The terpenoids Myrtenol and Verbenol act on δ subunit-containing GABAA receptors and enhance tonic inhibition in dentate gyrus granule cells.
Sideritis plants and their extracts have been used in traditional medicine as sedatives, anxiolytics and anticonvulsant agents. Pinenes are the most prevalent of the volatile aroma components in Siderites extracts and the pinene metabolites myrtenol and verbenol have been identified as the most potent positive allosteric modulators of synaptic GABAA receptors composed of α1β2 and α1β2γ2 subunits. In view of their therapeutic spectrum, we wondered whether these two terpenoids would also augment tonic GABA currents mediated by extrasynaptic GABAA receptors containing the δ subunit. When we expressed α4β2δ receptors in HEK293 cells, we found that co-application of myrtenol or verbenol enhanced whole-cell current responses to GABA by up to 100%. Consistent with their effects on heterologous α1β2γ2 receptors, we found that myrtenol and verbenol, when co-applied with GABA via local perfusion, increased the amplitude and area of miniature inhibitory postsynaptic potentials (mIPSCs) recorded in whole-cell voltage-clamp recordings from granule cells in the dentate gyrus of mouse hippocampal brain slices. In addition, co-application of terpenoids with GABA was also able to enhance tonic GABA current, measured from the change in baseline current and current noise, compared to GABA perfusion alone. Our results suggest that myrtenol and verbenol act as positive allosteric modulators at synaptic and extrasynaptic GABAA receptors, thereby augmenting phasic and tonic GABAergic inhibition. Thus, our study reveals an important pharmacological and therapeutic target of bicyclic monoterpenoids.
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Johannes
J
van Brederode
Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany.
Sinem
S
Atak
Department of Chemistry and Pharmacy, Food Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany.
Artur
A
Kessler
Department of Chemistry and Pharmacy, Food Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany.
Monika
M
Pischetsrieder
Institute for Clinical Neurobiology, Julius-Maximilians-University of Würzburg, 97078 Würzburg, Germany.
Carmen
C
Villmann
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: Christian.Alzheimer@fau.de.
Christian
C
Alzheimer
D000818:Animals; D000081008:Bicyclic Monoterpenes; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055369:Miniature Postsynaptic Potentials; D039821:Monoterpenes / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000081008:Bicyclic Monoterpenes; D039821:Monoterpenes; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C009951:verbenol; C534317:myrtenol
Dentate gyrus granule cells; GABA(A) receptor subunit; Miniature inhibitory postsynaptic current; Terpenoids; Tonic GABA current; Volatile odorants