RT Journal Article SR Electronic T1 Menthol Inhibits 5-HT3 Receptor–Mediated Currents JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 398 OP 409 DO 10.1124/jpet.113.203976 VO 347 IS 2 A1 Ashoor, Abrar A1 Nordman, Jacob C. A1 Veltri, Daniel A1 Yang, Keun-Hang Susan A1 Shuba, Yaroslav A1 Al Kury, Lina A1 Sadek, Bassem A1 Howarth, Frank C. A1 Shehu, Amarda A1 Kabbani, Nadine A1 Oz, Murat YR 2013 UL http://jpet.aspetjournals.org/content/347/2/398.abstract AB 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 [3H]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.