API

Event: 663

Key Event Title

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Short name

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Desensitization, Nicotinic acetylcholine receptor

Biological Context

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Cell term

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Organ term

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Key Event Components

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Key Event Overview

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AOPs Including This Key Event

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Stressors

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Taxonomic Applicability

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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:

"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

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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

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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.

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.