RT Journal Article
SR Electronic
T1 Chronic Menthol Does Not Change Stoichiometry or Functional Plasma Membrane Levels of Mouse <em>α</em>3<em>β</em>4-Containing Nicotinic Acetylcholine Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 398
OP 407
DO 10.1124/mol.118.114769
VO 95
IS 4
A1 Selvan Bavan
A1 Charlene H. Kim
A1 Brandon J. Henderson
A1 Henry A. Lester
YR 2019
UL http://molpharm.aspetjournals.org/content/95/4/398.abstract
AB 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 Zn2+ 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.