The stoichiometry of the α4β2 neuronal nicotinic acetylcholine receptors determines the pharmacological properties of the neonicotinoids, and recently introduced butenolide and sulfoximine.

Although neonicotinoids were considered safe for mammals for many decades, recent research has proven that these insecticides can alter cholinergic functions by interacting with neuronal nicotinic acetylcholine (ACh) receptors (nAChRs). One such receptor is the heteromeric α4β2 nAChR, which exists under two different stoichiometries: high sensitivity and low sensitivity α4β2 nAChRs. To replace these insecticides, new classes of insecticides have been developed, such as, sulfoximine, sulfoxaflor, and the butanolide, flupyradifurone.

Pharmacology and molecular modeling studies of sulfoxaflor, flupyradifurone and neonicotinoids on the human neuronal α7 nicotinic acetylcholine receptor.

We conducted electrophysiological and molecular docking studies using a heterologous expression system (Xenopus oocytes) to compare the effects of four neonicotinoids (acetamiprid, imidacloprid, clothianidin and thiamethoxam), one sulfoximine, (sulfoxaflor), and one butenolide (flupyradifurone), on human α7 neuronal nicotinic acetylcholine receptors (nAChRs). All neonicotinoids (except thiamethoxam), as well as the recently introduced nAChR competitive modulators, flupyradifurone and sulfoxaflor, appear to be weaker agonists than acetylcholine. Two mutations in loop C (E211N and E211P) and one mutation in loop D (Q79K), known to be involved in the binding properties of neonicotinoids were introduced to the α7 wild type.

Navigating the complexities of docking tools with nicotinic receptors and acetylcholine binding proteins in the realm of neonicotinoids.

Molecular docking, pivotal in predicting small-molecule ligand binding modes, struggles with accurately identifying binding conformations and affinities. This is particularly true for neonicotinoids, insecticides whose impacts on ecosystems require precise molecular interaction modeling. This study scrutinizes the effectiveness of prominent docking software (Ledock, ADFR, Autodock Vina, CDOCKER) in simulating interactions of environmental chemicals, especially neonicotinoid-like molecules with nicotinic acetylcholine receptors (nAChRs) and acetylcholine binding proteins (AChBPs).

Corrigendum: Cloning and expression of cockroach α7 nicotinic acetylcholine receptor subunit.

[This corrects the article DOI: 10.3389/fphys.2020.

The calcium-calmodulin-dependent protein kinase kinase inhibitor, STO-609, inhibits nicotine-induced currents and intracellular calcium increase in insect neurosecretory cells.

Insect neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane receptors that play a key role in the development and synaptic plasticity of both vertebrates and invertebrates and are considered to be major targets of neonicotinoid insecticides. We used dorsal unpaired median (DUM) neurons, which are insect neurosecretory cells, in order to explore the intracellular mechanisms leading to the regulation of insect neuronal nAChRs in more detail. Using whole-cell patch-clamp and fura-2AM calcium imaging techniques, we found that a novel CaMKK/AMPK pathway could be involved in the intracellular regulation of DUM neuron nAChRs.

Effect of Acetamiprid, a Neonicotinoid Insecticide, on Locomotor Activity of the American Cockroach.

Toxicological studies have shown that the American cockroach (Linnaeus) is a classical model for studying the mode of action of commonly used insecticides. In a previous study, we demonstrated that thiamethoxam and clothianidin decreased locomotor activity in an open-field-like apparatus. Here, we tested the effect of the neonicotinoid acetamiprid when applied orally, topically, or injected into the haemolymph.

Development of CHARMM compatible force field parameters and molecular dynamics simulations for the pesticide flupyradifurone.

Flupyradifurone (FLU) is a novel butenolide insecticide with partial agonist activity for insect nicotinic acetylcholine receptors. Its safety for non-target organisms has been questioned in the literature, despite initial claims of its harmlessness. Detailed understanding of its toxicity and related molecular mechanisms remain under discussion.

Molecular Mechanism of Action of Neonicotinoid Insecticides.

Since neonicotinoid insecticides were first introduced several years ago, most of them have been banned by the European Union due to their potentially adverse effects on humans and useful insects [...

Identification of sulfonamide compounds active on the insect nervous system: Molecular modeling, synthesis and biological evaluation.

