Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors
Open accessAbstract
Chronic exposure to nicotine up-regulates high sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain. This up-regulation partially underlies addiction and may also contribute to protection against Parkinson’s disease. nAChRs containing the α6 subunit (α6* nAChRs) are expressed in neurons in several brain regions, but comparatively little is known about the effect of chronic nicotine on these nAChRs. We report here that nicotine up-regulates α6* nAChRs in several mouse brain regions (substantia nigra pars compacta, ventral tegmental area, medial habenula, and superior colliculus) and in neuroblastoma 2a cells. We present evidence that a coat protein complex I (COPI)-mediated process mediates this up-regulation of α6* or α4* nAChRs but does not participate in basal trafficking. We show that α6β2β3 nAChR up-regulation is prevented by mutating a putative COPI-binding motif in the β3 subunit or by inhibiting COPI. Similarly, a COPI-dependent process is required for up-regulation of α4β2 nAChRs by chronic nicotine but not for basal trafficking. Mutation of the putative COPI-binding motif or inhibition of COPI also results in reduced normalized Förster resonance energy transfer between α6β2β3 nAChRs and εCOP subunits. The discovery that nicotine exploits a COPI-dependent process to chaperone high sensitivity nAChRs is novel and suggests that this may be a common mechanism in the up-regulation of nAChRs in response to chronic nicotine.
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Because β2-to-β4 replacement increases nAChR levels at the plasma membrane without nicotine, nicotine's proposed chaperoning function may be less effective.
“As replacement of β2 by β4 is sufficient to increase nAChR levels at the plasma membrane in the absence of nicotine, the proposed “chaperoning” function of nicotine might not be as effective (Srinivasan et al. 2011; Henderson et al. 2014).”
From Nicotine Withdrawal (2015) · cites this paper as Henderson et al. 2014
The Results section on nicotine-induced up-regulation (page unavailable) reports a greater than threefold increase in plasma-membrane α6β4* receptors after nicotine treatment, while α6β2 receptors showed no increase at 50 nM. That is contrary to the suggested weaker nicotine effect with β4. The paper’s separate finding that β3 increases baseline membrane density does not establish the claimed effect of replacing β2 with β4. (LLM, conf=0.82)
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Experimental — accuracy not yet measuredMultiple cellular processes influence nAChR upregulation.
“A variety of cellular processes influence receptor upregulation (Govind et al. 2009; Rezvani et al. 2009, 2010; Henderson et al. 2014).”
From Nicotine Withdrawal (2015) · cites this paper as Henderson et al. 2014
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References 68 · Cited by 78
- Authors
- Henderson, B. J., Srinivasan, R., Nichols, W. A., Dilworth, C. N., Gutierrez, D. F., Mackey, E. D. W., McKinney, S., Drenan, R. M., Richards, C. I., & Lester, H. A.
- Affiliations
- California Institute of Technology (US)
- Purdue University West Lafayette (US)
- University of Kentucky (US)
- Corresponding author
- Lester, Henry A.
- Venue
- Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 2013-12-30
- Volume
- 143
- Issue
- 1
- Pages
- 51-66
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC3874574
- OpenAlex
- W2154470758
- Cited by
- 78
- References
- 68
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 1 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 10 · 2015: 11 · 2014: 8 · 2013: 1
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of General Physiology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc-sa)
- Funders
- Tobacco-Related Disease Research Program (17RT0127)
- National Institutes of Health (NS034407, DA019375, DA030396)
- National Institute on Aging (R01AG033954, AG033954)
- National Institute on Drug Abuse (U19DA019375, DA030396, DA 019375, K99DA030396, R01DA017279, F32DA033721, DA017279, DA033721, R00DA030396)
- National Institute of Neurological Disorders and Stroke (R01NS034407, NS034407, R37NS034407)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- nicotine, nicotinic acetylcholine receptors, receptor up-regulation, COPI, alpha4beta2 nAChR, receptor trafficking, Parkinson's disease, nicotine dependence, substantia nigra pars compacta, ventral tegmental area, medial habenula, superior colliculus
- MeSH terms
- Animals, Binding Sites, Brain, Nicotine, Protein Binding, Receptors, Nicotinic, Up-Regulation, Nicotinic Agonists, Coat Protein Complex I, Amino Acid Motifs, Protein Subunits, Protein Transport, Cell Line, Tumor, Mice
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