Effects of ginsenosides on GABA(A) receptor channels expressed in Xenopus oocytes.
ABSTRACT Ginsenosides, major active ingredients of Panax ginseng, are known to regulate excitatory ligand-gated ion channel activity such as nicotinic acetylcholine and NMDA receptor channel activity. However, it is not known whether ginsenosides affect inhibitory ligand-gated ion channel activity. We investigated the effect of ginsenosides on human recombinant GABA(A) receptor (alpha1beta1gamma2S) channel activity expressed in Xenopus oocytes using a two-electrode voltage-clamp technique. Among the eight individual ginsenosides examined, namely, Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg2, we found that Rc most potently enhanced the GABA-induced inward peak current (I(GABA)). Ginsenoside Rc alone induced an inward membrane current in certain batches of oocytes expressing the GABA(A) receptor. The effect of ginsenoside Rc on I(GABA) was both dose-dependent and reversible. The half-stimulatory concentration (EC50) of ginsenoside Rc was 53.2 +/- 12.3 microM. Both bicuculline, a GABA(A) receptor antagonist, and picrotoxin, a GABA(A) channel blocker, blocked the stimulatory effect of ginsenoside Rc on I(GABA). Niflumic acid (NFA) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), both Cl- channel blockers, attenuated the effect of ginsenoside Rc on I(GABA). This study suggests that ginsenosides regulated GABA(A) receptor expressed in Xenopus oocytes and implies that this regulation might be one of the pharmacological actions of Panax ginseng.
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ABSTRACT: Ginsenosides, one of the active ingredients of Panax ginseng, show various pharmacological and physiological effects, and they are converted into compound K (CK) or protopanaxatriol (M4) by intestinal microorganisms. CK is a metabolite derived from protopanaxadiol (PD) ginsenosides, whereas M4 is a metabolite derived from protopanaxatriol (PT) ginsenosides. The γ-aminobutyric acid receptorC (GABAC) is primarily expressed in retinal bipolar cells and several regions of the brain. However, little is known of the effects of ginsenoside metabolites on GABAC receptor channel activity. In the present study, we examined the effects of CK and M4 on the activity of human recombinant GABAC receptor (ρ1) channels expressed in Xenopus oocytes by using a 2-electrode voltage clamp technique. In oocytes expressing GABAC receptor cRNA, we found that CK or M4 alone had no effect in oocytes. However, co-application of either CK or M4 with GABA inhibited the GABA-induced inward peak current (IGABA ). Interestingly, pre-application of M4 inhibited IGABA more potently than CK in a dose-dependent and reversible manner. The half-inhibitory concentration (IC50) values of CK and M4 were 52.1±2.3 and 45.7±3.9 µM, respectively. Inhibition of IGABA by CK and M4 was voltage-independent and non-competitive. This study implies that ginsenoside metabolites may regulate GABAC receptor channel activity in the brain, including in the eyes.Korean Journal of Physiology and Pharmacology 04/2013; 17(2):127-32. · 1.00 Impact Factor
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ABSTRACT: Ginseng, the root of Panax ginseng, has been used in traditional Chinese medicine as a tonic herb that provides many beneficial effects. Pharmacologic studies in the last decades have shown that ginsenosides (ginseng saponins) are primarily responsible for the actions of ginseng. However, the effects of ginseng are not fully explained by ginsenosides. Recently, another class of active ingredients called gintonin was identified. Gintonin is a complex of glycosylated ginseng proteins containing lysophosphatidic acids (LPAs) that are the intracellular lipid mitogenic media¬tor. Gintonin specifically and potently activates the G protein-coupled receptors (GPCRs) for LPA. Thus, the actions of ginseng are now also linked to LPA and its GPCRs. This linkage opens new dimensions for ginseng pharmacology and LPA therapeutics. In the present review, we evaluate the pharmacology of ginseng with the traditional viewpoint of Yin and Yang components. Furthermore, we will compare ginsenoside and gintonin based on the modern view of molecular pharmacology in terms of ion channels and GPCRs.Acta Pharmacologica Sinica 10/2013; · 2.35 Impact Factor
