API

Relationship: 658

Title

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

Upstream event

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Activation, Nicotinic acetylcholine receptor

Downstream event

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Desensitization, Nicotinic acetylcholine receptor

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Evidence Supporting this KER

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Biological Plausibility

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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 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).

Empirical Evidence

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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:

"It has been demonstrated in various models that nAChR agonism
does indeed lead to desensitization. For example, upon exposure of
human α7 nAChR expressed in African clawed frog (Xenopus laevis) oocytes
to classical nAChR agonists, including nicotine, Briggs and
McKenna (1998) showed that even weak or low concentrations of an
agonist could act asmore potent inhibitors than activators of the receptor
through desensitization. Further, in another examplemeasuring current
across the neuron and activity of the natural nAChR ligand and ACh
neurotransmitter, Zwart et al. (1994) demonstrated that six nAChR agonists
induced nAChR-mediated inward ionic current, and that their
continued presence significantly blocked ACh-induced inward current
in whole-cell voltage-clamped African locust (Locusta migratoria) thoracic
ganglion neurons. In that study, it was shown that concentrations
of 0.1 μM and 10 μM imidacloprid induced ACh-inward current with
peak amplitudes of 4% and 30%, respectively (Zwart et al., 1994). Continued
exposure to 0.1 μMimidacloprid led to desensitization that reduced
the amplitude of 1 mM ACh-induced inward current by 73%; whereas,
continued exposure to 10 μM imidacloprid completely blocked inward
current indicting that the potency to block the ACh-induced ion current
was greater than the potency to induce inward current (Zwart et al.,
1994).
Specific evidence of desensitization exists in honey bees as well. Exposure
of cultured Kenyon cells from honey bee brains to imidacloprid
yielded partial nAChR agonist activity, eliciting 36% of the ACh-induced
current and causing desensitization of the receptor after prolonged
(16 s) exposure (Deglise et al., 2002). Further, when 10−5 M
imidacloprid was co-applied with ACh, the mean amplitude of ACh-induced
currents was significantly lowered (64%) compared to ACh coapplication
with saline, thereby providing evidence that imidacloprid
antagonized the ACh-induced receptor activation by out-competing
ACh for the same binding site (Deglise et al., 2002). Interestingly, an antagonist
of the nAChR (mecamylamine) demonstrated similar properties,
likely affecting neurotransmission, in that direct injection into the
brain hemolymph of honey bee was shown to not only impair olfactory
learning but, in patch-clamp experiments with cultured Kenyon cells,
completely block the ACh-induced current (Lozano et al., 1996;
Wüstenberg and Grünewald, 2004).
Recovery from desensitization depends on the availability of phosphorylation
sites on the nAChR subunits and the number of
phosphotyrosine residues. Mutation of key PKC phosphorylation sites
on the rat α4 nAChR subunit expressed in Xenopus oocytes resulted in
impaired recovery from deep desensitization (Fenster et al., 1999).
Further inhibition of PKC or knockout of PKC in a mouse model
(Prkce−/−) also led to impaired recovery from desensitization (Lee
et al., 2015a). Phosphorylation sites on nAChR subunits as well as PKC
isozymes continue to be identified. Cross species differences in those
sites may contribute to the differences in sensitivity to various
chemicals that act on the nAChR (Hug and Sarre, 1993). Demonstration
that perturbation to PKC can impact recovery fromdesensitization is an
important piece of evidence, describing a potential feedback loop
linking the downstreamKE of altered Ca2+-calmodulin activated signal
transduction back to desensitization (see Fig. 2; step 6). Kinases phosphorylate
nAChR subunits, indicating that disruption of downstream
signaling could further impact nAChR desensitization status."

Uncertainties and Inconsistencies

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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:

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.

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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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.

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.