Menthol binding and inhibition of α7-nicotinic acetylcholine receptors

PLoS One. 2013 Jul 23;8(7):e67674. doi: 10.1371/journal.pone.0067674. Print 2013.


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 α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+)-dependent Cl(-) channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+) chelator BAPTA and perfusion with Ca(2+)-free bathing solution containing Ba(2+). Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125)I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca(2+) transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcholine / pharmacology
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Bungarotoxins / metabolism
  • Calcium Signaling / drug effects
  • Female
  • Humans
  • Ion Channel Gating / drug effects
  • Membrane Potentials / drug effects
  • Menthol / metabolism*
  • Menthol / pharmacology
  • Molecular Sequence Data
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurotransmitter Agents / metabolism
  • Oocytes / drug effects
  • Oocytes / metabolism
  • PC12 Cells
  • Rats
  • Sequence Alignment
  • Time Factors
  • Xenopus laevis
  • alpha7 Nicotinic Acetylcholine Receptor / antagonists & inhibitors
  • alpha7 Nicotinic Acetylcholine Receptor / chemistry
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*


  • Bungarotoxins
  • Neurotransmitter Agents
  • alpha7 Nicotinic Acetylcholine Receptor
  • Menthol
  • Acetylcholine

Grant support

This study was supported by grants from CMHS, UAE University and support from IRP/NIDA of NIH, DHHS to MO and a Jeffress Memorial Trust Grant (J-953) to NK. DV is supported in part by NSF IIS CAREER Award No. 1144106 to AS. Research in our laboratory is also supported by LABCO partner of Sigma-Aldrich. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.