Insect nicotinic acetylcholine receptors (nAChRs) are a recognized target for insecticide design. In this work, we have identified, from a structure-based approach using molecular modeling tools, ligands with potential selective activity for pests versus pollinators. A high-throughput virtual screening with the Openeye software was performed using a library from the ZINC database, thiacloprid being used as the target structure.

Effect of the combination of DEET and flupyradifurone on the tick Ixodes ricinus: Repellency bioassay and pharmacological characterization using microtransplantation of synganglion membranes.

Ticks are vectors of many human and animal pathogens, and represent a major threat to public health. In recent years, an increase in tick-borne diseases has been observed, and new strategies are therefore needed in order to control tick numbers and reduce human tick bites. In the present study, we adapted the previous tick repellency bioassay based on the exploration behavior of the tick, using the ToxTrac software and video-tracking, to compare the repellent effect of two compounds on the tick Ixodes ricinus: N,N-diethyl-methyl-m-toluamide (DEET), and butenolide, flupyradifurone (FLU).

Impairments in learning and memory performances associated with nicotinic receptor expression in the honeybee Apis mellifera after exposure to a sublethal dose of sulfoxaflor.

Sulfoxaflor is a new insecticide which acts on the nicotinic acetylcholine receptor (nAChRs) in a similar way to neonicotinoids. However, sufloxaflor (SFX) is thought to act in a different manner and is thus proposed as an alternative in crop protection. The goal of this study is to evaluate the toxicity of SFX and its sublethal effect on the honeybee Apis mellifera after acute exposure.

The use of insecticide mixtures containing neonicotinoids as a strategy to limit insect pests: Efficiency and mode of action.

Synthetic insecticides continue to be the main strategy for managing insect pests, which are a major concern for both crop protection and public health. As nicotinic acetylcholine receptors play a central role in insect neurotransmission, they are the molecular target of neurotoxic insecticides such as neonicotinoids. These insecticides are used worldwide and have shown high efficiency in culture protection.

Calmidazolium induces a decrease in nicotine-induced currents and intracellular calcium levels after pulse application of nicotine onto insect neurosecretory cells.

Dorsal unpaired median (DUM) neurons, are a class of insect neurosecretory cells, which are involved in the control of several functions, such as excretion and reproduction, or the release of neurohormones. Previous studies demonstrated that they express different nicotinic acetylcholine receptor subtypes, in particular α-bungarotoxin-insensitive receptors, with nAChR1 and nAChR2 subtypes. Here, we demonstrated that pulse application of 1 mM nicotine (300 ms pulse duration) induced inward currents which were reduced under bath application of 15 µM calmidazolium, a calmodulin inhibitor.

Mode of Action of Neonicotinoid Insecticides Imidacloprid and Thiacloprid to the Cockroach Pameα7 Nicotinic Acetylcholine Receptor.

The functional expression of the cockroach Pameα7 nicotinic acetylcholine receptor subunit has been previously studied, and was found to be able to form a homomeric receptor when expressed in oocytes. In this study, we found that the neonicotinoid insecticide imidacloprid is unable to activate the cockroach Pameα7 receptor, although thiacloprid induces low inward currents, suggesting that it is a partial agonist. In addition, the co-application or 5 min pretreatment with 10 µM imidacloprid increased nicotine current amplitudes, while the co-application or 5 min pretreatment with 10 µM thiacloprid decreased nicotine-evoked current amplitudes by 54% and 28%, respectively.

Nicotinic acetylcholine receptors in the synganglion of the tick Ixodes ricinus: Functional characterization using membrane microtransplantation.

Nicotinic acetylcholine receptors are an important class of excitatory receptors in the central nervous system of arthropods. In the ticks Ixodes ricinus, the functional and pharmacological properties of nicotinic receptors located in their neurons are still unknown. The objective of this study was to characterize the pharmacological properties of tick nicotinic receptors using membrane microtransplantation in Xenopus laevis oocytes and two-electrodes voltage clamp method.

Synergic effect of a quinuclidine benzamide complexed with borane, the LMA10233, in combination with seven pesticides.

Some quinuclidine benzamide compounds have been found to modulate nicotinic acetylcholine receptors in both mammals and insects. In particular, the quaternarization of 3-amino quinuclidine benzamide derivatives with dichloromethane gave charged N-chloromethylated quinuclidine compounds, disclosing an antagonist profile on homomeric α7 nAChRs. Here, we synthesized and studied the toxicological effect of LMA10233, a quinuclidine-borane complex analogue, the LMA10233, on the pea aphid Acyrthosiphon pisum and found that LMA10233 only exhibit proper toxicity on A.

