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Event: 663

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Desensitization, Nicotinic acetylcholine receptor

Short name

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
neuron

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
acetylcholine receptor activator activity	Nicotinic acetylcholine receptor	increased
receptor regulator activity		decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status
nAChR activation - colony loss 7	KeyEvent	Carlie LaLone (send email)	Open for comment. Do not cite
nAChR activation - colony loss 6	KeyEvent	Carlie LaLone (send email)	Open for comment. Do not cite
nAChR activation - colony loss 8	KeyEvent	Carlie LaLone (send email)	Open for comment. Do not cite

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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

Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. 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:

"Upon prolonged and repeated exposure to a nAChR agonist, desensitizationmay occur.Desensitization is characterized by an initial opening of the ion channel and ion exchange across the cell membrane followed by rapid channel closure and inactivity, effectively inhibiting neurotransmission (Quick and Lester, 2002). Further, inhibition of nAChR activity from desensitization can lead to an up-regulation in nAChR expression, termed pharmacological chaperoning (Srinivasan et al., 2012; Flores et al., 1992; Marszalec et al., 2005). Exposure to imidacloprid and thiamethoxam for 72 or 48 h, respectively was shown to significantly increase transcriptional abundance of nAChRα1 subunit in the honey bee brain (Christen et al., 2016). In the desensitized state, nAChR receptors have high affinity for the agonist and therefore establish a blockade to subsequent agonist binding (Ochoa et al., 1989). It has been demonstrated that recovery from nAChR desensitization occurs (though not always complete) upon removal of the agonist (Ochoa et al., 1989). However, the speed of recovery is dependent on the concentration and duration of exposure to the agonist, with longer exposures typically resulting in slower recovery times (Quick and Lester, 2002). In fact, loss of functional nAChR channels has been reported in neuronal cell line PC12 (rat adrenal gland pheochromocytoma tumor) upon prolonged exposure to carbachol, a cholinergic agonist (Simasko et al., 1986). Phosphorylation of nAChR subunits is another factor that regulates the rate of desensitization and subsequent recovery. Nicotinic acetylcholine receptor subunits possess phosphorylation sites for cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), calciumcalmodulin- dependent protein kinase (CaM kinase) and endogenous protein tyrosine kinase (Hopfield et al., 1988; Thany et al., 2007). Evidence suggests that phosphorylation of nAChR subunits regulate the rate of desensitization,with the greater number of phosphotyrosines indicative of rapid recovery from desensitization (Hopfield et al., 1988; Thany et al., 2007)."

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Text from Table 2 in 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:

"• Electrophysiological characterization for investigation of desensitization. Patch-clamp, number of channel openings per unit time • Immunoblotting to determine phosphotyrosine content of purified nAChR"

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

List of the literature that was cited for this KE 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.

Quick, M.W., Lester, R.A., 2002. Desensitization of neuronal nicotinic receptors. J. Neurobiol. 53 (4), 457–478.

Srinivasan, R., Richards, C.I., Xiao, C., Rhee, D., Pantoja, R., Dougherty, D.A., Miwa, J.M., Lester, H.A., 2012. Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the endoplasmic reticulumstress response.Mol. Pharmacol. 81 (6), 759–769.

Flores, C.M., Rogers, S.W., Pabreza, L.A.,Wolfe, B.B., Kellar, K.J., 1992. A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is upregulated by chronic nicotine treatment. Mol. Pharmacol. 41 (1), 31–37.

Marszalec, W., Yeh, J.Z., Narahashi, T., 2005. Desensitization of nicotine acetylcholine receptors: modulation by kinase activation and phosphatase inhibition. Eur. J. Pharmacol. 514 (2–3), 83–90.

Christen, V., Mittnter, F., Fent, K., 2016. Molecular effects of neonicotinoids in honey bees (Apis mellifera). Environ. Sci. Technol. 50 (7), 4071–4081.

Ochoa, E.L., Chattopadhyay, A., McNamee, M.G., 1989. Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators. Cell. Mol. Neurobiol. 9 (2), 141–178.

Simasko, S.M., Soares, J.R., Weiland, G.A., 1986. Two components of carbamylcholine-induced loss of nicotinic acetylcholine receptor function in the neuronal cell line PC12. Mol. Pharmacol. 30 (1), 6–12.

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.