Desensitization of neuronal nicotinic receptors

Abstract

ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

Prenatal Nicotine Exposure Alters the Response to Nicotine Administration in Adolescence: Effects on Cholinergic Systems During Exposure and Withdrawal

“…Rx ¼ treatment. (Buisson and Bertrand, 2002;Dani and De Biasi, 2001;Quick and Lester, 2002). Our results therefore suggest two mutually exclusive scenarios.…”

Short-Term Adolescent Nicotine Exposure has Immediate and Persistent Effects on Cholinergic Systems: Critical Periods, Patterns of Exposure, Dose Thresholds

“…Notably, the nAChR ligand we used, [ 3 H]cytisine, binds to the a4b2 receptor, the most widely distributed subtype in the brain (Buisson and Bertrand, 2002). Upregulation of a4b2 nAChRs is thought to be initiated by receptor desensitization (Fenster et al, 1999) and both desensitization and upregulation are hypothesized to play a role in addiction mechanisms Bertrand, 2001, 2002;Dani and De Biasi, 2001;Quick and Lester, 2002).…”

Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death

“…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).…”

“…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).…”

“…Although there is evidence from mammalian studies that nAChR desensitization could lead to impacts on Ca 2+ -calmodulin activated signal transduction (KE3) and impaired signaling downstream (e.g., Fucile, 2004;Quick and Lester, 2002;Dani and Bertrand, 2007;Marszalec et al, 2005), there are uncertainties associated with the KER. This uncertainty is related to concentrations and durations of agonist exposure that would lead to nAChR desensitization to the degree that there is an impact on downstream signaling.…”