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Mol Nutr Food Res
2014 Apr 01;584:851-62. doi: 10.1002/mnfr.201300420.
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GABA(A) receptor modulation by terpenoids from Sideritis extracts.
Kessler A
,
Sahin-Nadeem H
,
Lummis SC
,
Weigel I
,
Pischetsrieder M
,
Buettner A
,
Villmann C
.
???displayArticle.abstract??? GABAA receptors are modulated by Sideritis extracts. The aim of this study was to identify single substances from Sideritis extracts responsible for GABAA receptor modulation. Single volatile substances identified by GC have been tested in two expression systems, Xenopus oocytes and human embryonic kidney cells. Some of these substances, especially carvacrol, were highly potent on GABAA receptors composed of α1β2 and α1β2γ2 subunits. All effects measured were independent from the presence of the γ2 subunit. As Sideritis extracts contain a high amount of terpenes, 13 terpenes with similar structure elements were tested in the same way. Following a prescreening on α1β2 GABAA receptors, a high-throughput method was used for identification of the most effective terpenoid substances on GABA-affinity of α1β2γ2 receptors expressed in transfected cell lines. Isopulegol, pinocarveol, verbenol, and myrtenol were the most potent modifiers of GABAA receptor function. Comparing the chemical structures, the action of terpenes on GABAA receptors is most probably due to the presence of hydroxyl groups and a bicyclic character of the substances tested. We propose an allosteric modulation independent from the γ2 subunit and similar to the action of alcohols and anesthetics.
Figure 1. Representative gas chromatographic pattern (GC-flame ionization detector, analytical column DB5) of a Sideritis stricta extract for identification of single substances as candidates for GABAAR modulation.
Figure 2. GABAAR modulation by Sideritis components. (A) Comparison of whole-cell currents (Iabs) following GABA (1 μM) application ± Sideritis components especially various pinenes at 1 mM from HEK293 cells expressing rat α1β2γ2 GABAARs. Data are mean current values ± SD, mean Iabs of GABA application alone = 100%, n = number of measured cells; n = 4–8. (B) Similar experiment to (A) but recordings were performed using Xenopus oocytes expressing rat α1β2 GABAARs. GABAergic currents ± single components from Sideritis extract at 1 mM, GABA = 1 μM concentration, n = 4–8 (C) Representative traces following GABA coapplication with the most potent substance carvacrol (range from 30 μM–1 mM). (D) Bar diagram demonstrating the mean current amplitudes for the potentiation of GABAergic currents by different carvacrol concentrations. Mean absolute current values are shown ± SD, n = 3–6. The significance of the depicted currents were compared to control (GABA application alone), **p < 0.01 with Dunnett post hoc test.
Figure 3. Modulatory effects of terpenoid structures. Currents elicited using two-electrode voltage clamp technique recordings on rat α1β2 expressing oocytes by coapplication of GABA (1 μM) and various terpenoid substances with structural similarities to single components of Sideritis extracts. Substance concentration was 600 μM. Mean current amplitudes compared to GABA application alone (100%) ± SD values, n = 3–8, significance value **p < 0.01.
Figure 4. Potentiating effect on GABAergic responses by metabolites of pinenes. Typical traces recorded from oocytes expressing rat α1β2 GABAARs and activated by GABA (1 μM) plus (A) myrtenol, and (B) verbenol at various concentrations (3 μM–100 μM). (C) Bar diagram representing the dose-dependent potentiation of GABA-mediated currents by verbenol (black bars) and myrtenol (gray bars). Data = mean ± SD, n = 3–9. The significance was tested compared to control (GABA alone), *p< 0.05; **p < 0.01.
Figure 5. Flexstation data for the most potent modulators. (A) Concentration response curves for human α1β2 and human α1β2γ2 GABAARs results in a decrease in GABA EC50. (B–G) Dose–response curves with either GABA alone (used at concentrations 0.46 μM–1000 μM) or in the presence of different modulators (used at a fixed concentration of 300 μM). Data = mean ± SD, n = 3. (H) Bar diagram representing the shift in GABA-affinity (fold in EC50 shift).
Figure 6. Modulatory effects of volatile terpenoid structures are independent of the origin of GABAARs subunits. (A) Typical traces of Zn2+-mediated inhibition of GABAergic currents on human α1β2 GABAARs expressed in Xenopus oocytes. (B) No Zn2+ inhibition was observed when human α1β2γ2 GABAA subunits are expressed. (C) Typical traces to application of various GABA concentrations measured from human α1β2γ2 GABAAR expressing oocytes (D) GABA dose–response curve of the human α1β2γ2 GABAAR expressed in Xenopus oocytes. Data = mean ± SD, n = 5; EC50 for GABA 59 ± 1.2 μM, the Hill coefficient nH was determined to 0.7. (E–G) Dose-dependent modulation of GABAergic currents by various terpenoids carvacrol, carveol, pinocarveol, isopulegol, myrtenol, and verbenol as well as linalool and 1-octen-3-ol as controls. *p < 0.5; **p < 0.01.
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