API

Event: 559

Key Event Title

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Activation, Nicotinic acetylcholine receptor

Short name

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Activation, Nicotinic acetylcholine receptor

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
neuron


Organ term

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Key Event Components

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Process Object Action
acetylcholine receptor activity Nicotinic acetylcholine receptor increased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
nAChR activation - colony death 1 MolecularInitiatingEvent
nAChR activation - colony death/failure2 MolecularInitiatingEvent
nAChR activation - colony loss 3 MolecularInitiatingEvent
nAChR activation - colony loss 5 MolecularInitiatingEvent
nAChR activation - colony loss 6 MolecularInitiatingEvent
nAChR activation - colony loss 7 MolecularInitiatingEvent
nAChR activation - colony loss 8 MolecularInitiatingEvent
nAChR activation - colony loss 4 MolecularInitiatingEvent
nAChR to colony loss/failure MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. Science of the Total Environment 584-585, 751-775:

"Nicotinic acetylcholine receptors belong to the
cys-loop superfamily of ligand-gated ion channels, responsible for
rapid neurotransmission (Karlin, 2002). In insects nAChR have signaling
roles in nervous systems and neuromuscular junctions and other cells
(Jones and Sattelle, 2010; Lindstrom, 2003). Under normal conditions
the endogenous neurotransmitter, acetylcholine (ACh), attaches to the
ligand binding domains on the extracellular region of the pentameric
nAChR. This initiates a conformation change that promotes the influx
and efflux of calcium (Ca2+) and extracellular sodium and intracellular
potassiumions, respectively, to create the action potential necessary for
synaptic signaling (Jones and Sattelle, 2010). Activation of the nAChR,
by natural or synthetic agonists, and subsequent involvement in neurotransmission
is well established. Although the nAChR is conserved
across vertebrates and invertebrates, the diverse composition and assembly
of α-(containing two adjacent cysteine residues important in
ACh binding) and non α-(lacking the cysteine residues) subunits confer
diverse functional architecture and, therefore, toxicological responses
(Jones and Sattelle, 2010)."


How It Is Measured or Detected

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Text fromTable 2 of LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. Science of the Total Environment 584-585, 751-775:

"• Radiolabeled nAChR agonists, (e.g., [3H] imidacloprid) or nAChR subunit specific antibodies to detect location and subunit
composition of nAChR
• Ligand competition studies evaluating [3H] agonist displacement to determine ligand affinities to the nAChR
• Whole-cell voltage clamp electrophysiological measurements with agonists to measure nAChR activation"


Domain of Applicability

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Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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Text from LaLone et al. (2017) Weight of evidence evaluation of a network of adverse outcome pathways linking activaiton of the nicotinic acetylcholine receptor in honey bees to colony death. Science of the Total Environment 584-585, 751-775:

"The nicotinoids and neonicotinoids are both agonists of the nAChR
(Tomizawa and Casida, 2003); however, neonicotinoids are the primary
chemicals considered in the AOPs relevant to bees.
The potency of a nAChR agonist is dependent on the receptor subunit
composition, structurally important amino acid residues at the
binding site, and the ionization status of the chemical at physiological
pH (Tomizawa and Casida, 2003; Dani and Bertrand, 2007). For example,
nicotine is a classical vertebrate nAChR agonist; however, it has relatively
low affinity (and insecticidal activity) for the invertebrate
nAChR. Due to ionization, nicotine is poor at passing though the ion-impermeable
barrier surrounding the insect central nervous system(CNS;
Tomizawa and Casida, 2003). Conversely, non-ionizable neonicotinoids
readily translocate into the insect CNS and have high affinity for the
nAChR (e.g., Drosophila nAChR IC50 4.6 nM imidacloprid), with limited
or no binding activity to vertebrate nAChR (Tomizawa and Casida,
2003). Various studies have demonstrated that similarities and differences
in key amino acid residues in the ligand binding domain across
species can lead to structural and binding site differences that dictate
chemical interaction with the receptor (Dani and Bertrand, 2007;
Matsuda et al., 2009; Tomizawa and Casida, 2009; Jones and Sattelle,
2010; LaLone et al., 2016). Due to the intended insecticidal action of
neonicotinoids, a growing number of studies have been conducted to

evaluate potential adverse effects in non-target species such as honey
bees exposed to neonicotinoids, particularly imidacloprid, clothianidin,
and thiamethoxam. Some of the results of these studies are included
in subsequent AOP descriptions."



References

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LaLone, C.A., Villeneuve, D.L., Wu-Smart, J., Milsk, R.Y., Sappington, K., Garber, K.V., Housenger, J. and Ankley, G.T., 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death. STOTEN. 584-585, 751-775.

Karlin, A., 2002. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev.
Neurosci. 3 (2), 102–114.

Jones, A.K., Sattelle, D.B., 2010. Diversity of insect nicotinic acetylcholine receptor subunits.
Adv. Exp. Med. Biol. 683, 25–43.

Lindstrom, J.M., 2003. Nicotinic acetylcholine receptors of muscles and nerves. Ann. N. Y.
Acad. Sci. 998 (1), 41–52.

Tomizawa,M., Casida, J.E., 2003. Selective toxicity of neonictinoids attributable to specificity
of insect and mammalian nicotinic receptors. Annu. Rev. Entomol. 48, 339–364.

Dani, J.A., Bertrand, D.D., 2007. Nicotinic acetylcholine receptors and nicotinic cholinergic
mechanisms of the central nervous system.Annu. Rev. Pharmacol. Toxicol. 47, 699–729.

Matsuda, K., Kanaoka, S., Akamatsu,M., Sattelle, D.B., 2009. Diverse actions and target-site
selectivity of neonicotinoids: structural insights. Mol. Pharmacol. 76 (1), 1–10.

LaLone, C.A., Villeneuve, D.L., Lyons, D., Helgen, H.W., Robinson, S.L., Swintek, J.A., Saari,
T.W., Ankley, G.T., 2016. Sequence alignment to predict across species susceptibility
(SeqAPASS): a web-based tool for addressing the challenges of cross-species extrapolation
of chemical toxicity. Toxicol. Sci. 153 (2), 228–245.