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ABSTRACT: In a previous report, we demonstrated that ginsenoside Rc, one of major ginsenosides from Panax ginseng, enhances γ-aminobutyric acid (GABA) receptorA (GABAA)-mediated ion channel currents. However, little is known about the effects of ginsenoside metabolites on GABAA receptor channel activity. The present study investigated the effects of ginsenoside metabolites on human recombinant GABAA receptor (α1β1γ2s) channel activity expressed in Xenopus oocytes using a two-electrode voltage clamp technique. M4, a metabolite of protopanaxatriol ginsenosides, more potently inhibited the GABA-induced inward peak current (IGABA ) than protopanaxadiol (PPD), a metabolite of PPD ginsenosides. The effect of M4 and PPD on IGABA was both concentration-dependent and reversible. The half-inhibitory concentration (IC50) values of M4 and PPD were 17.1±2.2 and 23.1±8.6 μM, respectively. The inhibition of IGABA by M4 and PPD was voltage-independent and non-competitive. This study implies that the regulation of GABAA receptor channel activity by ginsenoside metabolites differs from that of ginsenosides.Journal of ginseng research 01/2012; 36(1):55-60. · 2.26 Impact Factor
Arch Pharm Res Vol 26, No 1, 28-33, 2003
Effects of Ginsenosides on GABAA Receptor Channels
Expressed in Xenopus Oocytes
Se-Eun Choi, Seok Choi, Jun-Ho Lee, Paul J. Whiting1, Sang-Mok Lee, and Seung-Yeol Nah
Department of Physiology, College of Veterinary Medicine Konkuk University, Seoul 143-701, Korea and 1Merck
Sharp & Dohme Research Lab., Neuroscience Research Center, Essex, CM20 2QR, United Kingdom
(Received November 5, 2002)
Ginsenosides, major active ingredients of Panax ginseng, are known to regulate excitatory
ligand-gated ion channel activity such as nicotinic acetylcholine and NMDA receptor channel
activity. However, it is not known whether ginsenosides affect inhibitory ligand-gated ion chan-
nel activity. We investigated the effect of ginsenosides on human recombinant GABAA recep-
tor (α1β1γ2S) channel activity expressed in Xenopus oocytes using a two-electrode voltage-
clamp technique. Among the eight individual ginsenosides examined, namely, Rb1, Rb2, Rc,
Rd, Re, Rf, Rg1 and Rg2, we found that Rc most potently enhanced the GABA-induced inward
peak current (IGABA). Ginsenoside Rc alone induced an inward membrane current in certain
batches of oocytes expressing the GABAA receptor. The effect of ginsenoside Rc on IGABA was
both dose-dependent and reversible. The half-stimulatory concentration (EC50) of ginsenoside
Rc was 53.2 ± 12.3 µM. Both bicuculline, a GABAA receptor antagonist, and picrotoxin, a
GABAA channel blocker, blocked the stimulatory effect of ginsenoside Rc on IGABA. Niflumic
acid (NFA) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), both Cl- channel block-
ers, attenuated the effect of ginsenoside Rc on IGABA. This study suggests that ginsenosides
regulated GABAA receptor expressed in Xenopus oocytes and implies that this regulation
might be one of the pharmacological actions of Panax ginseng.
Key words: Panax ginseng, Ginsenosides, GABA, GABAA receptor, Ligand-gated ion channels,
Ginseng, the root of Panax ginseng C.A. Meyer, is a well
known traditional medicine and tonic. The main molecular
components responsible for the actions of ginseng are
ginsenosides, which are also known as ginseng saponins.
Ginsenosides have a four-ring, steroid-like structure with
attached sugar moieties. About 30 different types of gin-
senosides have been isolated and identified from the root
of Panax ginseng. The ginsenosides are classified into pro-
topanaxadiol and protopanaxatriol ginsenosides according
to the positioning of sugar moieties at the carbon-3 and -6
(Attele et al., 1999).
