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Key Event Title
Desensitization, Nicotinic acetylcholine receptor
|Level of Biological Organization|
Key Event Components
|acetylcholine receptor activator activity||Nicotinic acetylcholine receptor||increased|
|receptor regulator activity||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD 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 Do not cite|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 Do not cite|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 Do not cite|
Key Event Description
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
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
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.