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Relationship: 658
Title
Activation, Nicotinic acetylcholine receptor leads to Desensitization, Nicotinic acetylcholine receptor
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Nicotinic acetylcholine receptor activation followed by desensitization contributes to abnormal foraging and directly leads to colony loss/failure | adjacent | Arthur Author (send email) | Open for comment. Do not cite | |||
Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony loss/failure via abnormal role change within caste | adjacent | Brendan Ferreri-Hanberry (send email) | Open for comment. Do not cite | |||
Nicotinic acetylcholine receptor activation contributes to abnormal roll change within the worker bee caste leading to colony loss/failure 2 | adjacent | Agnes Aggy (send email) | Open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
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
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
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
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
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.