Valerenic acid potentiates and inhibits GABAA receptors: Molecular mechanism and subunit specificity

Valerian is a commonly used herbal medicinal product for the treatment of anxiety and insomnia. Here we report the stimulation of chloride currents through GABAA receptors (IGABA) by valerenic acid (VA), a constituent of Valerian. To analyse the molecular basis of VA action, we expressed GABAA receptors with 13 different subunit compositions in Xenopus oocytes and measured IGABA using the two-microelectrode voltage-clamp technique. We report a subtype-dependent stimulation of IGABA by VA. Only channels incorporating β2 or β3 subunits were stimulated by VA. Replacing β2/3 by β1 drastically reduced the sensitivity of the resulting GABAA channels. The stimulatory effect of VA on α1β2 receptors was substantially reduced by the point mutation β2N265S (known to inhibit loreclezole action). Mutating the corresponding residue of β1 (β1S290N) induced VA sensitivity in α1β1S290N comparable to α1β2 receptors. Modulation of IGABA was not significantly dependent on incorporation of α1, α2, α3 or α5 subunits. VA displayed a significantly lower efficiency on channels incorporating α4 subunits. IGABA modulation by VA was not γ subunit dependent and not inhibited by flumazenil (1 μM). VA shifted the GABA concentration–effect curve towards lower GABA concentrations and elicited substantial currents through GABAA channels at ≥30 μM. At higher concentrations (≥100 μM), VA and acetoxy-VA inhibit IGABA. A possible open channel block mechanism is discussed. In summary, VA was identified as a subunit specific allosteric modulator of GABAA receptors that is likely to interact with the loreclezole binding pocket.