Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABA\(_{A}\) receptor function in vitro
Please always quote using this URN: urn:nbn:de:bvb:20-opus-259546
- 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 andNaturally 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.…
Author: | Dieter Janzen, Benedikt Slavik, Markus Zehe, Christoph Sotriffer, Helene M. Loos, Andrea Buettner, Carmen VillmannORCiD |
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URN: | urn:nbn:de:bvb:20-opus-259546 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Institut für Klinische Neurobiologie |
Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie | |
Language: | English |
Parent Title (English): | Journal of Neurochemistry |
Year of Completion: | 2021 |
Volume: | 159 |
Issue: | 1 |
Pagenumber: | 101–115 |
Source: | Journal of Neurochemistry 2021, 159(1):101–115. DOI: 10.1111/jnc.15469 |
DOI: | https://doi.org/10.1111/jnc.15469 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | GABA\(_{A}\) receptor; allosteric modulation; patch clamp recording |
Release Date: | 2022/04/05 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |