Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABA_A receptor...

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 γ₂ 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 α₁ β₂ γ₂ 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.