Menthol inhibits 5-HT3 receptor-mediated currents

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 347; no. 2; pp. 398 - 409
• Main Authors: Ashoor, Abrar, Nordman, Jacob C, Veltri, Daniel, Yang, Keun-Hang Susan, Shuba, Yaroslav, Al Kury, Lina, Sadek, Bassem, Howarth, Frank C, Shehu, Amarda, Kabbani, Nadine, Oz, Murat
• Format: Journal Article
• Language: English
• Published: United States 01.11.2013
• Subjects: Animals; Binding, Competitive; Dose-Response Relationship, Drug; Female; Humans; Imidazoles - pharmacology; Indoles - pharmacology; Membrane Potentials - drug effects; Menthol - pharmacology; Molecular Docking Simulation; Oocytes - metabolism; Patch-Clamp Techniques; Protein Binding; Radioligand Assay; Rats; Receptors, Serotonin, 5-HT3 - genetics; Receptors, Serotonin, 5-HT3 - metabolism; Serotonin 5-HT3 Receptor Antagonists - pharmacology; Transfection; Xenopus laevis
• ISSN: 1521-0103
• DOI: 10.1124/jpet.113.203976

The effects of alcohol monoterpene menthol, a major active ingredient of the peppermint plant, were tested on the function of human 5-hydroxytryptamine type 3 (5-HT3) receptors expressed in Xenopus laevis oocytes. 5-HT (1 μM)-evoked currents recorded by two-electrode voltage-clamp technique were reversibly inhibited by menthol in a concentration-dependent (IC50 = 163 μM) manner. The effects of menthol developed gradually, reaching a steady-state level within 10-15 minutes and did not involve G-proteins, since GTPγS activity remained unaltered and the effect of menthol was not sensitive to pertussis toxin pretreatment. The actions of menthol were not stereoselective as (-), (+), and racemic menthol inhibited 5-HT3 receptor-mediated currents to the same extent. Menthol inhibition was not altered by intracellular 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid injections and transmembrane potential changes. The maximum inhibition observed for menthol was not reversed by increasing concentrations of 5-HT. Furthermore, specific binding of the 5-HT3 antagonist [(3)H]GR65630 was not altered in the presence of menthol (up to 1 mM), indicating that menthol acts as a noncompetitive antagonist of the 5-HT3 receptor. Finally, 5-HT3 receptor-mediated currents in acutely dissociated nodose ganglion neurons were also inhibited by menthol (100 μM). These data demonstrate that menthol, at pharmacologically relevant concentrations, is an allosteric inhibitor of 5-HT3 receptors.