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 (
Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop family of ligand-gated ion channels. The Cys-loop family also includes serotonin (5-HT3), gamma-amino-butyric acid (GABAA), and glycine receptors (Jensen
In previous reports, we have shown that the application of the flavonoid quercetin inhibits 5-HT- and glycine-induced peak inward currents (
On the other hand, in addition to quercetin, quercetin glycosides are also compounds of low molecular weight and are mainly found in apples, tomatoes, gingko, other red fruits, and vegetables (Havsteen, 2002). In fruits and vegetables, quercetin naturally exists in glycosylated forms such as Rham 1, Rutin, Rham2, or other glycosidic forms (Azevedo
In this study, we investigated the regulation of α7 nAChR channel activity expressed in
We found that co- or pre-application of quercetin with ACh enhanced
Human wild-type α7 nAChR cDNA was kindly provided by Dr. S. Heinemann (Salk Institute, California, USA). Quercetin (Fig. 1) and all other reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA).
A custom-made Plexiglas net chamber was used for two-electrode voltage-clamp recordings, as previously reported (Lee
To obtain the concentration-response curves for quercetin and quercetin glycosides on the inward peak
Treatment of ACh (200 μM) to oocytes injected with human α7 nAChR cRNA induced a large inward current (
In concentration-dependent experiments with quercetin, pre-application with quercetin for 30 s enhanced
Similar to our previous report (Lee
Next, to further study the mechanism by which quercetin glycosides inhibit
In the current-voltage relationship, the membrane potential, which was held at −80 mV, and a voltage ramp was applied from −100 to +50 mV for 300 ms. In the absence of ACh, the inward current (at −100 mV) and the outward current (at +50 mV) were negligible (data not shown). Treatment of ACh to in oocytes expressing the α7 nAChR induced a mainly inward current and outward current at negative- and positive voltages, respectively. Pre-application of quercetin with ACh enhanced both inward and outward currents. The reversal potential was near 0 mV for both ACh alone and for ACh with quercetin. This indicates that Na+ and Ca2+ are main charge carriers (Revah
The above results indicate that quercetin glycosides may be novel regulators of α7 nAChR channel activity and that their actions could be different from those of quercetin. Therefore, we investigated the effect of quercetin on
Quercetin is a flavonoid that shows diverse effects in nervous and non-nervous systems (Kandaswami and Middleton, 1994; Harborne and Williams, 2000). For example, quercetin protects the central nervous system against oxidative effects and exerts effects on analgesia, locomotor activity and sleep (Speroni and Minghetti, 1988; Picq
In the present study, we have investigated the effects of quercetin glycosides on human α7 nAChRs heterologously expressed in
It will be questioned how structural differences between quercetin and quercetin glycosides induce differential regulations of α7 nAChR channel activity. One possibility is that the carbohydrates attached to quercetin might cause a different behavior in the regulations of α7 nAChRs. For example, quercetin enhances
The activation of the α7 nAChR is known to be linked to many physiological conditions (Khiroug
In previous studies, we have shown that quercetin inhibits 5-HT3 receptor-gated ion currents through interactions within the pre-transmembrane domain I. Furthermore, quercetin can inhibit or potentiate glycine receptor-gated ion currents through interactions with the amino acid Ser256 residue in transmembrane domain II (Lee
In conclusion, we found that quercetin increased
This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP(2015M3A9E3052336).
This paper was also written as part of Konkuk University’s research support program for its faculty on sabbatical leave in 2015 to S.M. Lee.