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Nicotine Upregulates Its Own Receptors through Enhanced Intracellular Maturation
Open accessAbstract
Chronic exposure to nicotine elicits upregulation of high-affinity nicotinic receptors in the smoker's brain. To address the molecular mechanism of upregulation, we transfected HEK293 cells with human alpha4beta2 receptors and traced the subunits throughout their intracellular biosynthesis, using metabolic labeling and immunoprecipitation techniques. We show that high-mannose glycosylated subunits mature and assemble into pentamers in the endoplasmic reticulum and that only pentameric receptors reach the cell surface following carbohydrate processing. Nicotine is shown to act inside the cell and to increase the amount of beta subunits immunoprecipitated by the conformation-dependent mAb290, indicating that nicotine enhances a critical step in the intracellular maturation of these receptors. This effect, which also takes place at concentrations of nicotine found in the blood of smokers upon expression of alpha4beta2 in SH-SY5Y neuroblastoma cells, may play a crucial role in nicotine addiction and possibly implement a model of neural plasticity.
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“but instead appears to be attributable to occupancy of the nicotine binding site that bridges the ␣/ subunit interface of the nAChR in an immature, low-affinity conformation that facilitates glycosylation and maturation of the ␣ 4  2 nAChR to a more stable conformation with higher affinity for nicotine (Darsow et al., 2005;Sallette et al., 2005).”
From Human Tobacco Smokers in Early Abstinence Have Higher Levels of β2* Nicotinic Acetylcholine Receptors than Nonsmokers (2006) · cites this paper as Sallette et al., 2005
Experimental — accuracy not yet measuredIn the citing paper
“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., 2005
In the citing paper
“These data correspond with previous results based on glycosylation and molecular weight measures, showing that up-regulation is initiated in the ER (Nelson et al., 2003; Kuryatov et al., 2005; Sallette et al., 2005).”
From Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning (2011) · cites this paper as Sallette et al., 2005
In the citing paper
“Descriptions that may be essentially equivalent to SePhaChARNS are the statements that nicotine acts as a “maturational enhancer” or a “novel slow stabilizer” for α4β2* receptors (39,50–52).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [50]
In the citing paper
“however, as discussed above, it is more likely that the quaternary drugs have sufficient membrane permeability to allow intracellular actions at the rather high concentrations (0.1–1 mM) that produce upregulation (50,65,66).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [50]
In the citing paper
“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 [50]
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Metadata
- Authors
- Sallette, J., Pons, S., Devillers-Thiery, A., Soudant, M., Prado de Carvalho, L., Changeux, J.-P., & Corringer, P. J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Changeux, Jean-Pierre
- Corringer, Pierre Jean
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 46
- Issue
- 4
- Pages
- 595-607
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1994720205
- Cited by
- 261
- References
- 46
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 11 · 2016: 17 · 2015: 11 · 2014: 18 · 2013: 19 · 2012: 16
- FWCI
- 7.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2999 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- 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
- nicotine, nicotinic acetylcholine receptors, alpha4beta2 receptor, receptor up-regulation, glycosylation, high-mannose glycosylation, endoplasmic reticulum, receptor trafficking, nicotine dependence, neuroplasticity
- MeSH terms
- Antibodies, Autoradiography, Binding, Competitive, Carbachol, Cell Line, Dihydro-beta-Erythroidine, Dose-Response Relationship, Drug, Drug Interactions, Fluorescent Antibody Technique, Glycosylation, Humans, Membrane Potentials, Models, Biological, Nicotine, Protein Binding, Pyridines, Receptors, Nicotinic, Time Factors, Transfection, Tritium, Blotting, Western, Up-Regulation, Patch-Clamp Techniques, Nicotinic Agonists, Nicotinic Antagonists, Bridged Bicyclo Compounds, Heterocyclic, Protein Subunits, Intracellular Space, Immunoprecipitation
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