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. 2017 Jun 21:5:46.
doi: 10.3389/fchem.2017.00046. eCollection 2017.

Metabolic Products of Linalool and Modulation of GABAA Receptors

Sinem Milanos  1   2 , Shaimaa A Elsharif  2 , Dieter Janzen  1 , Andrea Buettner  2   3 , Carmen Villmann  1
Affiliations

Metabolic Products of Linalool and Modulation of GABAA Receptors

Sinem Milanos et al. Front Chem. .

Abstract

Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABAA receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at α1β2γ2 GABAA receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC10-30 together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.

Keywords: Cys-loop receptor; GABAA receptor; linalool; linalyl acetate; oxygenation; patch-clamp.

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Figures

Figure 1
Figure 1
Linalool and linalool metabolites. Linalool a monoterpene alcohol (3,7-dimethyl-1,6-octadiene-3-ol), linalyl acetate and its derivatives. Compounds L1-3 are acetylated at carbon 3. Compound L1 (8-hydroxylinalyl acetate), compound L2 (8-oxolinalyl acetate), compound L3 (8-carboxylinalyl acetate). Compounds L4-7 are linalool metabolites substituted at carbon atom 8. Compound L4 (8-hydroxylinalool), compound L5 (8-oxo-dihydrolinalool), compound L6 (8-oxolinalool), compound L7 (8-carboxylinalool).
Figure 2
Figure 2
HEK293 transiently expressing GABAA α1β2 receptors and GAP-43 fused with red fluorescent protein. (A) Upper lane demonstrates transfection efficiency controlled by co-transfection of the membrane marker protein GAP-43 fused to dsRed (magenta). The α1 subunit of the GABAA receptor was stained specifically at the cellular surface (green). The merged picture represents co-localization resulting in a white signal of both the GABAA α1 receptor subunit and GAP43 (magenta) at the plasma membrane. (B) The lower lane shows an enlarged image of a single stained cell. DAPI staining was used to mark the nucleus of the cell (blue), α1 subunit is marked in green and GAP-43 in magenta.
Figure 3
Figure 3
GABAA α1β2γ2 receptor EC50 determination for the agonist GABA. (A) Calculation of half-maximal receptor activation using seven different concentrations of the agonist (0.3–1,000 μM). The EC50 was determined at 37 ± 0.4 μM GABA, while EC10−30was calculated to 10 μM. (B) The black bar illustrates the mean relative current of GABAA receptors α1β2γ2 at 10 μM GABA. Potentiation of GABAergic currents by linalool (2 mM) at EC10−30GABA concentrations (10 μM) refers to the white bar, *P < 0.05; linalyl acetate (striped bar); n = number of cells recorded.
Figure 4
Figure 4
Acetylated linalool derivatives do not potentiate GABAergic currents in HEK293 cells. Ten micromolars of GABA were applied to α1β2γ2 receptors and refers to 100% (100 ± 15% GABA application, black bar; relative to GABA + linalyl acetate). Acetylated linalool compounds such as linalyl acetate (striped bar), L1 (8-hydroxylinalyl acetate), L2 (8-oxolinalyl acetate), L3 (8-carboxylinalyl acetate) used in a 2 mM concentration were co-applied with GABA (gray bars), n = number of cells recorded.
Figure 5
Figure 5
Oxygenated linalool derivatives potentiated GABAergic currents in HEK293 cells. (A) 10 μM GABA applications are nominated to 100% (100 ± 15% GABA application relative to GABA + linalool, black bar), linalool (white bar), *P < 0.05. Compounds L4 (8-hydroxylinalool) and L7 (8-carboxylinalool) did not enhance or reduce GABA-evoked currents significantly. Compounds L5 (8-oxo-dihydrolinalool) and L6 (8-oxolinalool) enhanced GABAergic currents (gray bars). (B) Representative current traces detected from transfected HEK293 cells with GABAA receptor subunits α1β2γ2 following an application of 10 μM GABA for 500 ms (black trace) or a co-application on the same cell of 10 μM GABA + L6 (dark gray trace, potentiating) or L7 (light gray trace, not potentiating), small bars above the traces refer to the time the agonist ± modulator were applied to the cell, n = number of cells recorded.
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