Cloning and Expression of Cockroach α7 Nicotinic Acetylcholine Receptor Subunit.

Understanding insect nicotinic acetylcholine receptor (nAChR) subtypes is of major interest because they are the main target of several insecticides. In this study, we have cloned a cockroach Pameα7 subunit that encodes a 518 amino acid protein with futures typical of nAChR subunit, and sequence homology to α7 subunit. Pameα7 is differently expressed in the cockroach nervous system, in particular in the antennal lobes, optical lobes and the mushroom bodies where specific expression was found in the non-compact Kenyon cells.

An Overview on the Effect of Neonicotinoid Insecticides on Mammalian Cholinergic Functions through the Activation of Neuronal Nicotinic Acetylcholine Receptors.

Neonicotinoid insecticides are used worldwide and have been demonstrated as toxic to beneficial insects such as honeybees. Their effectiveness is predominantly attributed to their high affinity for insect neuronal nicotinic acetylcholine receptors (nAChRs). Mammalian neuronal nAChRs are of major importance because cholinergic synaptic transmission plays a key role in rapid neurotransmission, learning and memory processes, and neurodegenerative diseases.

Effects of the DAG analogue 1,2-dioctanoyl-sn-glycerol (DiC8) on nicotine- and clothianidin-evoked currents through α-bungarotoxin-insensitive nicotinic acetylcholine receptors expressed on cockroach neurosecretory cells.

We previously demonstrated that the cockroach α-bungarotoxin-sensitive nicotinic acetylcholine receptors, nAChR1 and nAChR2 subtypes, are differently sensitive to intracellular calcium pathways. Here, using whole cell patch-clamp recordings, we studied the effects of the diacylglycerol (DAG) analogue 1,2-dioctanoyl-sn-glycerol (DiC8) on nicotine- and clothianidin-evoked currents under an α-bungarotoxin treatment. Our results demonstrated that DiC8 reduced nicotine and clothianidin evoked currents.

Binding of Sulfoxaflor to -AChBP: Computational Insights from Multiscale Approaches.

Structural features and binding properties of sulfoxaflor (SFX) with -AChBP, the surrogate of the insect nAChR ligand binding domain (LBD), are reported herein using various complementary molecular modeling approaches (QM, molecular docking, molecular dynamics, and QM/QM'). The different SFX stereoisomers show distinct behaviors in terms of binding and interactions with -AChBP. Molecular docking and Molecular Dynamics (MD) simulations highlight the specific intermolecular contacts involved in the binding of the different SFX isomers and the relative contribution of the SFX functional groups.

Mode of action of sulfoxaflor on α-bungarotoxin-insensitive nAChR1 and nAChR2 subtypes: Inhibitory effect of imidacloprid.

Cockroach neurosecretory cells, dorsal unpaired median (DUM) neurons, express two distinct α-bungarotoxin-insensitive nicotinic acetylcholine receptor subtypes, nAChR1 and nAChR2 which are differently sensitive to the neonicotinoid insecticides and intracellular calcium pathways. The aim of this study is to determine whether sulfoxaflor acts as an agonist of nAChR1 and nAChR2 subtypes. We demonstrated that 1 mM sulfoxaflor induced high current amplitudes, compared to acetylcholine, suggesting that it was a full agonist of DUM neuron nAChR subtypes.

Neonicotinoid insecticides mode of action on insect nicotinic acetylcholine receptors using binding studies.

Nicotinic acetylcholine receptors (nAChRs) are the main target of neonicotinoid insecticides, which are widely used in crop protection against insect pests. Electrophysiological and molecular approaches have demonstrated the presence of several nAChR subtypes with different affinities for neonicotinoid insecticides. However, the precise mode of action of neonicotinoids on insect nAChRs remains to be elucidated.

Permethrin enhances the agonist activity of dinotefuran on insect cholinergic synaptic transmission and isolated neurons.

Insect resistance mechanisms against pesticides lead to the development and the search of new pesticide combinations in order to delay the resistance. The combination of neonicotinoids with pyrethroids was currently proposed but the mode of action of these compounds at synaptic and extrasynaptic levels needs to be further explored. In the present study, we evaluated the effect of the combination of two insecticides, permethrin and dinotefuran, on cockroach cholinergic synaptic transmission and on isolated cell bodies.