Cited by 74Nicotinic Acetylcholine Receptors StudyReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

Changes in Conformation and Subcellular Distribution of α4β2 Nicotinic Acetylcholine Receptors Revealed by Chronic Nicotine Treatment and Expression of Subunit Chimeras

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Harkness, Patricia C., Millar, Neil S.·2002·The Journal of Neuroscience

Abstract

Chronic exposure to nicotine, as occurs during tobacco smoking, is one of several factors that have been reported to cause an upregulation of neuronal nicotinic acetylcholine receptors (nAChRs). Here, the influence of both chronic exposure to nicotine (10 microm, 24 hr) and the coexpression of subunit chimeras has been examined in cultured cell lines expressing recombinant alpha4beta2 nAChRs, a major nicotinic receptor subtype expressed in the mammalian brain. Evidence is presented which demonstrates that both chronic exposure to nicotine and the coexpression of subunit chimeras upregulates levels of receptor expressed on the cell surface. Immunoblotting data indicate that neither chronic nicotine treatment nor coexpressed subunit partners greatly affect the level of total subunit protein. This finding, together with radioligand and antibody binding studies conducted on both intact and permeabilized cells, reveals that receptor upregulation corresponds to an increase in the proportion of total receptor expressed on the cell surface. It is also apparent that nicotine-induced nAChR upregulation is very strongly dependent on subunit composition and subunit domains. An important aspect of this study is that direct evidence has been obtained indicating that both chronic exposure to nicotine and coexpressed subunit partners can influence subunit conformation. The influence of chronic nicotine treatment on subunit folding may help to explain the phenomenon of nicotine-induced receptor upregulation. The finding that subunit conformation can be influenced by coassembled subunit partners is in agreement with models of receptor assembly which propose that subunit folding continues after initial subunit-subunit interactions.

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Crossref · 10.1523/jneurosci.22-23-10172.2002

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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.”

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Authors
Harkness, P. C., & Millar, N. S.
Affiliations
University College London (GB)
Venue
The Journal of Neuroscience
Published
2002-12-01
Volume
22
Issue
23
Pages
10172-10181
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2158978268
Cited by
74
References
41
Citations by year
2025: 1 · 2024: 2 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 3
FWCI
1.86
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Wellcome Trust
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
α4β2 nicotinic acetylcholine receptor, chronic nicotine exposure, receptor up-regulation, subcellular localization, cell surface receptor expression, receptor assembly, smoking, subunit composition
MeSH terms
Animals, Binding Sites, Binding, Competitive, Cell Line, Cell Membrane, Humans, Kidney, Ligands, Nicotine, Protein Conformation, Pyridines, Radioligand Assay, Receptors, Nicotinic, Recombinant Fusion Proteins, Time, Immunoblotting, Up-Regulation, Protein Folding, Bridged Bicyclo Compounds, Heterocyclic, Protein Subunits, Mice, Rats

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