The Acetylcholine Receptor: A Model of an Allosteric Membrane Protein Mediating Intercellular Communication

Changeux, Jean‐Pierre; Devillers‐Thiéry, Anne; Galzi, Jean‐Luc; Revah, Frédéric

doi:10.1002/9780470514207.ch6

Cited by 7 publications

(5 citation statements)

References 95 publications

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“…Agonists may also stabilize a receptor transition from “active” to an inactive “desensitized” state. There are multiple allosteric sites elsewhere on the multimeric nAChR complex, which by themselves do not stimulate opening or closing of the receptor channel, but instead modify the activity of the receptor once activated by orthosteric ligands (Changeux, 1990; Changeux et al, 1984; Changeux et al, 1992; Chemouilli et al, 1985; Lena and Changeux, 1993). Positive allosteric modulators (PAMs) are ligands that bind to allosteric sites to facilitate agonist-induced stabilization of the “open” conformation or to reduce agonist-facilitated receptor desensitization, with PAMs unable to influence receptor function in the absence of orthosteric agonists.…”

Section: Novel Smoking Cessation Agents That Modulate Nicotine Avoidancementioning

confidence: 99%

Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

2014

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Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered.

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Section: Novel Smoking Cessation Agents That Modulate Nicotine Avoidancementioning

confidence: 99%

Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

2014

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“…The γ-subunit distinguishes the embryonic from the adult AChR (ε-AChR, α 2 βδε). Normally, the γ-subunit is expressed during embryonic and neonatal stages, and is replaced by the ε-subunit during the first 2 weeks after birth (γ/ε switch) (Changeux et al, 1992;Mishina et al, 1986). The physiological role of this switch is not well understood, but evidence suggests that the γ-subunit and the ε-subunit each play specific roles in embryonic and adult NMJs, respectively.…”

Section: Introductionmentioning

confidence: 99%

Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning

et al. 2008

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Formation of the vertebrate neuromuscular junction (NMJ) takes place in a stereotypic pattern in which nerves terminate at select sarcolemmal sites often localized to the central region of the muscle fibers. Several lines of evidence indicate that the muscle fibers may initiate postsynaptic differentiation independent of the ingrowing nerves. For example, nascent acetylcholine receptors (AChRs) are pre-patterned at select regions of the muscle during the initial stage of neuromuscular synaptogenesis. It is not clear how these pre-patterned AChR clusters are assembled, and to what extent they contribute to pre-and post-synaptic differentiation during development. Here, we show that genetic deletion of the AChR γ-subunit gene in mice leads to an absence of pre-patterned AChR clusters during initial stages of neuromuscular synaptogenesis. The absence of pre-patterned AChR clusters was associated with excessive nerve branching, increased motoneuron survival, as well as aberrant distribution of acetylcholinesterase (AChE) and rapsyn. However, clustering of muscle specific kinase (MuSK) proceeded normally in the γ-null muscles. AChR clusters emerged at later stages owing to the expression of the AChR epsilon-subunit, but these delayed AChR clusters were broadly distributed and appeared at lower level compared with the wild-type muscles. Interestingly, despite the abnormal pattern, synaptic vesicle proteins were progressively accumulated at individual nerve terminals, and neuromuscular synapses were ultimately established in γ-null muscles. These results demonstrate that the γ-subunit is required for the formation of pre-patterned AChR clusters, which in turn play an essential role in determining the subsequent pattern of neuromuscular synaptogenesis.

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“…The clustering and maintenance of nicotinic acetylcholine receptors (AChRs) at high density in the postsynaptic membrane is a hallmark of the mammalian neuromuscular junction (NMJ) [ 1 , 2 , 3 ]. AChRs are transmembrane ligand-gated ion channels, composed of five protein subunits [ 4 ]. In the unborn, the composition of AChR consists of α 2 βγδ (immature form) and within a very short time after birth, γ-subunits are replaced by the adult specific ε-subunits to yield the mature AChRs α 2 βεδ.…”

Section: Introductionmentioning

confidence: 99%

The Metabolic Stability of the Nicotinic Acetylcholine Receptor at the Neuromuscular Junction

Valenzuela

Akaaboune

2021

Cells

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The clustering and maintenance of nicotinic acetylcholine receptors (AChRs) at high density in the postsynaptic membrane is a hallmark of the mammalian neuromuscular junction (NMJ). The regulation of receptor density/turnover rate at synapses is one of the main thrusts of neurobiology because it plays an important role in synaptic development and synaptic plasticity. The state-of-the-art imaging revealed that AChRs are highly dynamic despite the overall structural stability of the NMJ over the lifetime of the animal. This review highlights the work on the metabolic stability of AChRs at developing and mature NMJs and discusses the role of synaptic activity and the regulatory signaling pathways involved in the dynamics of AChRs.

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The Acetylcholine Receptor: A Model of an Allosteric Membrane Protein Mediating Intercellular Communication

Cited by 7 publications

References 95 publications

Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability

Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning

The Metabolic Stability of the Nicotinic Acetylcholine Receptor at the Neuromuscular Junction

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