Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids

Effects of common monoterpenoid alcohols and ketones were investigated on recombinant human γ-aminobutyric acid A (GABAA; α1β2γ2s) and glycine (α1 homomers) receptors expressed in Xenopus oocytes. GABA currents were enhanced by coapplications of 10–300 μM: (+)-menthol>(−)-menthol>(−)-borneol≫(−)-menthone=camphor enantiomers>carvone enantiomers, with menthol acting stereoselectively. By contrast, thujone diastereomers inhibited GABAA receptor currents while glycine currents were only markedly potentiated by menthol. Positive modulation by (+)-menthol was explored given its pronounced effects (e.g., at 100 μM, GABA and glycine EC20 responses increased by 496±113% and 135±56%, respectively). (+)-Menthol, 100 μM, reduced EC50 values for GABA and glycine from 82.8±9.9 to 25.0±1.8 μM, and from 98.7±8.6 to 75.7±9.4 μM respectively, with negligible effects on maximal currents. This study reveals a novel neuroactive role for menthol as a stereoselective modulator of inhibitory ligand-gated channels.