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Chronic menthol does not change stoichiometry or functional plasma membrane levels of mouse α3β4-containing nicotinic acetylcholine receptors

Bavan, Selvan and Kim, Charlene H. and Henderson, Brandon J. and Lester, Henry A. (2019) Chronic menthol does not change stoichiometry or functional plasma membrane levels of mouse α3β4-containing nicotinic acetylcholine receptors. Molecular Pharmacology, 95 (4). pp. 398-407. ISSN 0026-895X. PMCID PMC6399576. doi:10.1124/mol.118.114769.

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Heteromeric α3β4 nicotinic acetylcholine (ACh) receptors (nAChRs) are pentameric ligand-gated cation channels that include at least two α3 and two β4 subunits. They have functions in peripheral tissue and peripheral and central nervous systems. We examined the effects of chronic treatment with menthol, a major flavor additive in tobacco cigarettes and electronic nicotine delivery systems, on mouse α3β4 nAChRs transiently transfected into neuroblastoma-2a cells. Chronic menthol treatment at 500 nM, near the estimated menthol concentration in the brain following cigarette smoking, altered neither the [ACh]-response relationship nor Zn^(2+) sensitivity of ACh-evoked currents, suggesting that menthol does not change α3β4 nAChR subunit stoichiometry. Chronic menthol treatment failed to change the current density (peak current amplitude/cell capacitance) of 100 μM ACh-evoked currents. Chronic menthol treatment accelerated desensitization of 100 and 200 μM ACh-evoked currents. Chronic nicotine treatment (250 μM) decreased ACh-induced currents, and we found no additional effect of including chronic menthol. These data contrast with previously reported, marked effects of chronic menthol on β2* nAChRs studied in the same expression system. Mechanistically, the data support the emerging interpretation that both chronic menthol and chronic nicotine act on nAChRs in the early exocytotic pathway, and that this pathway does not present a rate-limiting step to the export of α3β4 nAChRs; these nAChRs include endoplasmic reticulum (ER) export motifs but not ER retention motifs. Previous reports show that smoking mentholated cigarettes enhances tobacco addiction; but our results show that this effect is unlikely to arise via menthol actions on α3β4 nAChRs.

Item Type:Article
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URLURL TypeDescription CentralArticle
Henderson, Brandon J.0000-0003-0381-028X
Lester, Henry A.0000-0002-5470-5255
Alternate Title:α3β4 AChRs slightly modified by chronic menthol
Additional Information:© 2019 The American Society for Pharmacology and Experimental Therapeutics. Received October 5, 2018; accepted January 12, 2019; Published on January 22, 2019. We are grateful to Suparna Patowary for performing preliminary experiments on chronic menthol treatment effects at mouse α3β4 nAChRs (Patowary et al., 2016). Author Contributions: Participated in research design: Bavan, Henderson, and Lester. Conducted experiments: Bavan and Kim. Contributed new reagents or analytic tools: not applicable. Performed data analysis: Bavan, Henderson, and Lester. Wrote or contributed to the writing of the manuscript: Bavan, Kim, Henderson, and Lester. This study was supported by National Institutes of Health [Grants DA037743, DA046335, and DA036061].
Funding AgencyGrant Number
Subject Keywords:Acetylcholine receptors; Addiction; Electrophysiology; Ion channels; Nicotinic cholinergic receptors; Patch clamp recording; Receptor trafficking
Issue or Number:4
PubMed Central ID:PMC6399576
Record Number:CaltechAUTHORS:20190128-151017476
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Official Citation:α3β4 AChRs Slightly Modified by Chronic Menthol. Selvan Bavan, Charlene H. Kim, Brandon J. Henderson and Henry A. Lester. Molecular Pharmacology April 1, 2019, 95 (4) 398-407; DOI:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92501
Deposited By: Tony Diaz
Deposited On:29 Jan 2019 16:10
Last Modified:15 Feb 2022 23:44

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