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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
.
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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. (AâB) 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=9â12/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 â80 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 â80 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. (CâD) 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=9â12/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 (3â3000 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 (â¡) 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 â80 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 â100 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=7â9/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=8â12/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 â80 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=7â12/group). Each point represents the mean ± S.E.M (*p<0.05, **p<0.005 compared to quercetin).
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