section: Resultsmentioning

confidence: 99%

Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels

Nomura

Zhorov

et al. 2016

Journal of Biological Chemistry

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“…3). This suggests a specific effect of the DSC1 channel on modulating pyrethroid sensitivity because indoxacab/DCJW is a sodium channel blocker insecticide and has a mode of action opposite to pyrethroids (i.e., inhibiting neuronal excitability) [3] and fipronil causes neuronal hyperexcitability like pyrethoids, but by blocking the GABA-gated Cl − channel [24]. The specific effect of DSC1 knockout on pyrethroid sensitivity suggests that DSC1 knockout flies are more susceptible to neuronal stimulation by sodium channel activators.…”

Section: Dsc1 Knockout Flies Are More Sensitive To Pyrethroid Insectimentioning

confidence: 96%

“…They are the primary targets of pyrethroids, a large class of insecticides structurally derived from naturally occurring pyrethrins from Chrysanthemum plant species [1]. Pyrethroids modify the transitions between opening and closing (i.e., gating) of sodium channels, resulting in the disruption of the proper function of the nervous system [2][3][4]. Pyrethroids are highly insecticidal, but have low toxicity to mammals, and are used as major weapons against a wide range of arthropod disease vectors and agricultural pests.…”

Section: Introductionmentioning

confidence: 99%

The Drosophila Sodium Channel 1 (DSC1): The founding member of a new family of voltage-gated cation channels

Dong

Rinkevich

et al. 2015

Pesticide Biochemistry and Physiology

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“…The critical roles that VGSCs play in cell excitability have made them excellent targets for a wide variety of natural toxins used in predation and self-defense by some organisms, as well as synthetic insecticides used to control agricultural, structural, or medical insect pests. Among these, several classes of insecticides, including pyrethroids and sodium channel blocker insecticides (SCBIs), target and modify or block the activity of VGSCs, thus disrupting the function of the nervous system [1, 2]. …”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides

Silver

Dong

Zhorov

2017

CMC

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Sodium channel blocker insecticides (SCBIs) are a relatively new class of insecticides that are represented by two commercially registered compounds, indoxacarb and metaflumizone. SCBIs, like pyrethroids and DDT, target voltage-gated sodium channels (VGSCs) to intoxicate insects. In contrast to pyrethroids, however, SCBIs inhibit VGSCs at a distinct receptor site that overlaps those of therapeutic inhibitors of sodium channels, such as local anesthetics, anticonvulsants and antiarrhythmics. This review will recount the development of the SCBI insecticide class from its roots as chitin synthesis inhibitors, discuss the symptoms of poisoning and evidence supporting inhibition of VGSCs as their mechanism of action, describe the current model for SCBI-induced inhibition of VGSCs, present a model for the receptor for SCBIs on VGSCs, and highlight differences between data collected from mammalian and insect experimental models.

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Voltage-Gated Sodium Channels as Insecticide Targets

Cited by 142 publications

References 156 publications

Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels

Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels

The Drosophila Sodium Channel 1 (DSC1): The founding member of a new family of voltage-gated cation channels

Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides

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