TY  - JOUR
A1  - Milanos, Sinem
A1  - Elsharif, Shaimaa A.
A1  - Janzen, Dieter
A1  - Buettner, Andrea
A1  - Villmann, Carmen
T1  - Metabolic Products of Linalool and Modulation of GABA\(_{A}\) Receptors
JF  - Frontiers in Chemistry
N2  - 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 GABA\(_{A}\) 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 GABA\(_{A}\) 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 EC\(_{10-30}\) 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.
KW  - Cys-loop receptor
KW  - GABA\(_{A}\)
KW  - receptor
KW  - linalool
KW  - linalyl acetate
KW  - oxygenation
KW  - patch-clamp
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170779
VL  - 5
IS  - 46
ER  - 
TY  - JOUR
A1  - Janzen, Dieter
A1  - Slavik, Benedikt
A1  - Zehe, Markus
A1  - Sotriffer, Christoph
A1  - Loos, Helene M.
A1  - Buettner, Andrea
A1  - Villmann, Carmen
T1  - Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABA\(_{A}\) receptor function in vitro
JF  - Journal of Neurochemistry
N2  - Naturally occurring compounds such as sesquiterpenes and sesquiterpenoids (SQTs) have been shown to modulate GABA\(_{A}\) receptors (GABA\(_{A}\)Rs). In this study, the modulatory potential of 11 SQTs at GABA\(_{A}\)Rs was analyzed to characterize their potential neurotropic activity. Transfected HEK293 cells and primary hippocampal neurons were functionally investigated using electrophysiological whole-cell recordings. Significantly different effects of β-caryophyllene and α-humulene, as well as their respective derivatives β-caryolanol and humulol, were observed in the HEK293 cell system. In neurons, the concomitant presence of phasic and tonic GABA\(_{A}\)R configurations accounts for differences in receptor modulation by SQTs. The in vivo presence of the γ\(_{2}\) and δ subunits is important for SQT modulation. While phasic GABA\(_{A}\) receptors in hippocampal neurons exhibited significantly altered GABA-evoked current amplitudes in the presence of humulol and guaiol, negative allosteric potential at recombinantly expressed α\(_{1}\)β\(_{2}\)γ\(_{2}\) receptors was only verified for humolol. Modeling and docking studies provided support for the binding of SQTs to the neurosteroid-binding site of the GABA\(_{A}\)R localized between transmembrane segments 1 and 3 at the (\(^{+}\)α)-(\(^{-}\)α) interface. In sum, differences in the modulation of GABA\(_{A}\)R isoforms between SQTs were identified. Another finding is that our results provide an indication that nutritional digestion affects the neurotropic potential of natural compounds.
KW  - allosteric modulation
KW  - GABA\(_{A}\) receptor
KW  - patch clamp recording
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259546
VL  - 159
IS  - 1
ER  -