Differential Regulations of Quercetin and Its Glycosides on Ligand-Gated Ion Channels

Lee, Byung-Hwan; Pyo, Mi Kyung; Lee, Jun-Ho; Choi, Sun-Hye; Shin, Tae‐Joon; Lee, Sang-Mok; Lim, Yoongho; Han, Ye; Paik, Hyun‐Dong; Cho, Ssang-Goo; Yun‐Choi, Hye Sook; Rhim, Hyewhon; Nah, Seung‐Yeol

doi:10.1248/bpb.31.611

Cited by 20 publications

(13 citation statements)

References 27 publications

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“…Under our experimental conditions an EC 50 value for 5-HT of 2.39 ± 0.06 μM was determined for the 5-HT 3A receptor (Supplementary Figure 1 ). This EC 50 value is similar to previously reported EC 50 values evaluated in Xenopus oocytes (about 2 μM 5-HT) (Lee et al, 2008 ; Schreiner et al, 2014 ). The tinctures from rikkunshito and its constituents Aurantii , Ginseng , Zingiberis , Atractylodis , and Glycyrrhiza , inhibited the 5-HT 3A receptor responses (5-HT 2.5 μM, approximately EC 50 ) at a concentration of 1 Vol.-%, whereas the tinctures of Poria cocos , Jujubae and Pinellia exhibited no effect (Figure 1A ).…”

Section: Resultssupporting

confidence: 91%

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Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

et al. 2015

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The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT3 receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT3 receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT3Areceptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from Aurantii, Ginseng, Zingiberis, Atractylodis and Glycyrrhiza inhibited the 5-HT3A receptor response, whereas the tinctures of Poria cocos, Jujubae and Pinellia exhibited no effect. Surprisingly, the strongest antagonism was found for Glycyrrhiza, whereas the Zingiberis tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT3A receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT3 receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from Glycyrrhiza species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from Aurantii inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of 5-HT3A receptors. Thus, this study reveals new 5-HT3A receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito.

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Section: Resultssupporting

confidence: 91%

“…However, other glycosylated flavonoids are known, e.g., rutin from Aurantii , which shows an antagonistic effect on 5-HT 3 receptors. However, also in this case, quercetin, the aglycone of rutin, is the more potent substance (Lee et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

et al. 2015

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“…As shown in previous studies, 20) the addition of glycine to the bathing solution induced a large inward current (I Gly ) in oocytes injected with glycine α1 receptor cRNA (Fig. 1B).…”

Section: Resultssupporting

confidence: 87%

Resveratrol Inhibits Glycine Receptor-Mediated Ion Currents

Lee

Hwang

Choi

et al. 2014

Biological & Pharmaceutical Bulletin

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Resveratrol is found in grapes, red wine, and berries. Resveratrol has been known to have many beneficial health effects, such as anti-cancer, neuroprotective, anti-nociceptive, and life-prolonging effects. However, the single cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. The glycine receptor is an inhibitory ligand-gated ion channel involved in fast synaptic transmission in spinal cord. In the present study, we investigated the effect of resveratrol on human glycine receptor channel activity. Glycine α1 receptors were expressed in Xenopus oocytes and glycine receptor channel activity was measured using a two-electrode voltage clamp technique. Treatment with resveratrol alone had no effect on oocytes injected with H 2 O or on oocytes injected with glycine α1 receptor cRNA. In the oocytes injected with glycine α1 receptor cRNA, co-or pretreatment of resveratrol with glycine inhibited the glycine-induced inward peak current (I Gly ) in a reversible manner. The inhibitory effect of resveratrol on I Gly was also concentration dependent, voltage independent, and non-competitive. These results indicate that resveratrol regulates glycine receptor channel activity and that resveratrol-mediated regulation of glycine receptor channel activity is one of several cellular action mechanisms of resveratrol for pain regulation.Key words resveratrol; glycine; glycine receptor; ligand-gated ion channel; Xenopus oocyte Resveratrol is a phytoalexin found in grapes, red wine, and other berries (Fig. 1A) and is also produced as an anti-fungal chemical by plants.1) The concentration of resveratrol in red wine is as high as 0.2-5.8 mg/L.2) Resveratrol exhibits diverse physiological and pharmacological activities, such as anti-cancer, chemopreventive, antiviral, cardio-protective, anti-aging, anti-nociceptive, and life-prolonging effects.2-4) Resveratrol exhibits beneficial effects on the nervous system. It attenuates neurodegenerative disorders such as Alzheimer's disease.5) It also attenuates neuronal cell death from in vitro or in vivo brain hypoxia or ischemic conditions. 6,7) Although accumulating evidence indicates that resveratrol has diverse beneficial properties, including protective effects on the nervous system, relatively little is known about its cellular action, especially with respect to possible regulation of the receptors involved in synaptic transmission.The glycine receptor belongs to the superfamily of ligandgated ion channel receptors that are structurally similar to nicotinic acetylcholine, 5-HT 3 , and γ-aminobutyric acid A (GABA A ) receptors. 8,9) Glycine receptors are dominantly expressed in the spinal cord.10) The physiological roles of glycine receptors in these regions mediate post-synaptic inhibition for reflex responses, voluntary motor control, and the processing of sensory signals, 10) because the glycine receptor forms a chloride-permeable and -selective transmembrane channel. Glycine recep...

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“…Otherwise, WAY-100635 comprises a specific ligand with high affinity for the 5-HT 1A receptor (Passchier and Van Waarde, 2001). However, it is not possible to discard the probability that G-B modulation of this type of serotonergic signaling is a consequence of the activity of this substance on the ionic channels that maintain the nervous excitability, as is the case of K+ channels associated with the 5-HT 1A receptor (Lee et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Interaction of the natural anxiolytic Galphimine-B with serotonergic drugs on dorsal hippocampus in rats

Jiménez-Ferrer

Herrera-Ruíz

Ramírez-García

et al. 2011

Journal of Ethnopharmacology

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Differential Regulations of Quercetin and Its Glycosides on Ligand-Gated Ion Channels

Cited by 20 publications

References 27 publications

Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

Resveratrol Inhibits Glycine Receptor-Mediated Ion Currents

Interaction of the natural anxiolytic Galphimine-B with serotonergic drugs on dorsal hippocampus in rats

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