Role of nicotinic acetylcholine receptor subunits in the mode of action of neonicotinoid, sulfoximine and spinosyn insecticides in Drosophila melanogaster

Perry, Trent; Chen, Wei; Ghazali, Razi; Yang, Ying; Christesen, Danielle; Martelli, Felipe; Lumb, Chris; Lương, Hằng Ngọc Bảo; Mitchell, Judith; Holien, Jessica K.; Parker, Michael W.; Sparks, Thomas C.; Batterham, Philip J.

doi:10.1016/j.ibmb.2021.103547

Cited by 47 publications

(69 citation statements)

References 74 publications

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“…Our genome engineering approach generated viable and fertile mutations in nine out of the ten subunit genes encoded in the D. melanogaster genome and is largely concordant with the recently described work by Perry and colleagues 2 . In both studies, null mutations in the nAChR1 gene were inviable as stocks.…”

Section: Discussionsupporting

confidence: 79%

“…The pharmacology of Hv1a and α-Btx binding has been shown to be distinctive (Chambers et al, 2019), correlating with our demonstration that these two peptide toxins mediate their effects through different receptor alpha subunits. Furthermore, resistance to neonicotinoid insecticides, which interact most strongly with Hv1a binding, has been associated with Dβ2 (Perry et al, 2008;Perry et al, 2021), consistent with the involvement of this subunit in the response to Hv1a. However, no resistance to neonicotinoids was seen in D. melanogaster carrying a nAChRa4 gene deletion (Perry et al, 2021), which could be explained if neonicotinoids act at multiple receptor classes.…”

Section: Discussionmentioning

confidence: 53%

“…Even in the tractable D. melanogaster insect model, there has until recently been no systematic isolation of mutations in nAChR subunit genes. Perry and colleagues described the generation of a new set of null mutations in nine out of the ten D. melanogaster subunit genes, however, these were generated in different genetic backgrounds necessitating additional work to assay background sensitive phenotypes such as neural or behavioural defects 2 .…”

Section: Introductionmentioning

confidence: 99%

“…An essential pre-requisite for effective design of new insecticides targeting these receptors is understanding the subunit composition of nAChRs and their distinctive binding properties. For many reasons, including low expression in endogenous tissues or difficulties in expressing insect receptors in heterologous systems, the characterisation of functional insect receptors has been challenging (Perry et al, 2021;Zuo et al, 2021;Salgado, 2021). Even in the tractable D. melanogaster insect model, there has been no systematic isolation of mutations in nAChR subunit genes, until recently, when Perry and colleagues described the generation of a new set of null mutations in nine out of the ten D. melanogaster subunit genes (Perry et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…For many reasons, including low expression in endogenous tissues or difficulties in expressing insect receptors in heterologous systems, the characterisation of functional insect receptors has been challenging (Perry et al, 2021;Zuo et al, 2021;Salgado, 2021). Even in the tractable D. melanogaster insect model, there has been no systematic isolation of mutations in nAChR subunit genes, until recently, when Perry and colleagues described the generation of a new set of null mutations in nine out of the ten D. melanogaster subunit genes (Perry et al, 2021). These mutations, however, were generated in different genetic backgrounds necessitating additional work to assay background sensitive phenotypes such as neural or behavioural defects.…”

Section: Introductionmentioning

confidence: 99%

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Drosophila nicotinic acetylcholine receptor subunits and their native interactions with insecticidal peptide toxins