Recent reports have shown that ginsenosides might
regulate ligand-gated ion channel activity. Moreover, gin-
senosides are known to inhibit acetylcholine-stimulated cat-
echolamine release in cells expressing nicotinic acetylcholine
receptors, such as bovine chromaffin cells (Kudo et al.,
1998; Tachikawa et al., 1999). In addition, Choi et al. (2002)
and Sala et al. (2002) showed that protopanaxatriol gin-
senosides inhibit acetylcholine-induced inward current in
Xenopus oocytes expressing neuronal and muscle-type
nicotinic acetylcholine receptors. In addition, in cultured rat
hippocampal neurons, ginsenoside Rb1 and Rg1 were found
to reduce glutamate-induced cell death (Abe et al., 1994).
Moreover, ginsenosides and ginsenoside Rg3 also atten-
uated glutamate-induced neurodegeneration by inhibit-
ing the overproduction of nitric oxide, the formation of mal-
ondialdehyde, and Ca2+ influx in rat cortical cultures and in
hippocampal slices (Kim et al., 1998; Kim et al., 2002). Finally,
Seong et al. (1995) showed that ginsenosides attenuate
the glutamate-induced swelling of cultured rat astrocytes.
The GABAA receptor is one of a superfamily of ligand-
gated ion channel receptors, which share structural simi-
larity with nicotinic acetylcholine, 5-HT3, and glycine receptors
Correspondence to: Dr. Seung-Yeol Nah, Dept. of Physiology,
College of Veterinary Medicine, Konkuk University, Seoul 143-701,
Effects of Ginsenosides on GABAA Receptor Channels Expressed in Xenopus Oocytes29
(Ortells and Lunt, 1995). The GABAA receptor is predomi-
nantly expressed in the central nervous system (Bloom
and Iversen, 1971; McCabe and Wamsley, 1986), and
forms a chloride-selective transmembrane channel in the
post-synaptic sites of nerve terminals. Thus, the GABAA
receptor is responsible for fast inhibitory synaptic transmis-
sion (Macdonald and Olsen, 1994; Whiting et al., 1995).
Recent biochemical binding assays produced evidence
that ginsenosides might regulate the GABAA receptor. For
example, Kimura et al. (1994) showed that ginsenosides
differentially regulate [3H] flunitrazepam or [3H] muscimol
binding to the GABAA receptor in a rat brain membrane
fraction. Whereas, Kim et al. (2001) showed that prolong-
ed infusion with ginsenoside Rc but not with ginsenoside
Rg1 into rat brain elevates [3H] muscimol binding to the
GABAA receptor in a brain region-specific manner.
Thus, ginsenosides may regulate the GABAA receptor
by affecting ligands affinity on its receptor, but there is no
direct evidence the regulation of GABAA receptor channel
activity by ginsenosides. In this study, we examined the
effects of ginsenosides on GABAA receptor channel activity.
For this study, we injected neuronal human GABAA (α1β1γ2S)
receptor cRNAs into Xenopus oocytes and examined the
effect of ginsenosides on the GABA-elicited inward peak
currents (IGABA). The reasons we used this system are as
follows: (1) Xenopus laevis oocytes have widely been
used as a tool to express membrane proteins encoded by
exogenously administered cDNAs or cRNAs, including
those of receptors, ion channels, and transporters (Dascal,
1987) and (2) The GABAA receptor (α1β1γ2S) channels ex-
pressed in Xenopus oocytes by injecting GABAA receptor
cRNAs subunits have been well studied and characteriz-
ed (Hill-Venning et al., 1997). Accordingly, in this study we
undertook to investigate the effect of ginsenosides on
human recombinant GABAA receptor (α1β1γ2S) channel activity
expressed in Xenopus oocytes using a two-electrode
voltage-clamp technique. We found that the treatment of
ginsenoside Rc enhanced IGABA in a reversible, dose-
dependent, bicuculline and picrotoxin-sensitive manner.
MATERIALS AND METHODS
Ginsenosides were kindly provided by the Korean
Ginseng and Tobacco Research Institute (Taejon, Korea).
Fig. 1 shows the structures of the five representative gin-
senosides. The ginsenosides used in this study were
dissolved in dimethyl sulfoxide (DMSO) and diluted with
bath medium before use. The final DMSO concentration
was less than 0.01%. Other chemical agents were obtain-
ed from Sigma (St. Louis, MO, USA).
