Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Differential Effects of Quercetin and Quercetin Glycosides on Human α7 Nicotinic Acetylcholine Receptor-Mediated Ion Currents.
Lee BH
,
Choi SH
,
Kim HJ
,
Jung SW
,
Hwang SH
,
Pyo MK
,
Rhim H
,
Kim HC
,
Kim HK
,
Lee SM
,
Nah SY
.
???displayArticle.abstract???
Quercetin is a flavonoid usually found in fruits and vegetables. Aside from its antioxidative effects, quercetin, like other flavonoids, has a various neuropharmacological actions. Quercetin-3-O-rhamnoside (Rham1), quercetin-3-O-rutinoside (Rutin), and quercetin- 3-(2(G)-rhamnosylrutinoside (Rham2) are mono-, di-, and tri-glycosylated forms of quercetin, respectively. In a previous study, we showed that quercetin can enhance α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated ion currents. However, the role of the carbohydrates attached to quercetin in the regulation of α7 nAChR channel activity has not been determined. In the present study, we investigated the effects of quercetin glycosides on the acetylcholine induced peak inward current (IACh) in Xenopus oocytes expressing the α7 nAChR. IACh was measured with a two-electrode voltage clamp technique. In oocytes injected with α7 nAChR copy RNA, quercetin enhanced IACh, whereas quercetin glycosides inhibited IACh. Quercetin glycosides mediated an inhibition of IACh, which increased when they were pre-applied and the inhibitory effects were concentration dependent. The order of IACh inhibition by quercetin glycosides was Rutin≥Rham1>Rham2. Quercetin glycosides-mediated IACh enhancement was not affected by ACh concentration and appeared voltage-independent. Furthermore, quercetin-mediated IACh inhibition can be attenuated when quercetin is co-applied with Rham1 and Rutin, indicating that quercetin glycosides could interfere with quercetin-mediated α7 nAChR regulation and that the number of carbohydrates in the quercetin glycoside plays a key role in the interruption of quercetin action. These results show that quercetin and quercetin glycosides regulate the α7 nAChR in a differential manner.
Fig. 1. Chemical structures of quercetin and its glycosides. (A) Quercetin, (B) quercetin-3-O-rhamnoside (Rham1), (C) quercetin-3-O-rutinoside (Rutin), and (D) quercetin-3-(2G-rhamnosylrutinoside) (Rham2).
Fig. 2. Effects of quercetin and its glycosides on IACh in oocytes expressing human α7 nAChRs. (A–B) Acetylcholine (ACh; 200 μM) was applied first, followed by co- or pre-application of quercetin (Que) or quercetin glycosides (Rham1, Rutin, Rham2) and ACh. Co-application of 100 μM quercetin with ACh enhanced IACh and pre-application of 100 μM quercetin with ACh further enhanced IACh. Whereas, co-application of 100 μM of quercetin glycosides with ACh inhibited IACh and pre-application of 100 μM quercetin glycosides with ACh further inhibited IACh. Traces represent six separate oocytes from three different batches of frogs. (C) Summary of IACh enhancement by co- or pre-application of quercetin (*p<0.05, **p<0.005 compared to the control; #p<0.005, compared to the co-application of quercetin). Each point represents the means ± S.E.M. (n=9–12/group).
Fig. 3. Concentration-dependent effects of quercetin and its glycosides on IACh. (A) The representative trace of quercetin- or quercetin gly-coside- (30 μM each) mediated effects on IACh. IACh in oocytes expressing the α7 nAChR was elicited at a holding potential of −80 mV for 30 s in the presence of 200 μM ACh. Quercetin and its glycosides were pre-applied 30 s before ACh application. (B) The representative trace of quercetin- and quercetin glycoside- (300 μM each) mediated effects on IACh. IACh in oocytes expressing the α7 nAChRs was elicited at a holding potential of −80 mV for 30 s in the presence of 200 μM ACh. Quercetin and its glycosides were pre-applied 30 s before ACh application. Traces represent six separate oocytes from three different batches of frogs. (C–D) Concentration-dependent effects of quercetin and quercetin glycosides on IACh. The solid lines were fit using the Hill equation. Each point represents the mean ± S.E.M. (n=9–12/group).
Fig. 4. Concentration-dependent effects of ACh on quercetin- and quercetin glycoside-mediated regulation of IACh. (A) Concentration-response relationships for oocytes expressing the α7 nAChRs treated with ACh (3–3000 μM) alone or with ACh plus 100 μM quercetin and 100 μM quercetin glycoside. The IACh of oocytes expressing α7 nAChRs was measured using the indicated concentration of ACh in the absence (□) or presence of quercetin (Que), Rham1, Rutin and Rham2. Oocytes were exposed to ACh alone or to ACh with quercetin and quercetin glycosides for 30 s before application. Oocytes were voltage-clamped at a holding potential of −80 mV.
