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Relationship: 658


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, Nicotinic acetylcholine receptor leads to Desensitization, Nicotinic acetylcholine receptor

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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 first draft of the honey bee genome became available through the efforts of the Honey Bee Genome Sequencing Consortium (2006),

and has provided valuable insights on evolution and comparisons between species. The honey bee has 11 genes that encode nAChR subunits - nineα and two β subunits (Jones et al., 2006), consistentwith the condensed number of genes seen in other insects compared to vertebrates (Tomizawa and Casida, 2001). The primary location of insect nAChRs is the brain. In honey bees, nAChRs have been identified in Kenyon cells located onmushroombodies and antennal lobes, both involved in olfactory learning (Deglise et al., 2002; Dupuis et al., 2011).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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:

Desensitizationis a well-studied biological function that occurs upon activation of ligand- gated ion channels, such as the nAChR, with prolonged or repeated exposure to variable concentrations (typically low) of agonist; thus, biological plausibility of activation leading to desensitization is quite strong.However, there are relatively significant uncertainties associated with desensitization of the insect neuronal nAChR, due to incomplete characterization of the subunit combinations that make-up the nAChR in neurons of the honey bee (or other invertebrates), which may affect both chemical binding affinity and available phosphorylation sites involved in recovery from the desensitized state (Hopfield et al., 1988; Thany et al., 2007). Although progress has been made in characterizing the composition of the nAChR subunits, most recombinant hybrid nAChRs evaluated consist of a combination of both insect and vertebrate subunits (Ihara et al., 2007). Therefore, the composition and activity of insect subunits alone have not been elucidated nor evaluated. Further, concentrations and durations of agonist exposure that would lead to a prolonged desensitized state of the receptor, effectively inactivating it, are uncertain. Research focused on characterization of insect nAChR, with evaluation of temporal and dosimetric concordancewould provide greater understanding of the mechanism through which activation of the nAChR can lead to desensitization and subsequent downstream events.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

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.

Honey Bee Genome Sequencing Consortium, 2006. Insights into social insects from the genome of the honeybee Apis mellifera. Nature 443 (7114), 931.

Jones, A.K., Raymond-Delpech, V., Thany, S.H., Gauthier, M., Sattelle, D.B., 2006. The nicotinic acetylcholine receptor gene family of the honey bee, Apis mellifera. Genome Res. 16 (11), 1422–1430.

Tomizawa, M., Casida, J.E., 2001. Structure and diversity of insect nicotinic acetylcholine receptors. Pest Manag. Sci. 57 (10), 914–922.

Deglise, P., Grunewald, B., Gauthier, M., 2002. The insecticide imidacloprid is a partial agonist of the nicotinic receptor of honeybee Kenyon cells. Neurosci. Lett. 321 (1–2), 13–16.

Dupuis, J.P., Gauthier, M., Raymond-Delpech, V., 2011. Expression patterns of nicotinic subunits alpha2, alpha7, alpha8, and beta1 affect the kinetics and pharmacology of ACh-induced currents in adult bee olfactory neuropiles. J. Neurophysiol. 106 (4), 1604–1613.

Briggs, C.A., McKenna, D.G., 1998. Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists. Neuropharmacology 37 (9), 1095–1102.

Zwart, R., Oortgiesen, M., Vijverberg, H.P., 1994. Nitromethylene heterocycles: selective agonists of nicotinic receptors in locust neurons compared to mouse N1E-115 and BC3H1 cells. Pestic. Biochem. Physiol. 48, 202–213.

Lozano, V.C., Bonnard, E., Gauthier, M., Richard, D., 1996.Mecamylamine-induced impairment of acquisition and retrieval of olfactory conditioning in the honeybee. Behav. Brain Res. 81 (1–2), 215–222.

Wüstenberg, D.G., Grünewald, B., 2004. Pharmacology of the neuronal nicotinic acetylcholine receptor of cultured Kenyon cells of the honeybee, Apis mellifera. J. Comp. Physiol. A. 190 (10), 807–821.

Fenster, C.P., Beckman, M.L., Parker, J.C., Sheffield, E.B., Whitworkth, T.L., Quick, M.W., Lester, R.A., 1999. Regulation of alpha4beta2 nicotinic receptor desensitization by calcium and protein kinase C. Mol. Pharmacol. 55 (3), 432–443.

Lee, A.M., Wu, D.F., Dadgar, J., Wang, D., McMahon, T., Messing, R.O., 2015a. PKCε phosphorylates α4β2 nicotinic ACh receptors and promotes recovery from desensitization. Br. J. Pharmacol. 172 (17), 4430–4441.

Hug, H., Sarre, T.F., 1993. Protein kinase C isoenzymes: divergence in signal transduction? Biochem. J. 291, 329–343.

Hopfield, J.F., Tank, D.W., Greengard, P., Huganir, R.L., 1988. Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336 (6200), 677–680.

Thany, S.H., Lenaers, G., Raymond-Delpech, V., Sattelle, D.B., Lapied, B., 2007. Exploring the pharmacological properties of insect nicotinic acetylcholine receptors. Trends Pharmacol. Sci. 28 (1), 14–22.

Ihara, M., Shimomura, M., Ishida, C., Nishiwaki, H., Akamatsu, M., Sattelle, D.B., Matsuda, K., 2007. A hypothesis to account for the selective and diverse actions of neonicotinoid insecticides at their molecular targets, nicotinic acetylcholine receptors: catch and release in hydrogen bond networks. Invertebr. Neurosci. 7 (1), 47–51.