ReviewDesensitized nicotinic receptors in brain
Introduction
Desensitization is a general characteristic of ligand-gated channels, whereby a decrease or loss of biological response occurs following prolonged or repetitive stimulation [50], [93], [123], [132], [155], [175]. As a member of the ligand-gated ion channel family, nicotinic acetylcholine receptor (nAChR) causes desensitization in the brain [17]. This occurs as a result of extended nicotine exposure during smoking, or via the treatment of Alzheimer's disease (AD) with cholinesterase inhibitors, or as a result of poisoning by an anticholinesterase agent.
Nicotine is a specific and highly selective ligand that binds readily to nAChRs. Repeated or chronic exposure to nicotine induces a decrease or loss of the N-like response and increases the number of nAChRs, rather than reducing their number [77]. This response may result from the ability of nicotine to desensitize or inactivate nAChRs [62], [93]. Indeed, prolonged incubation with low levels of nicotine, such as that which occurs when smoking, results in little receptor activation; however, it effectively blocks the nAChRs by stabilizing the desensitized states of the receptor [30], [35]. Accumulating evidence from epidemiological studies on smoking that links nAChRs and age-related neurodegenerative diseases has revealed a negative association between cigarette smoking and Parkinson's disease (PD) and AD, suggesting that, in addition to nicotine, desensitized nAChRs may be responsible for their neuroprotective actions [16], [17], [135]. Further, the potential clinical applications of nicotine and/or nicotinic agonists in a variety of central nervous system (CNS) diseases in general, and behavioral disorders in particular have been examined extensively [69], [127], [138], [148], [149], [179], [184]. In addition, nAChR desensitization also may play important roles in many biological processes including the regulation of muscarinic receptors, synapse plasticity, learning and memory [96], [144]. Accordingly, it is reasonable to propose the working hypothesis that pharmacological consequences of desensitization beyond simply nicotinic receptor inactivation may contribute to the array of potential effects associated with chronic nicotine exposure.
Section snippets
Brain nicotinic receptor's structure
Brain nAChRs differ from the muscle-type heteropentameric subtypes because they contain no γ, δ or ɛ subunits, and consist of various complements of α2–α10 and β2–β4 subunits [153]. Additionally, α2–α10 and β2–β4 subunits have been identified and cloned from human brain [60], [74], [82], [130]. Neuronal nAChRs subunits assemble according to a general 2α3β stoichiometry [10], [66], [105], However, α7, α8 and α9 are known to form functional homo-oligomers consisting of a single a subunit subtype
Brain nicotinic receptors function
Brain nAChRs distribute postsynaptic, as well as pre-, peri- and extra-synaptic sites, where they may modulate the neurotransmitter release, synapse action and neuronal activity by a varions of functional states [11], [54], [82], [145], playing important roles in many physiological and pathological processes including neuron development, learning and memory, and the rewarding response induced by addictive drugs [82], [90], [175].
The subtypes of brain nAChR with different subunits, mediate
Brain nicotinic receptors desensitization
Research about nAChRs desensitization began with the classics experiment of Katz and Thesleff in 1957 [94]. For nAChRs, desensitization can be described as a decline in response to nicotine after repetitive exposure to nicotine. The onset of desensitization is both time- and concentration-dependent [77], [93]. This process reflects the time-dependent accumulation of receptors in long-lived nonconducting states [167]. Desensitization can be modified by a variety of cellular agents and exogenous
Regulation of brain nicotinic receptor desensitization
Many factors regulate the kinetics of receptor activation and desensitization, including subunits composition, temperature, membrane potential, post-translational modification, ligands, ions and interactions with the cytoskeleton [29], [53], [144], [180].
Biological function of desensitized brain nAChRs
The physiological significance of nAChR desensitization has been investigated since the 1950s. Under physiological conditions, neurotransmitter release is generally not sufficient to desensitize receptors. However, for receptors that desensitize rapidly, such as the α7 subunit nAChR, or those with high affinities for ACh that remain bound to agonists for a long time after free transmitter is cleared, desensitization may occur after repetitive stimulation. Moreover, the selective agonist for α7
Tobacco addiction
Nicotine, as the major addictive component of tobacco, is a selective agonist of nAChRs [125]. Nicotine is well known to stimulate release of DA in the mesolimbic DA pathway, which is thought to play key roles in mediating the addictive effects of nicotine and other drugs of abuse [14], [125], [145]. It is proposed that the desensitization and up-regulation of nAChRs that follows chronic nicotine exposure is the basis of tolerance to nicotine displayed by smokers, and is also influential in
Conclusion
Desensitization is an intrinsic property of brain nAChRs, playing an important role in the signal transduction mediated by membrane receptors. The desensitized nAChRs can not only reduce or stop the N-like response to a repetitive agonist, but also exert important modulatory effects on brain function. These effects include homologous up-regulation of nAChRs, hypersensitization of muscarinic receptors, modulation of gene expression for ion channels, membrane receptors and signal transduction
Acknowledgment
The work was supported by a grant from National Natural Science Foundation of China (No. 30371641). The authors thank Prof. Peter W. Kalivas for reviewing this manuscript.
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2019, Neurobiology of DiseaseCitation Excerpt :This isolated finding was unexpected given that other studies found more widespread changes, including our study in the mouse model of pre- into post-natal cigarette smoke exposure (Vivekanandarajah et al., 2016), studies of mRNA in the rat with similar exposure (Eppolito et al., 2010), and studies of receptor binding and expression (reviewed in Vivekanandarajah et al., 2019). Desensitization due to reduced numbers of receptors (Reitstetter et al., 1999; Wang and Sun, 2005) is thought to reduce or eliminate biological responses after prolonged or repetitive stimulation by an agonist. Acute nicotine injected in rats resulted in cholinergic receptor desensitization for up to 6 h (Hulihan-Giblin et al., 1990a; Sharp and Beyer, 1986) while chronic nicotine exposure resulted in a loss of receptor function for up to 8 days (Hulihan-Giblin et al., 1990b).