The terpenoids Myrtenol and Verbenol act on δ subunit-containing GABAA receptors and enhance tonic inhibition in dentate gyrus granule cells
| Autor: | Sinem Atak, Christian Alzheimer, Johannes van Brederode, Artur Kessler, Monika Pischetsrieder, Carmen Villmann |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Allosteric regulation Pharmacology Hippocampal formation Inhibitory postsynaptic potential Mice 03 medical and health sciences 0302 clinical medicine Postsynaptic potential Myrtenol Animals Humans Receptor gamma-Aminobutyric Acid Bicyclic Monoterpenes Neurons Chemistry GABAA receptor General Neuroscience Dentate gyrus Miniature Postsynaptic Potentials Receptors GABA-A Mice Inbred C57BL HEK293 Cells 030104 developmental biology Inhibitory Postsynaptic Potentials nervous system Dentate Gyrus Monoterpenes Female 030217 neurology & neurosurgery |
| Zdroj: | Neuroscience Letters. 628:91-97 |
| ISSN: | 0304-3940 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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