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Cited by 391Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover

Peng, X, Gerzanich, V, Anand, R, Whiting, P J, Lindstrom, J·1994·Molecular Pharmacology
DOI 10.1016/s0026-895x(25)09730-5
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Abstract

Chronic nicotine exposure in tobacco smokers or experimental animals is known to cause an increase in brain binding sites for nicotine. It has been proposed that this is an adaptive response of neurons to accumulation of chronically desensitized receptors. Acetylcholine receptors of the same (alpha 4)2(beta 2)3 subunit composition as the predominant subtype of brain nicotinic receptors with high affinity for nicotine have been expressed in Xenopus oocytes and in a permanently transfected fibroblast cell line. Chronic exposure of these cells to nicotine or another agonist is shown to result in an increase in receptor amount, indicating that nicotine-induced up-regulation reflects properties of the alpha 4 beta 2 receptor protein, rather than being an adaptive response unique to the neurons in which these receptors are normally expressed. The nicotine concentration dependence, time course, and extent of receptor up-regulation are similar to those reported for receptors in brain. Up-regulation does not appear to require ion flow through the ion channel, because it is also caused by mecamylamine, which blocks the ion channel, and because after prolonged exposure to nicotine most receptors become permanently unable to open their channels in response to nicotine binding. The noncompetitive antagonist mecamylamine blocks open channels more effectively, and so it is more effective at blocking channels in the presence of nicotine. Mecamylamine and nicotine are also synergistic in causing receptor up-regulation. Ligands that cause up-regulation appear to induce a conformation of the receptor that is removed from the surface and degraded more slowly.

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  • Higher β2*-nAChR availability in smokers may be due to increased assembly of α4 and β2 subunits in endoplasmic reticulum, increased transport of receptors to membrane, decreased receptor turnover, and/or presence of nicotine promoting intracellular maturation of α4β2-nAChR to high-affinity conformation.

    “Higher β2*-nAChR availability in smokers may be due to a variety of molecular changes including increased assembly of α4 and β2 subunits in the endoplasmic reticulum9, increased transport of receptors to the membrane10, decreased receptor turnover11, and/or the presence of nicotine promoting intracellular maturation of the α4β2-nAChR to a high-affinity conformation12.”

    From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [11]

  • Greater β2*-nAChR availability is not associated with changes in β2*-nAChR mRNA, protein synthesis, rate of receptor internalization, postendocytic trafficking, or lysosomal degradation.

    “Greater ␤ 2 *- nAChR availability is not associated with changes in ␤ 2 *-nAChR mRNA (Marks et al., 1992;Peng et al., 1994;Zhang et al., 1994) protein synthesis (Buisson and Bertrand, 2001), rate of receptor internalization, postendocytic trafficking, or lysosomal degradation (Darsow et al., 2005)”

    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 Peng et al., 1994

  • nAChR mRNA levels remain constant after nicotine exposure.

    “Moreover, nAChR mRNA levels remain constant after nicotine exposure (Marks et al., 1992; Peng et al., 1994; Ke et al., 1998).”

    From Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning (2011) · cites this paper as Peng et al., 1994

  • 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.

    “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 [66]

  • During prolonged exposure to nicotine, there is decreased receptor degradation, presumably via endocytosis.

    “During prolonged exposure to nicotine, there is deceased receptor degradation (presumably via endocytosis), and this mechanism for upregulation must be considered as an adjunct to SePhaChARNS (8,39,66,87).”

    From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [66]

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Authors
Peng, X., Gerzanich, V, Anand, R., Whiting, P. J., & Lindstrom, J.
Affiliations
University of Pennsylvania (US)
ORCID
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
1994-09
Volume
46
Issue
3
Pages
523-530
ISSN
0026-895X (ISSN-L)
DOI
10.1016/s0026-895x(25)09730-5
OpenAlex
W2335199875
Cited by
391
References
0
Citations by year
2025: 1 · 2024: 1 · 2023: 3 · 2021: 1 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 15 · 2014: 9 · 2013: 11 · 2012: 12
FWCI
6.34
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • PubMed
Funders
National Institute of Neurological Disorders and Stroke (NS11323, R01NS011323)
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, receptor up-regulation, receptor turnover, chronic nicotine exposure, mecamylamine, receptor desensitization, ion channel blockade, receptor degradation, receptor conformation, smoking
MeSH terms
Animals, Antibodies, Monoclonal, Binding Sites, Brain, Cell Line, Chickens, Dose-Response Relationship, Drug, Electrophysiology, Fibroblasts, Nicotine, Oocytes, Receptors, Nicotinic, Xenopus laevis, Blotting, Northern, Up-Regulation, Mice

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