Menthol Binding and Inhibition of α7-Nicotinic Acetylcholine Receptors

Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the alpha(7) subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit alpha(7)-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca2+-dependent Cl- channels, since menthol inhibition remained unchanged by intracellular injection of the Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing Ba2+. Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [I-125] alpha-bungarotoxin was not attenuated by menthol. Studies of alpha(7)-nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates alpha(7) mediated Ca2+ transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits alpha(7)-nACh receptors in a noncompetitive manner.