A-type GABA receptor as a central target of TRPM8 agonist menthol.
Menthol is a widely-used cooling and flavoring agent derived from mint leaves. In the peripheral nervous system, menthol regulates sensory transduction by activating TRPM8 channels residing specifically in primary sensory neurons. Although behavioral studies have implicated menthol actions in the brain, no direct central target of menthol has been identified. Here we show that menthol reduces the excitation of rat hippocampal neurons in culture and suppresses the epileptic activity induced by pentylenetetrazole injection and electrical kindling in vivo. We found menthol not only enhanced the currents induced by low concentrations of GABA but also directly activated GABA(A) receptor (GABA(A)R) in hippocampal neurons in culture. Furthermore, in the CA1 region of rat hippocampal slices, menthol enhanced tonic GABAergic inhibition although phasic GABAergic inhibition was unaffected. Finally, the structure-effect relationship of menthol indicated that hydroxyl plays a critical role in menthol enhancement of tonic GABA(A)R. Our results thus reveal a novel cellular mechanism that may underlie the ambivalent perception and psychophysical effects of menthol and underscore the importance of tonic inhibition by GABA(A)Rs in regulating neuronal activity.
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xiao-Bing
XB
Zhang
Peng
P
Jiang
Neng
N
Gong
Xiao-Ling
XL
Hu
Da
D
Fei
Zhi-Qi
ZQ
Xiong
Lin
L
Xu
Tian-Le
TL
Xu
D000818:Animals; D004594:Electrophysiology; D004827:Epilepsy / Q000517:prevention & control; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D008610:Menthol / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects*; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000819:agonists*
D018756:GABA Antagonists; D018079:Receptors, GABA; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; D008610:Menthol