Xenopus laevis care and handling was in accordance
with the guide for the Care and Use of Laboratory Animals
published by NIH, USA. Frogs underwent surgery only
twice, separated by at least 3 weeks. To isolate oocytes,
frogs were anesthetized with an aerated solution of 3-
amino benzoic acid ethyl ester. Oocytes were separated
by treatment with collagenase, followed by gentle shaking
for 2 h in CaCl2-free medium containing 82.5 NaCl, 2 mM
KCl, 1 mM MgCl2, 5 mM HEPES, 2.5 mM sodium pyruvate,
100 units of penicillin per ml, and 100 µg streptomycin/ml.
Only stage 5 or 6 oocytes were collected and maintained
at 18°C with continuous gentle shaking in ND96 (96 mM
NaCl, 2 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, and 5 mM
HEPES, pH 7.5) supplemented with 0.5 mM theophylline
and 50 µg gentamycin/ml. All solutions were changed daily,
and experiments were performed within 2-4 days following
the isolation of the oocytes.
A single oocyte was placed in a small Plexiglas net
chamber (0.5 ml), which was constantly superfused with
ND96 medium in the absence or presence of GABA or
ginsenosides during recording. The microelectrodes were
filled with 3 M KCl and had a resistance of 0.2-0.7 MΩ Ω Ω Ω.
Two-electrode voltage-clamp recordings were performed
at room temperature using an Oocyte Clamp (OC-725C,
Warner Instrument, Hamden, CT, USA) equipped with
Digidata 1200A. For most of the electrophysiological ex-
periments, the oocytes were clamped at a holding potential
of -80 mV, and 300-ms voltage steps were applied from
-100 to +40 mV to determine the nature of the current-
voltage relationship. Linear leak currents were corrected
using the leak subtraction procedure.
cRNA preparation of GABAA (α α α α1β β β β1γ γ γ γ2s) receptor and
cDNAs encoding human GABAA receptor subunits (α1β1γ2s)
Fig. 1. Structure of the five representative ginsenosides
30 S.-E. Choi et al.
were linearized with appropriate restriction enzymes, and
the cRNAs were transcribed from linearized templates
using an in vitro transcription kit (mMessage mMachine;
Ambion, Austin, TX, USA) and T7 polymerase. The cRNA
was dissolved in RNase-free water at a final concentration
of approximately 1 µg/µl and stored at -70oC until used.
Oocytes were injected with H2O or human GABAA receptor
cRNAs (5-10 ng) by using a Nanoject Automatic Oocyte
Injector (Drummond Scientific, Broomall, PA, USA). The
injection pipette was pulled from glass capillary tubing
used for recording electrodes and the tip was broken to
All values are presented as means ± S.E.M. Differences
between the means of control and ginsenosides treatment
data were analyzed using the unpaired Students t test. A
P value of < 0.05 was considered statistically significant.
RESULTS AND DISCUSSION
The addition of GABA (10 µM) to the bathing medium
induced a large inward current (IGABA) in oocytes injected
with GABAA receptor subunits cRNAs, indicating that the
GABAA receptor was functionally expressed (Fig. 2A). In a
certain batch of oocytes expressing GABAA receptor, the
treatment of ginsenoside Rc had no effect; however,
another batch of oocytes expressing the GABAA receptor
induced an inward current when treated with Rc at a
holding potential of -80 mV (Figs. 2A and 3A). Moreover,
pretreatment with ginsenoside Rc for 1 min before GABA
induced a large increase of IGABA in a reversible manner
(Fig. 2B, n = 15 from three different frogs). We also tested
the effects of other ginsenosides, namely, Rb1, Rb2, Rd,
Re, Rf, Rg1, or Rg2 on IGABA in oocytes expressing the GABAA
receptor. As shown in Fig. 2B, Rc significantly enhanced
IGABA, and the order of potency in terms of IGABA enhance-
ment was Rc > Rb2> Rd; however, Rb1, Re, Rf, Rg1, and
Rg2 had no of insignificant effect on IGABA (Fig. 2).
