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Valerenic Acid Potentiates and Inhibits GABAA Receptors: Molecular Mechanism and Subunit Specificity

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Valerenic Acid Potentiates and Inhibits GABAA Receptors: Molecular Mechanism and Subunit Specificity ARTICLE IN PRESS + MODEL Neuropharmacology xx (2007) 1e10 www.elsevier.com/locate/neuropharm Valerenic acid potentiates and inhibits GABAA receptors: Molecular mechanism and subunit specificity S. Khom a, I. Baburin a, E. Timin a, A. Hohaus a, G. Trauner b, B. Kopp b, S. Hering a,* a Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria b Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria Received 8 December 2006; received in revised form 11 April 2007; accepted 30 April 2007 Abstract 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 b2 or b3 subunits were stimulated by VA. Replacing b2/3 by b1 drastically reduced the sensitivity of the resulting GABAA channels. The stimulatory effect of VA on a1b2 receptors was substantially reduced by the point mutation b2N265S (known to inhibit loreclezole action). Mutating the corresponding residue of b1 (b1S290N) induced VA sensitivity in a1b1S290N comparable to a1b2 receptors. Modulation of IGABA was not significantly dependent on incorporation of a1, a2, a3 or a5 subunits. VA displayed a significantly lower efficiency on channels incorporating a4 subunits. IGABA modulation by VA was not g subunit dependent and not inhibited by flumazenil (1 mM). VA shifted the GABA concentrationeeffect curve towards lower GABA concentrations and elicited substantial currents through GABAA channels at 30 mM. At higher concentrations (100 mM), 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. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: GABAA-receptors; 2-Microelectrode voltage-clamp technique; Xenopus oocyte; Subunit specific modulation; Valerenic acid 1. Introduction (Hevers and Lu¨ddens, 1998; Sieghart, 1995; Boileau et al., 2002). Both binding sites for GABA and for benzodiazepines g-Aminobutyric acid (GABA) mediates fast synaptic inhi- (BZDs) are assumed to be located at subunit interfaces (for re- bition by interaction with the GABA type A (GABAA) recep- view see Galzi and Changeux, 1995; Sigel and Buhr, 1997). tor. GABAA receptors are assembled from individual subunits Mutational studies suggest that the binding pocket for BZDs forming a pentameric structure. Nineteen isoforms of mamma- is located at the interface between a and g subunits, whereas lian GABAA receptor subunits have been cloned: a1e6, b1e3, binding of GABA is believed to occur at the interfaces g1e3, d, 3, p, r1e3 and q (Barnard et al., 1998; Simon et al., between a and b subunits (Sigel, 2002; Ernst et al., 2003; 2004). Ernst et al., 2005). The subunit composition determines the GABA sensitivity GABAA channels are modulated by numerous structurally and the pharmacological properties of the GABAA receptor distinct substances including clinically important drugs as BZDs, barbiturates and various general anaesthetics (see Sieghart, 1995 for review), but also by several compounds * Corresponding author. Tel.: þ43 1 4277 55301; fax: þ43 1 4277 9553. of plant origin, including flavonoids, e.g. methyl-apigenin E-mail address: [email protected] (S. Hering). (Marder et al., 2003) or wogonin (from Scutellaria baicalensis, 0028-3908/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2007.04.018 Please cite this article in press as: Khom, S. et al., Valerenic acid potentiates and inhibits GABAA receptors: Molecular mechanism and subunit specificity, Neuropharmacology (2007), doi:10.1016/j.neuropharm.2007.04.018 ARTICLE IN PRESS + MODEL 2 S. Khom et al. / Neuropharmacology xx (2007) 1e10 Hui et al., 2002; Huen et al., 2003), monoterpenes, e.g. bor- Microelectrodes were filled with 2 M KCl and had resistances between 1 neol (Granger et al., 2005) and thymol (Garcia et al., 2006) and 3 MU. or polyacetylenes, e.g. MS-1, MS-2 and MS-4 (from Cussonia zimmermannii, Baur et al., 2005). In the present study, we an- 2.3. Perfusion system alysed the molecular mechanism of action of VA and the two structurally closely related compounds acetoxy-VA and hy- GABA and VAwere applied by means of a newly developed fast perfusion droxy-VA from Valerian root on GABA channels. Previous system (Baburin et al., 2006; see also Khom et al., 2006). Drug or control A solutions were applied by means of a TECAN Miniprep 60 permitting automa- in vitro studies on a neonatal rat brainstem preparation suggest tion of the experiments. To elicit IGABA the chamber was perfused with 120 ml that the Valerian effects may be mediated through VA action of GABA-containing solution at volume rate