Exocytic trafficking is required for nicotine-induced up-regulation of α4β2 nicotinic acetylcholine receptors
Open accessAbstract
The primary target for nicotine in the brain is the neuronal nicotinic acetylcholine receptor (nAChR). It has been well documented that nAChRs respond to chronic nicotine exposure by up-regulation of receptor numbers, which may underlie some aspects of nicotine addiction. In order to investigate the mechanism of nicotine-induced nAChR up-regulation, we have developed a cell culture system to assess membrane trafficking and nicotine-induced up-regulation of surface-expressed α4β2 nAChRs. Previous reports have implicated stabilization of the nAChRs at the plasma membrane as the potential mechanism of up-regulation. We have found that whereas nicotine exposure results in up-regulation of surface receptors in our system, it does not alter surface receptor internalization from the plasma membrane, postendocytic trafficking, or lysosomal degradation. Instead, we find that transport of nAChRs through the secretory pathway to the plasma membrane is required for nicotine-induced up-regulation of surface receptors. Therefore, nicotine appears to regulate surface receptor levels at a step prior to initial insertion in the plasma membrane rather than by altering their endocytic trafficking or degradation rates as had been previously suggested. The primary target for nicotine in the brain is the neuronal nicotinic acetylcholine receptor (nAChR). It has been well documented that nAChRs respond to chronic nicotine exposure by up-regulation of receptor numbers, which may underlie some aspects of nicotine addiction. In order to investigate the mechanism of nicotine-induced nAChR up-regulation, we have developed a cell culture system to assess membrane trafficking and nicotine-induced up-regulation of surface-expressed α4β2 nAChRs. Previous reports have implicated stabilization of the nAChRs at the plasma membrane as the potential mechanism of up-regulation. We have found that whereas nicotine exposure results in up-regulation of surface receptors in our system, it does not alter surface receptor internalization from the plasma membrane, postendocytic trafficking, or lysosomal degradation. Instead, we find that transport of nAChRs through the secretory pathway to the plasma membrane is required for nicotine-induced up-regulation of surface receptors. Therefore, nicotine appears to regulate surface receptor levels at a step prior to initial insertion in the plasma membrane rather than by altering their endocytic trafficking or degradation rates as had been previously suggested. Neuronal nicotinic acetylcholine receptors (nAChRs) 1The abbreviations used are: nAChR, nicotinic acetylcholine receptor; PBS, phosphate-buffered saline; mAb, monoclonal antibody; FACS, fluorescence-activated cell sorting; BFA, brefeldin A; ER, endoplasmic reticulum; HA, hemagglutinin. in mammalian brain compose a family of proteins encoded by 11 genes (α2-7, α9-10, and β2-4) that assemble into pentameric ligand-gated ion channels (1Dani J.A. Biol. Psychiatry. 2001; 49: 166-174Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 2Elgoyhen A.B. Vetter D.E. Katz E. Rothlin C.V. Heinemann S.F. Boulter J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3501-3506Crossref PubMed Scopus (564) Google Scholar, 3Lindstrom J. North R.A. Handbook of Receptors and Channels. CRC Press, Inc., Boca Raton, FL1995: 153-175Google Scholar, 4McGehee D.S. Role L.W. Annu. Rev. Physiol. 1995; 57: 521-546Crossref PubMed Scopus (898) Google Scholar). 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Greater β2*-nAChR availability appears attributable to occupancy of the nicotine binding site that bridges the α/β subunit interface in an immature, low-affinity conformation that facilitates glycosylation and maturation of the α4β2 nAChR to a more stable conformation with higher affinity for nicotine.
“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 β<sub>2</sub>* Nicotinic Acetylcholine Receptors than Nonsmokers (2006) · cites this paper as Darsow et al., 2005
Upregulation of α4β2 nAChRs may involve increased receptor protein through post-translational events, possibly including changes in nAChR maturation and trafficking.
“Thus, upregulation of α4β2 nAChRs may involve an increase in receptor protein through post-translational events that may include changes in nAChR maturation and trafficking (Darsow et al., 2005; Kane et al., 2004; Lomazzo et al., 2011; Rezvani et al., 2007).”
From The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation (2012) · cites this paper as Darsow et al., 2005
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 [54]
Hexamethonium, mecamylamine, or decamethonium by themselves do not produce appreciable up-regulation.
“Unsurprisingly, hexamethonium, mecamylamine, or decamethonium by themselves do not produce appreciable up-regulation (54,65).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [54]
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- Authors
- Darsow, T., Booker, T. K., Piña-Crespo, J. C., & Heinemann, S. F.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Darsow, Tamara
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 280
- Issue
- 18
- Pages
- 18311-18320
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1987632317
- Cited by
- 76
- References
- 44
- Citations by year
- 2024: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 5 · 2013: 7 · 2012: 6
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA13018, R01AA013018)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- α4β2 nicotinic acetylcholine receptor, receptor up-regulation, secretory pathway, membrane trafficking, receptor internalization, lysosomal degradation, nicotine dependence, receptor surface expression
- MeSH terms
- Animals, Cell Line, Exocytosis, Humans, Nicotine, Receptors, Nicotinic, Up-Regulation, Protein Transport, Mice
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