title: Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors.
abstract: The α3β4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves. The nAChR subtype transduces the irritant effects of nicotine in tobacco smoke and, in certain brain areas, may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine's actions in the brain. We examined menthol's effects on recombinant human α3β4 nAChRs and native nAChRs in mouse sensory neurons. Menthol markedly decreased nAChR activity as assessed by Ca(2+) imaging, (86)Rb(+) efflux, and voltage-clamp measurements. Coapplication of menthol with acetylcholine or nicotine increased desensitization, demonstrated by an increase in the rate and magnitude of the current decay and a reduction of the current integral. These effects increased with agonist concentration. Pretreatment with menthol followed by its washout did not affect agonist-induced desensitization, suggesting that menthol must be present during the application of agonist to augment desensitization. Notably, menthol acted in a voltage-independent manner and reduced the mean open time of single channels without affecting their conductance, arguing against a simple channel-blocking effect. Further, menthol slowed or prevented the recovery of nAChRs from desensitization, indicating that it probably stabilizes a desensitized state. Moreover, menthol at concentrations up to 1 mM did not compete for the orthosteric nAChR binding site labeled by [(3)H]epibatidine. Taken together, these data indicate that menthol promotes desensitization of α3β4 nAChRs by an allosteric action.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia.
authors.forename: Hoai T
authors.initials: HT
authors.lastname: Ton
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Smart
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Aguilar
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia.
authors.forename: Thao T
authors.initials: TT
authors.lastname: Olson
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia gpa3@georgetown.edu kellark@georgetown.edu.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia gpa3@georgetown.edu kellark@georgetown.edu.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Ahern
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008610:Menthol / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018679:Cholinergic Agonists; D007473:Ion Channels; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D008610:Menthol; D009538:Nicotine; C082748:epibatidine; D000109:Acetylcholine