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Cited by 80Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

An extracellular protein microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine

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Sallette, Jérôme, Bohler, Sébastien, Benoit, Pierre, Soudant, Martine, Pons, Stéphanie, Le Novère, Nicolas, Changeux, Jean-Pierre, Corringer, Pierre Jean·2004·Journal of Biological Chemistry
DOI 10.1074/jbc.m308260200
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Abstract

In smoker's brain, rodent brain, and in cultured cells expressing nicotinic receptors, chronic nicotine treatment induces an increase in the total number of high affinity receptors for acetylcholine and nicotine, a process referred to as up-regulation. Up-regulation induced by 1 mm nicotine reaches 6-fold for alpha3beta2 nicotinic receptors transiently expressed in HEK 293 cells, whereas it is much smaller for alpha3beta4 receptors, offering a rationale to investigate the molecular mechanism underlying up-regulation. In this expression system binding sites are mainly intracellular, as shown by [(3)H]epibatidine binding experiments and competition with the impermeant ligand carbamylcholine. Systematic analysis of beta2/beta4 chimeras demonstrates the following. (i) The extracellular domain critically contributes to up-regulation. (ii) Only residues belonging to two beta2 segments, 74-89 and 106-115, confer up-regulation to beta4, mainly by decreasing the amount of binding sites in the absence of nicotine; on an atomic three-dimensional model of the alpha3beta2 receptor these amino acids form a compact microdomain that mainly contributes to the subunit interface and also faces the acetylcholine binding site. (iii) The beta4 microdomain is sufficient to confer to beta2 a beta4-like up-regulation. (iv) This microdomain makes an equivalent contribution to the up-regulation differences between alpha4beta2 and alpha4beta4. We propose that nicotine, by binding to immature oligomers, elicits a conformational reorganization of the microdomain, strengthening the interaction between adjacent subunits and, thus, facilitating maturation processes toward high affinity receptors. This mechanism may be central to nicotine addiction, since alpha4beta2 is the subtype exhibiting the highest degree of up-regulation in the brain.

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Crossref · 10.1074/jbc.m308260200

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  • Nicotine-induced increases in nAChR (upregulation) are conferred by a specific microdomain in the β2-subunit and are confined to nAChRs that contain the β2-subunit.

    “Importantly, nicotine induced increases in nAChR, termed “upregulation”, are conferred by a specific microdomain that is in the β2-subunit 34 and thus this upregulation is confined to nAChR that contain the β2-subunit4, 19, 31, 35-38.”

    From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [34]

  • The α4β2 combination is the most prevalent β2*-nAChR combination and the most sensitive to upregulation by nicotine.

    “Although ␤ 2 subunits exist in several different combi- nations with ␣ 2 , ␣ 3 , ␣ 4 , and ␣ 6 subunits, the ␣ 4 ␤ 2 combination is most prevalent and also the most sensitive to upregulation by nicotine (Nguyen et al., 2003;Sallette et al., 2004).”

    From Human Tobacco Smokers in Early Abstinence Have Higher Levels of β<sub>2</sub>* Nicotinic Acetylcholine Receptors than Nonsmokers (2006) · cites this paper as Sallette et al., 2004

  • Replacing β2 with β4 in α3* or α4* nAChRs significantly reduces receptor upregulation.

    “If β4 replaces β2 subunits in either α3* or α4* nAChRs, receptor upregulation is significantly reduced (Wang et al. 1998; Sallette et al. 2004).”

    From Nicotine Withdrawal (2015) · cites this paper as Sallette et al. 2004

  • Current evidence indicates that nicotine, and presumably varenicline, raise nicotinic receptor density by promoting subunit assembly into mature receptors in the endoplasmic reticulum.

    “where current evidence indicates that nicotine and presumably varenicline act to increase nAChR density by stimulating assembly of subunits into mature receptors (Sallette et al., 2004(Sallette et al., , 2005;;Kuryatov et al., 2005;Lomazzo et al., 2011;Srinivasan et al., 2011).”

    From Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain (2012) · cites this paper as Sallette et al., 2004

  • In previous studies on isolated cells, both agonists and antagonists can upregulate receptors.

    “In previous studies on isolated cells, both agonists and antagonists can upregulate receptors (50,52,54,58,59).”

    From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [58]

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Authors
Sallette, J., Bohler, S., Benoit, P., Soudant, M., Pons, S., Le Novère, N., Changeux, J.-P., & Corringer, P. J.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Changeux, Jean-Pierre
  • Corringer, Pierre Jean
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-04
Volume
279
Issue
18
Pages
18767-18775
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m308260200
OpenAlex
W2160879976
Cited by
80
References
51
Citations by year
2025: 1 · 2023: 2 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 5 · 2012: 3
FWCI
3.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nicotinic acetylcholine receptors, receptor up-regulation, nicotine, alpha4beta2 receptor, receptor maturation, subunit interface, nicotine dependence, smoking
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Humans, Models, Molecular, Nicotine, Receptors, Nicotinic, Recombinant Fusion Proteins, Transfection, Up-Regulation, Protein Structure, Tertiary, Protein Structure, Quaternary, Protein Subunits, Rats

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