The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

Crossthwaite, Andrew J.; Bigot, Aurélien; Camblin, Philippe; Goodchild, Jim; Lind, Robert J.; Slater, Russell; Maienfisch, Peter

doi:10.1584/jpestics.d17-019

Cited by 67 publications

(53 citation statements)

References 138 publications

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“…For example, competitive antagonists targeting the resting state appear to be important for smoking cessation drugs for attenuating nicotine‐induced reinforcement (Rollema & Hurst, ). Competitive nAChR antagonists are also insecticides, such as triflumezopyrim (DuPont), which is used to control rice grasshoppers (Crossthwaite et al, ). The structure that we propose should therefore be valuable for studying the activity of therapeutics or insecticidal compounds targeting the closed/resting state of vertebrate and insect nAChRs.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Tae

et al. 2019

British J Pharmacology

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Background and Purpose: The heteromeric α4β2 nicotinic acetylcholine receptor (nAChR) is abundant in the human brain and is associated with a range of CNS disorders. This nAChR subtype has been recently crystallised in a conformation that was proposed to represent a desensitised state. Here, we investigated the conformational transition mechanism of this nAChR from a desensitised to a closed/resting state.Experimental Approach: The competitive antagonist dihydro-β-erythroidine (DHβE) was modelled by replacement of the agonist nicotine in the α4β2 nAChR experimental structure. DHβE is used both in vitro and in vivo for its ability to block α4β2 nAChRs. This system was studied by three molecular dynamics simulations with a combined simulation time of 2.6 μs. Electrophysiological studies of mutated receptors were performed to validate the simulation results. Key Results: The relative positions of the extracellular and transmembrane domains in the models are distinct from those of the desensitised state structure and are compatible with experimental structures of Cys-loop receptors captured in a closed/resting state.Conclusions and Implications: Our model suggests that the side chains of α4 L257 (9′) and α4 L264 (16′) are the main constrictions in the transmembrane pore. The involvement of position 9′ in channel gating is well established, but position 16′ was only previously identified as a gate for the bacterial channels, ELIC and GLIC. L257 but not L264 was found to influence the slow component of desensitisation.The structure of the antagonist-bound state proposed here should be valuable for the development of therapeutic or insecticide compounds.

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Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Tae

et al. 2019

British J Pharmacology

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“…4) However, individuals carrying this mutation have only been found in southern Europe (Italy, France, and Spain) [4][5][6] and are less common than individuals overexpressing CYP6CY3. 7,8) While the R81T mutation confers cross-resistance to a range of IRAC Group 4 chemicals, including neonicotinoids (Group 4A), sulfoxaflor (Group 4C), flupyradifurone (Group 4D), and triflumezopyrim (Group 4E), 9) the overexpression of CYP6CY3 has only been reported to confer resistance against neonicotinoids belonging to IRAC Group 4A. 3) There is wide variation in the resistance of M. persicae to different neonicotinoids.…”

Section: Introductionmentioning

confidence: 99%

Differential metabolism of neonicotinoids by <i>Myzus persicae</i> CYP6CY3 stably expressed in <i>Drosophila</i> S2 cells

Kawashima

Banba

2019

J. Pestic. Sci.

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The peach-potato aphid, Myzus persicae, is a serious crop pest that has developed imidacloprid resistance, mainly through overexpression of CYP6CY3. Here, we established a metabolic assay using Drosophila S2 cells that stably expressed CYP6CY3. We found that CYP6CY3 showed metabolic activity against imidacloprid, as well as acetamiprid, clothianidin, and thiacloprid, but had no activity against dinotefuran. Our study suggested that stable gene expression in Drosophila S2 cells is useful for examining which insecticide is metabolized by P450 monooxygenases.

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“…Neonicotinoids act as agonists, competing with the neurotransmitter acetylcholine in binding to nicotinic acetylcholine receptors (nAChR) [10][11][12] . The increased toxicity for insects is thought to be caused by the characteristically high nAChR density within insect nervous systems [reviewed in 13 ].…”

Section: Introductionmentioning

confidence: 99%

Thiamethoxam exposure deregulates short ORF gene expression in the honey bee and compromises immune response to bacteria

Décio

Ustaoglu

Derecka

et al. 2019

Preprint

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Running title: Long-term low dose Thiamethoxam exposure induces short ORFs AbstractMaximizing crop yields heavily relies on the use of agrochemicals to control insect pests. One of the most widely used insecticides are neonicotinoids. Here, we analysed the impact of sub-lethal chronic long-term exposure to the neonicotinoid Thiamethoxam on gene expression and alternative splicing in brains of Africanized honey bees Apis mellifera. Our results reveal a small number of differentially regulated genes showing a concentration dependent response to two low doses of chronic, 10-day Thiamethoxam exposure. Unexpectedly, most of these genes have no annotated function, but encode short Open Reading Frames (sORFs), a characteristic feature of anti-microbial peptides. Likewise, we find that Thiamethoxam exposure sensitizes bees to infection by non-pathogenic bacteria Bacillus badius and Ochrobactrum anthropi. Moreover, infection with estimated single Serratia marcescens kills bees arguing that Varroa mites may essentially contribute to colony collapse by penetrating the cuticle to spread this pathogen. Our results implicate an altered immune response to Thiamethoxam exposure compromising the immune response leading to a decline in bee populations.Understanding the risk for honey bees requires detailed knowledge of cellular and molecular effects that result from the exposure to an insecticide in order to mitigate negative effects or refine the target specificity towards pest species.Changes in gene expression and processing of RNAs, including alternative splicing, are one of the options available to an organism to respond to environmental perturbations 15,16 . Sub-lethal exposure of xenobiotics can induce modulation of splicing reactions [17][18][19] .Neonicotinoid exposure has been linked to a decline in bee health including a reduction of immune competence 20 ;; 21-23 . Insects do not have antibodies and rely on the innate immune system to fight microbial infections. The best insight on insect immunity stems from studies in the fruit fly Drosophila melanogaster, where cellular and humoral immune responses have been identified 24,25 . The cellular response is mediated by three types of hematopoetic cell lineages 24,26,27 , while the humoral immune system can be split into Toll and Imd pathways [reviewed in 28 ]. The Tollpathway is triggered following an immune challenge by Gram-positive bacteria and fungi, ultimately leading to expression of antimicrobial peptides (AMPs) that are then secreted from the fat body into the hemolymph 24,29,30 . In contrast, the Immune deficiency (Imd) pathway leads to expression of a different set of AMPs after a Gramnegative bacterial infection activates pattern recognition receptors and a complex intracellular signaling cascade 24,25,29 . AMPs are short peptides of 10-100 amino acids and are characterised by an evolutionary dynamism among insect species 31 .We have previously shown that worker-bee larvae in colonies contaminated with the neonicotinoid imidacloprid, have altered expression o...

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The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

Cited by 67 publications

References 138 publications

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Molecular dynamics simulations of dihydro‐β‐erythroidine bound to the human α4β2 nicotinic acetylcholine receptor

Differential metabolism of neonicotinoids by <i>Myzus persicae</i> CYP6CY3 stably expressed in <i>Drosophila</i> S2 cells

Thiamethoxam exposure deregulates short ORF gene expression in the honey bee and compromises immune response to bacteria

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