Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel

Zhorov, Boris S.; Dong, Ke

doi:10.1016/j.neuro.2016.08.013

Cited by 41 publications

(34 citation statements)

References 71 publications

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“…Such was likely the case for the V410L mutation because the amino acid substitution was not located in one of the two recently described pyrethroid receptor sites11192026. One potential alternative explanation is that some kdr mutations reduce pyrethroid effects by altering the gating properties of the channel without inhibiting molecule docking.…”

Section: Discussionmentioning

confidence: 99%

Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control

Haddi

Tomé

et al. 2017

Sci Rep

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171

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The yellow fever mosquito, Aedes aegypti, particularly in Neotropical regions, is the principal vector of dengue, yellow fever, Zika and Chikungunya viruses. Pyrethroids remain one of the most used insecticides to control Aedes mosquitoes, despite the development of pyrethroid resistance in many mosquito populations worldwide. Here, we report a Brazilian strain of A. aegypti with high levels (approximately 100–60,000 fold) of resistance to both type I and type II pyrethroids. We detected two mutations (V410L and F1534C) in the sodium channel from this resistant strain. This study is the first report of the V410L mutation in mosquitoes. Alone or in combination with the F1534C mutation, the V410L mutation drastically reduced the sensitivity of mosquito sodium channels expressed in Xenopus oocytes to both type I and type II pyrethroids. The V410L mutation presents a serious challenge for the control of A. aegypti and will compromise the use of pyrethroids for the control of A. aegypti in Brazil; therefore, early monitoring of the frequency of the V410L mutation will be a key resistance management strategy to preserve the effectiveness of pyrethroid insecticides.

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Section: Discussionmentioning

confidence: 99%

Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control

Haddi

Tomé

et al. 2017

Sci Rep

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171

217

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“…Computer modeling predicts that pyrethroids bind to two homologous lipid-exposed interfaces between domains: one is formed by the linker helix connecting S4 and S5 in domain II (IIL45) and helices IIS5, IIS6, and IIIS6 [71,72,73], later named PyR1 (Figure 3), and the other is formed by the linker helix connecting S4 and S5 in domain I (IL45) and helices IS5, IS6, and IIS6, known as PyR2 (Figure 3) [66,74]. In the structural models, pyrethroids make multiple contacts with helices IIL45, IIS5, IIS6, and IIIS6, as well as IL45, IS5, IS6, and IIS6 that would stabilize the channel in the open state [3,75]. Simultaneous binding of pyrethroids to both PyR1 and PyR2 is thought to effectively prolong the opening of sodium channels [66].…”

Section: The Kdr Mutations From Aedes Aegypti Likely Confer Resistmentioning

confidence: 99%

Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti

Nomura

Zhorov

et al. 2016

Insects

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Pyrethroid insecticides are widely used to control insect pests and human disease vectors. Voltage-gated sodium channels are the primary targets of pyrethroid insecticides. Mutations in the sodium channel have been shown to be responsible for pyrethroid resistance, known as knockdown resistance (kdr), in various insects including mosquitoes. In Aedes aegypti mosquitoes, the principal urban vectors of dengue, zika, and yellow fever viruses, multiple single nucleotide polymorphisms in the sodium channel gene have been found in pyrethroid-resistant populations and some of them have been functionally confirmed to be responsible for kdr in an in vitro expression system, Xenopus oocytes. This mini-review aims to provide an update on the identification and functional characterization of pyrethroid resistance-associated sodium channel mutations from Aedes aegypti. The collection of kdr mutations not only helped us develop molecular markers for resistance monitoring, but also provided valuable information for computational molecular modeling of pyrethroid receptor sites on the sodium channel.

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“…Barbamide is a strong molluscicide, though its mechanism of action has yet to be determined. Given that barbamide contains thiazole and trichloromethyl, two pharmacophores known to interact with ion channels 45,46 , it is likely that barbamide also targets ion channels.…”

Section: Discussionmentioning

confidence: 99%

The evolutionary advantage of toxin production among cyanobacteria, the oldest known organisms on Earth

Ramos

Ionescu

Koča

2019

Preprint

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21 organisms on Earth 22 23Cyanobacteria produce toxic secondary metabolites for reasons hitherto unclear. Using a 24 phylogenetic approach that accounts for the high complexity of biosynthetic gene clusters (full or 25 partial inversions, variable length, different number of genes, non-orthologues), we analyzed the 26 sequences of 76 biosynthetic gene clusters covering 19 cyanotoxins. The phylogenetic tree of 27 biosynthetic gene clusters branches first according to the bioactivity of the toxic metabolite 28 (molecular target in another organism), then according to the chemical class and chemical 29 structure of the secondary metabolite, and finally according to the organism and area of origin. 30The bioactivity of a toxic metabolite can be deduced directly from the nucleotide sequence of the 31 biosynthetic gene cluster, without needing to examine the enzymes themselves or to measure 32 expression levels. Bioactivity may have been the primary driving force behind the diversity of 33 secondary metabolism in cyanobacteria. This genetic machinery evolved to facilitate three 34 specific survival strategies acting separately or in tandem, with dominant cyanobacteria 35 possessing the genetic machinery to support all three strategies. Transmembrane (direct) toxicity 36 targeting ion channels, intracellular (indirect) toxicity targeting cell-cycle regulation, and 37 digestion inhibition targeting proteases may have provided the survival advantage underpinning 38 the evolutionary success of both cyanobacteria and their early symbiotic hosts. 39 40 Keywords: cyanotoxin, evolutionary benefit, bioactivity, phylogenetic analysis 41 42 3 43 Introduction 44 Bioactive secondary metabolites, which are products of pathways not directly involved in 45 growth, development, or reproduction, often serve complex functions that aid survival and 46 increase dominance of an organism in a given ecological niche. Snake venoms are probably the 47 most famous examples of bioactive secondary metabolites, though not nearly the most versatile. 48 Bacteria, fungi, and plants all exhibit an impressive array of secondary metabolites, with 49 cyanobacteria being the earliest organisms to develop such capabilities. Cyanobacteria are 50 unicellular photosynthetic prokaryotes populating marine, fresh-water, and land ecosystems, 51 which drove the rapid oxygenation of Earth's atmosphere and are recognized as the ancestors of 52 plastids 1 . Cyanobacteria continue to exert a crucial environmental impact because they produce 53 about 25% of all carbohydrates on Earth and perform massive nitrogen fixation together with 54 sequestering trace metals and phosphorous from the environment, thus fueling most 55 contemporary food chains. In addition, many cyanobacteria produce unique secondary 56 metabolites (typically, peptides and alkaloids) via non-ribosomal peptide synthesis (NRPS) 57 and/or polyketide synthesis (PKS), with complex environmental, economic, and health impact 2 . 58The exact function of cyanobacterial secondary metabolites remains largely un...

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Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel

Cited by 41 publications

References 71 publications

Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control

Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control

Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti

The evolutionary advantage of toxin production among cyanobacteria, the oldest known organisms on Earth

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