Fig. 5. Current-voltage relationships and voltage-independent inhibition by quercetin and its glycosides. (A) Current-voltage relationships of IACh regulation by quercetin in the oocytes expressing α7 nAChRs. Representative current-voltage relationships were obtained using voltage ramps of −100 to +50 mV for 300 ms at a holding potential of 80 mV. Voltage steps were applied before and after application of 200 μM ACh in the absence or presence of 100 μM quercetin, Rham1, Rutin, and Rham2. Each point represents the mean ± S.E.M. (n=7–9/group). (B) Voltage-independent regulation of IACh in oocytes expressing α7 nAChRs by quercetin and quercetin glycosides (100 μM each). The values were obtained in the presence of 200 μM ACh at the indicated membrane holding potentials. Each point represents the mean ± SEM (n=8–12/group).
Fig. 6. Effects of quercetin glycosides on quercetin-induced IACh enhancement. IACh in oocytes expressing α7 nAChRs was elicited at a holding potential of −80 mV for 30 s in the presence of 200 μM ACh. 100 μM quercetin (Que) alone or with 100 μM quercetin glycoside (Rham1, Rutin, Rham2) were applied for 30 s before ACh addition. Summary histograms are from three different frogs (n=7–12/group). Each point represents the mean ± S.E.M (*p<0.05, **p<0.005 compared to quercetin).
Azevedo,
The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy.
2013, Pubmed
Azevedo,
The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy.
2013,
Pubmed
Boulter,
Functional expression of two neuronal nicotinic acetylcholine receptors from cDNA clones identifies a gene family.
1987,
Pubmed
,
Xenbase
Castro,
alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability.
1995,
Pubmed
Changeux,
Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors.
2001,
Pubmed
Chavez-Noriega,
Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Chini,
Molecular cloning and chromosomal localization of the human alpha 7-nicotinic receptor subunit gene (CHRNA7).
1994,
Pubmed
Couturier,
A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo-oligomeric channel blocked by alpha-BTX.
1990,
Pubmed
,
Xenbase
Dani,
Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.
2007,
Pubmed
Dascal,
The use of Xenopus oocytes for the study of ion channels.
1987,
Pubmed
,
Xenbase
Elgoyhen,
Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells.
1994,
Pubmed
,
Xenbase
Galzi,
Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic.
1992,
Pubmed
,
Xenbase
Gilbert,
Local and global calcium signals associated with the opening of neuronal alpha7 nicotinic acetylcholine receptors.
2009,
Pubmed
Gotti,
Neuronal nicotinic receptors: from structure to pathology.
2004,
Pubmed
Gotti,
Drugs selective for nicotinic receptor subtypes: a real possibility or a dream?
2000,
Pubmed
Griebel,
Pharmacological studies on synthetic flavonoids: comparison with diazepam.
1999,
Pubmed
Harborne,
Advances in flavonoid research since 1992.
2000,
Pubmed
Havsteen,
The biochemistry and medical significance of the flavonoids.
2002,
Pubmed
Jensen,
Charge selectivity of the Cys-loop family of ligand-gated ion channels.
2005,
Pubmed
Kandaswami,
Free radical scavenging and antioxidant activity of plant flavonoids.
1994,
Pubmed
Karlin,
Emerging structure of the nicotinic acetylcholine receptors.
2002,
Pubmed
Khiroug,
Functional mapping and Ca2+ regulation of nicotinic acetylcholine receptor channels in rat hippocampal CA1 neurons.
2003,
Pubmed
Kim,
Differential effects of quercetin glycosides on GABAC receptor channel activity.
2015,
Pubmed
,
Xenbase
Lee,
Quercetin enhances human α7 nicotinic acetylcholine receptor-mediated ion current through interactions with Ca(2+) binding sites.
2010,
Pubmed
,
Xenbase
Lee,
Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I.
2005,
Pubmed
,
Xenbase
Lee,
Human glycine alpha1 receptor inhibition by quercetin is abolished or inversed by alpha267 mutations in transmembrane domain 2.
2007,
Pubmed
,
Xenbase
Léna,
Pathological mutations of nicotinic receptors and nicotine-based therapies for brain disorders.
1997,
Pubmed
Marder,
6-Bromoflavone, a high affinity ligand for the central benzodiazepine receptors is a member of a family of active flavonoids.
1996,
Pubmed
Medina,
Overview--flavonoids: a new family of benzodiazepine receptor ligands.
1997,
Pubmed
Murota,
Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism.
2003,
Pubmed
Nashmi,
CNS localization of neuronal nicotinic receptors.
2006,
Pubmed
Nemeth,
Food content, processing, absorption and metabolism of onion flavonoids.
2007,
Pubmed
Oyama,
Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca(2+)-loaded brain neurons.
1994,
Pubmed
Picq,
Effect of two flavonoid compounds on central nervous system. Analgesic activity.
1991,
Pubmed
Revah,
Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor.
1991,
Pubmed
,
Xenbase
Speroni,
Neuropharmacological activity of extracts from Passiflora incarnata.
1988,
Pubmed
Séguéla,
Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium.
1993,
Pubmed
,
Xenbase
Weiland,
Neuronal nicotinic acetylcholine receptors: from the gene to the disease.
2000,
Pubmed
Yao,
Quercetin improves cognitive deficits in rats with chronic cerebral ischemia and inhibits voltage-dependent sodium channels in hippocampal CA1 pyramidal neurons.
2010,
Pubmed