In dose-dependent experiments with ginsenoside Rc,
pretreatment with Rc increased IGABA in a dose-dependent
manner in oocytes expressing the GABAA receptor (Fig.
3A). The EC50 of IGABA was 53.2 ± 12.3 µM in oocytes ex-
pressing the GABAA receptor (n = 9-12 from three different
frogs for each point) (Fig. 3B). In current-voltage experiments,
the membrane potential was held at -80 mV and a voltage
ramp was applied from -100 to +40 mV for 300 ms. In the
absence of GABA, the inward current at -100 mV was <0.3
µA and the outward current at +40 mV was 0.3-0.5 µA.
The addition of GABA to the bathing medium resulted in
an increase of the inward current at a potential more nega-
tive than ca -20 mV. In contrast, at a potential more positive
than ca -20 mV, GABA caused a large increase in the out-
ward current. Pretreatment with Rc before GABA increased
both inward and outward currents as compared with those
induced by GABA treatment alone. The reversal potential
was near -20mV in GABA alone and in GABA plus Rc, which
indicates that GABA induces the Cl− current (Macdonald
and Olsen, 1994). Also, pretreatment with Rc before GABA
did not affect the channel property of the GABAA receptor
To further verify that the extra current elicited by pre-
treatment with Rc was due to GABA receptor channel cur-
rent, we examined the effect of bicuculline, a GABAA re-
ceptor antagonist and picrotoxin, a GABAA channel blocker
(Krishek et al., 1996). As shown in Fig. 5, pretreatment with
bicuculline or picrotoxin almost blocked the current elicited
by the application of Rc plus GABA in a reversible manner.
Fig. 2. Expression of GABAA receptor channel in Xenopus oocytes
after GABAA receptor subunits cRNAs injection. The inward currents
were recorded at a holding potential of 70m V. A. GABA (GABA; 10
µM) induced a large inward current in oocytes expressing GABAA
receptor. Pretreatm ent with ginsenoside Rc but not with ginsenoside Rd
or Re (each 100µM) before GABA treatm ent enhanced IGABA. B.
Histogram representing peak inward currents recorded during treatm ent
with GABA alone (Con; 10µM) or after pretreatm ent with various in-
dividual ginsenosides (i.e., Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, and Rg2;
each at 100µM). Am ong the several ginsenosides exam ined, ginseno-
side Rc shows the strongest effect on GABA-induced inward peak
current. Each point represents a m ean±S.E.M. (n=8-10/group). * P<
0.05, * * P<0.01 com pared with the GABA-alone induced inward peak
Effects of Ginsenosides on GABAA Receptor Channels Expressed in Xenopus Oocytes 31
We also tested the effect of 4,4-diisothiocyanostilbene-2,2-
disulfonic acid (DIDS) and niflumic acid (NFA), Cl− channel
blockers, to ensure that both the inward currents elicited
by GABA and the extra current elicited by Rc were Cl-
currents (Frings et al., 2000). As shown in Fig. 5B, in the
presence of DIDS or NFA, the stimulatory effect of Rc on
IGABA was substantially reduced.
The present study demonstrates that; (1) ginsenoside
Rc enhanced IGABA in reversible and dose-dependent man-
ner in oocytes expressing the GABAA receptor; (2) the
ginsenoside Rc induced enhancement of IGABA was sensi-
tive to GABA receptor antagonist and GABAA receptor
channel blocker; (3) the protopanaxadiol ginsenoside Rc
much more potently increased IGABA than the protopanaxa-
triol ginsenosides such as Re, Rf, and Rg1.