Korona

Dirnberger

Giachello

et al. 2021

Preprint

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Drosophila nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that present a target for insecticides. However, a better understanding of receptor subunit composition is needed for effective design of insecticides. Peptide neurotoxins are known to block nAChRs by binding to its target subunits. To facilitate the analysis of nAChRs we used a CRISPR/Cas9 strategy to generate null alleles for all ten nAChR subunit genes. We studied interactions of nAChR subunits with peptide neurotoxins by larval injections and styrene maleic acid lipid particles (SMALPs) pull-down assays. For the null alleles we determined the effects of α-Bungarotoxin (α-Btx) and ω-Hexatoxin-Hv1a (Hv1a) administration, identifying potential receptor subunits implicated in the binding of these toxins. We employed pull-down assays to confirm α-Btx interactions with the Dα5, Dα6, Dα7 subunits. Finally, we report the localization of fluorescent tagged endogenous Dα6 during nervous system development. Taken together this study elucidates native Drosophila nAChR subunit interactions with insecticidal peptide toxins.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Drosophila nicotinic acetylcholine receptor subunits and their native interactions with insecticidal peptide toxins

Korona

Dirnberger

Giachello

et al. 2021

Preprint

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Molecular Targets of Neurotoxic Insecticides in Apis mellifera

et al. 2022

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The intensive use of insecticides, combined with other factors such as habitat loss, might explain worldwide decrease of insect populations documented in the past twenty years. However, due to the involvement of pest species in crop destruction and in vector‐borne diseases, insecticides will probably continue to be required still for decades. The most commercially successful insecticides are neurotoxicants acting on ion channels of the central nervous system affecting thereby cellular excitability and synaptic transmission and causing insect paralysis and fatality. In this article, we provide an overview of the insecticides acting on voltage‐gated sodium channels, GABA‐gated chloride channels and nicotinic acetylcholine receptors. We summarize the current knowledge on those ion channels from the honeybee Apis mellifera and discuss the possible mode of action of neurotoxic insecticides.

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Defining the Biologically Plausible Taxonomic Domain of Applicability of an Adverse Outcome Pathway: A Case Study Linking Nicotinic Acetylcholine Receptor Activation to Colony Death

Jensen

Blatz²,

LaLone

2022

Enviro Toxic and Chemistry

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For the majority of developed adverse outcome pathways (AOPs), the taxonomic domain of applicability (tDOA) is typically narrowly defined with a single or a handful of species. Defining the tDOA of an AOP is critical for use in regulatory decision‐making, particularly when considering protection of untested species. Structural and functional conservation are two elements that can be considered when defining the tDOA. Publicly accessible bioinformatics approaches, such as the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool, take advantage of existing and growing databases of protein sequence and structural information to provide lines of evidence toward structural conservation of key events (KEs) and KE relationships (KERs) of an AOP. It is anticipated that SeqAPASS results could readily be combined with data derived from empirical toxicity studies to provide evidence of both structural and functional conservation, to define the tDOA for KEs, KERs, and AOPs. Such data could be incorporated in the AOP‐Wiki as lines of evidence toward biological plausibility for the tDOA. We present a case study describing the process of using bioinformatics to define the tDOA of an AOP using an AOP linking the activation of the nicotinic acetylcholine receptor to colony death/failure in Apis mellifera. Although the AOP was developed to gain a particular biological understanding relative to A. mellifera health, applicability to other Apis bees, as well as non‐Apis bees, has yet to be defined. The present study demonstrates how bioinformatics can be utilized to rapidly take advantage of existing protein sequence and structural knowledge to enhance and inform the tDOA of KEs, KERs, and AOPs, focusing on providing evidence of structural conservation across species. Environ Toxicol Chem 2023;42:71–87. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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Role of nicotinic acetylcholine receptor subunits in the mode of action of neonicotinoid, sulfoximine and spinosyn insecticides in Drosophila melanogaster

Cited by 47 publications

References 74 publications

Drosophila nicotinic acetylcholine receptor subunits and their native interactions with insecticidal peptide toxins

Drosophila nicotinic acetylcholine receptor subunits and their native interactions with insecticidal peptide toxins

Molecular Targets of Neurotoxic Insecticides in Apis mellifera

Defining the Biologically Plausible Taxonomic Domain of Applicability of an Adverse Outcome Pathway: A Case Study Linking Nicotinic Acetylcholine Receptor Activation to Colony Death

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