Nicotinic receptors: From protein allostery to computational neuropharmacology

Cecchini, Marco; Changeux, Jean‐Pierre

doi:10.1016/j.mam.2021.101044

Cited by 16 publications

(21 citation statements)

References 69 publications

(88 reference statements)

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“…The neural mechanism underlying the impairment of learning and memory in bees is due to neonicotinoids acting as antagonists of nicotinic acetylcholine receptors (nAChRs). nAChRs play crucial roles in neuronal plasticity, brain development ( Cecchini and Changeux, 2022 ), and the formation of learning memory in honeybees ( Cano-Lozano et al, 1996 ; Grunewald and Siefert, 2019 ). Chronic exposure to neonicotinoids caused nAChR desensitization ( Mustard et al, 2020 ), altered odors encoding information ( Ohlinger et al, 2022 ), and reduced microglomerular density, which are responsible for olfactory learning and memory functions ( Peng and Yang, 2016 ; Tavares et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Chronic larval exposure to thiacloprid impairs honeybee antennal selectivity, learning and memory performances

Chen

Dai

et al. 2023

Front. Physiol.

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The use of agricultural neonicotinoid insecticides has sub-lethal chronic effects on bees that are more prevalent than acute toxicity. Among these insecticides, thiacloprid, a commonly used compound with low toxicity, has attracted significant attention due to its potential impact on the olfactory and learning abilities of honeybees. The effect of sub-lethal larval exposure to thiacloprid on the antennal activity of adult honeybees (Apis mellifera L.) is not yet fully understood. To address this knowledge gap, laboratory-based experiments were conducted in which honeybee larvae were administered thiacloprid (0.5 mg/L and 1.0 mg/L). Using electroantennography (EAG), the impacts of thiacloprid exposure on the antennal selectivity to common floral volatiles were evaluated. Additionally, the effects of sub-lethal exposure on odor-related learning and memory were also assessed. The results of this study reveal, for the first time, that sub-lethal larval exposure to thiacloprid decreased honeybee antenna EAG responses to floral scents, leading to increased olfactory selectivity in the high-dose (1.0 mg/L) group compared to the control group (0 mg/L vs. 1.0 mg/L: p = 0.042). The results also suggest that thiacloprid negatively affected odor-associated paired learning acquisition, as well as medium-term (1 h) (0 mg/L vs. 1.0 mg/L: p = 0.019) and long-term memory (24 h) (0 mg/L vs. 1.0 mg/L: p = 0.037) in adult honeybees. EAG amplitudes were dramatically reduced following R-linalool paired olfactory training (0 mg/L vs. 1.0 mg/L: p = 0.001; 0 mg/L vs. 0.5 mg/L: p = 0.027), while antennal activities only differed significantly in the control between paired and unpaired groups. Our results indicated that exposure to sub-lethal concentrations of thiacloprid may affect olfactory perception and learning and memory behaviors in honeybees. These findings have important implications for the safe use of agrochemicals in the environment.

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Section: Discussionmentioning

confidence: 99%

Chronic larval exposure to thiacloprid impairs honeybee antennal selectivity, learning and memory performances

Chen

Dai

et al. 2023

Front. Physiol.

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“…142 Insightfully, it was found that the differential binding affinity of the ligand for the open versus the closed state of the channel is able to discriminate between agonists and antagonists as predicted by the Monod−Wyman−Changeux (MWC) model. 132 In addition, it was shown that an analysis of the ΔΔG of binding (i.e., open versus closed) for seven analogues of Yoda1 by RBFE calculations yields chemical insights on the gain or loss of agonistic activity in agreement with efficacy data from the literature. The reported accuracy (<1 kcal/mol) and the potential throughput via RBFE calculations make the design of mechanosensitive channel agonists and antagonists within reach.…”

Section: Ion Channelsmentioning

confidence: 99%

Alchemical Free Energy Calculations on Membrane-Associated Proteins

Papadourakis,

Sinenka,

Matricon

et al. 2023

J. Chem. Theory Comput.

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Membrane proteins have diverse functions within cells and are well-established drug targets. The advances in membrane protein structural biology have revealed drug and lipid binding sites on membrane proteins, while computational methods such as molecular simulations can resolve the thermodynamic basis of these interactions. Particularly, alchemical free energy calculations have shown promise in the calculation of reliable and reproducible binding free energies of protein–ligand and protein–lipid complexes in membrane-associated systems. In this review, we present an overview of representative alchemical free energy studies on G-protein-coupled receptors, ion channels, transporters as well as protein–lipid interactions, with emphasis on best practices and critical aspects of running these simulations. Additionally, we analyze challenges and successes when running alchemical free energy calculations on membrane-associated proteins. Finally, we highlight the value of alchemical free energy calculations calculations in drug discovery and their applicability in the pharmaceutical industry.

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“…These distinct pharmacological profiles were interpreted in terms of the concerted two-state model (Monod et al, 1965) based upon a pre-existing equilibrium between the resting and active states that is differentially shifted depending on the nature of the effector [3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

Illumination of a progressive allosteric mechanism mediating the glycine receptor activation

Shi

Lefebvre

Peverini

et al. 2022

Preprint

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Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating transition of the glycine receptor fluorescently labeled at the extracellular-transmembrane interface by voltage-clamp fluorimetry (VCF). Fluorescence reports a glycine-elicited conformational transition that precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger the full fluorescence signal while weakly activating the channel. Molecular dynamic simulations of a partial agonist bound-closed Cryo-EM structure show a highly dynamic personality: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties that recapitulate VCF data. Data thus illuminate a progressive gating transition towards activation, displaying structural plasticity with novel implication concerning the mechanism of action of allosteric effectors.

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Nicotinic receptors: From protein allostery to computational neuropharmacology

Cited by 16 publications

References 69 publications

Chronic larval exposure to thiacloprid impairs honeybee antennal selectivity, learning and memory performances

Chronic larval exposure to thiacloprid impairs honeybee antennal selectivity, learning and memory performances

Alchemical Free Energy Calculations on Membrane-Associated Proteins

Illumination of a progressive allosteric mechanism mediating the glycine receptor activation

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