between 300 and 1000 ml/s. The on GABAA receptors (Yuan et al., 2004). The molecular mech- IGABA rise time ranged between 100 and 250 ms (see Khom et al., 2006). Care anism of action of VA remained, however, unknown. In order was taken to account for possible slow recovery from increasing levels of de- to clarify the molecular basis of VA action on GABA recep- sensitization in the presence of high GABA or VA concentrations. The dura- A tion of washout periods was therefore extended from 1.5 min (1e20 mM tors, we expressed 13 different subunit combinations in GABA, <10 mM VA) to 30 min (100 mM GABA, 10 mM VA), respectively. Xenopus oocytes and analysed the modulation of the corre- Oocytes with maximal current amplitudes >3 mA were discarded to exclude sponding receptors by VA. voltage-clamp errors. 2. Methods 2.4. Analysing concentration e response curves 2.1. Chemicals Stimulation of chloride currents by modulators of the GABAA receptor was measured at a GABA concentration eliciting between 5 and 10% of the Valerenic acid was obtained from Extrasynthese, France, Lyon, acetoxy- maximal current amplitude (EC5e10). The EC5e10 was determined at the be- valerenic acid from LGC Promochem, Wesel, Germany and hydroxy-valerenic ginning of each experiment. acid was isolated from Valerian root. The structural formulae are given in Enhancement of the chloride current was defined as (I(GABAþComp)/ Fig. 5. Stock solutions (100 mM) were prepared in DMSO (dimethyl IGABA) À 1, where I(GABAþComp) is the current response in the presence of sulfoxide, Sigma, Austria). Because of low solubility in ND96, VA and a given compound and IGABA is the control GABA current. To measure the two derivatives (Fig. 5) were only used up to a concentration of the sensitivity of the GABAA receptor for a given compound, it was applied 300 mM. Equal amounts of DMSO were present in control and VA-containing for an equilibration period of 1 min before applying GABA (EC5e10). Con- solutions. The maximum DMSO concentration in the bath (0.3%) did not centrationeresponse curves were generated and the data were fitted by non- affect IGABA. linear regression analysis using Origin Software (OriginLab Corporation, nH USA). Data were fitted to the equation 1=ð1 þðEC50=½CompÞ Þ, where nH is the Hill coefficient. Each data point represents the mean Æ S.E. 2.2. Expression and functional characterization of GABAA receptors from at least four oocytes and 2 oocyte batches. Statistical significance was calculated using paired Student t-test with a confidence interval of p < 0.05. Preparation of stage VeVI oocytes from Xenopus laevis, synthesis of cap- ped off run-off poly(Aþ) cRNA transcripts from linearized cDNA templates (pCMV vector) was performed as previously described (Khom et al., 2006). 3. Results Briefly, female Xenopus laevis (NASCO, USA) were anaesthetised by expos- ing them for 15 min to a 0.2% solution of MS-222 (methane sulfonate salt of 3-aminobenzoic acid ethyl ester; Sandoz) before surgically removing parts of 3.1. Potentiation of IGABA by VA through a1b2, a1b2g1 the ovaries. Follicle membranes from isolated oocytes were enzymatically and a1b2g2S channels digested with 2 mg/ml collagenase (Type 1 A, Sigma). One day after isolation, e the oocytes were injected with about 10 50 nl of DEPC-treated water (diethyl Functional effects of VA were investigated on recombinant pyrocarbonate, Sigma, Germany) containing the different cRNAs at a concen- tration of approximately 300e3000 pg/nl/subunit. The amount of cRNA was GABAA receptors expressed in Xenopus laevis oocytes. Mod- determined by means of a NanoDrop ND-1000 (Kisker-Biotech, Steinfurt, ulation of IGABA by VA was first studied on GABAA channels Germany). composed of either a1b2 or a1b2g1/2S subunits. As shown in Mutation b1S290N was introduced by the ‘‘gene SOEing’’ technique Fig. 1A, B, VA exhibited a positive allosteric modulatory ef- (Horton et al., 1989). This involved synthesizing mutagenic oligonucleotides fect at concentrations 1 mM by enhancing IGABA. The effect to introduce the desired mutation, and a silent restriction site was used to e screen for the mutation. The mutant cDNA was verified by sequencing. was dose-dependent and the averaged concentration response To ensure expression of the g subunit in the case of a1b2g1, a1b2g2S, curve shows that maximum stimulation of a1b2g2S receptors a2b2g2S and a2b2g1 receptors, cRNAs were mixed in a ratio of 1:1:10 except occurred at w100 mM(Fig. 1B). The maximal potentiation a b g (ratio 3:1:5). For receptors comprising only a and b subunits (a b , 4 2 2S 1 2 of IGABA (efficiency) through a1b2g1 (235.6 Æ 46.4%, n ¼ 8) a2b2, a1b3, a1b2N265S (cDNA gift of E.
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