@article{JanzenSlavikZeheetal.2021,
  author    = {Janzen, Dieter and Slavik, Benedikt and Zehe, Markus and Sotriffer, Christoph and Loos, Helene M. and Buettner, Andrea and Villmann, Carmen},
  title     = {Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABA\(_{A}\) receptor function in vitro},
  series = {Journal of Neurochemistry},
  volume    = {159},
  journal   = {Journal of Neurochemistry},
  number    = {1},
  doi       = {10.1111/jnc.15469},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259546},
  pages     = {101-115},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}