We also found that ginsenoside Rb2, although to a lesser
extent than Rc, also enhanced IGABA (Fig. 2). Interestingly,
ginsenoside Rc (20-S-Protopanaxadiol-3-[O-β-glucopy-
(1?2)-β-D-arabinopyranoside] has two glucoses at the C-
3 position and one glucose and one arabinose at the C-20
position, and ginsenoside Rb2 (20-S-Protopanaxadiol-3-
Fig. 3. Dose-dependent effect of ginsenoside Rc on IGABA. A. The trace
shows that ginsenoside Rc increased the currents elicited by GABA
(GABA; 10µM) in a dose-dependent m anner. B. Graphic illustration of
the m agnitude of the inward current evoked in each experim ental con-
dition is expressed as a percentage of the current that was evoked by
GABA treatm ent alone. Data are presented as m eans±S.E.M. (n=8-
Fig. 4. This representative current-voltage relationship was obtained
using voltage steps between -100 and +40m V and a ram p protocol. Pre-
treatm ent with ginsenoside Rc (GABA+Rc, Rc; 100µM) potentiated
both the inward and outward currents induced by GABA alone (GABA;
10µM). The reversal potential was near -20mV.
Fig. 5. Effects of the GABAA receptor antagonist, bicuculline or GABAA
receptor channel blocker, picrotoxin on ginsenoside Rc-induced poten-
tiation of IGABA. A. Representative trace showing inward currents in the
presence of GABA (GABA; 10µM) alone, picrotoxin (Pic; 30µM)+
ginsenoside Rc (Rc; 100µM)+GABA (GABA; 10µM), bicuculline (Bic;
30µM)+ginsenoside Rc (Rc; 100µM)+GABA (GABA; 10µM), or
ginsenoside Rc+GABA. B. Histogram showing peak inward currents
recorded during the treatm ent of GABA alone, ginsenoside Rc+GABA,
GABA+ginsenoside Rc+bicuculline, GABA+ginsenoside Rc+picro-
toxin, GABA+ginsenoside Rc+DIDS (100µM ), or GABA+ginsenoside
Rc+NFA (100µM). Each point represents the m ean± S.E.M. (n=8-
10/group). * P <0.05, * * P <0.01 com pared with the GABA-alone induc-
ed inward current.
32S.-E. Choi et al.
α-L-glucopyranosyl (1?2)-β-D-glucopyranoside] has two
glucoses at the C-3 position and two glucoses at the C-20
position (Fig. 1). Thus, ginsenoside Rc and Rb2 have similar
structures except that Rc has an arabinose instead of a
second glucose at the C-20 position. It seems that an arabi-
nose rather than a glucose at the C-20 position of ginseno-
side Rc may play an important role in the enhancement of
IGABA, though this issue certainly requires further investigation.
On the other hand, these results suggest that Rc affects
the GABAA receptor channel activity that mediates inhibitory
neurotransmission in the central nervous system. However,
it is unclear precisely how Rc acts to increase IGABA in oo-
cytes expressing GABAA receptor. The one possibility is
that Rc might open endogenous Cl− channels in Xenopus
oocytes, and that the extra inward current exhibited by
ginsenoside treatment in the presence of GABA might be
derived from the endogenous Cl− current, since in a previous
study we showed that several ginsenosides activate en-
dogenous Ca2+-activated Cl- channels via phospholipase
C and by intracellular Ca2+ mobilization (Choi et al., 2001).
However, this may be not the case because the GABAA
receptor channel blocker picrotoxin abolished Rc-induced
IGABA enhancement. Otherwise, the extra inward currents
elicited by ginsenoside Rc treatment in the presence of
picrotoxin were unaffected (Fig. 5A).
Another possibility is that Rc might act on GABA-bind-
ing sites in the GABA receptor in bicuculline sensitive manner
and might facilitate the delivery of GABA to its binding site
by stimulating GABA movement into GABAA receptor on
the plasma membrane. Similarly, a report by Kim et al.
(2001) showed that Rc increases the affinity of specific
[3H] muscimol binding in the membrane fraction of the rat
cortex following chronic infusion. However, to elucidate
the exact mechanism underlying Rc-induced IGABA increase,
further experiments are required to determine the location
of the ginsenoside interaction site in the GABAA receptor.
In summary, this study shows that ginsenosides enhance
IGABA in oocytes expressing human GABAA receptor. These
results indicate that ginsenosides may regulate the GABAA
receptor and hint that this regulation may be associated
with the pharmacological actions of Panax ginseng.
This work was supported by the Faculty Research Fund
of Konkuk University in 2002.
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