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Korean J Physiol Pharmacol
2013 Apr 01;172:175-80. doi: 10.4196/kjpp.2013.17.2.175.
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Resveratrol Inhibits GABAC ρ Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes.
Lee BH
,
Choi SH
,
Hwang SH
,
Kim HJ
,
Lee JH
,
Nah SY
.
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Resveratrol is a phytoalexin found in grapes, red wine, and berries. Resveratrol has been known to have many beneficial health effects, such as anti-cancer, neuroprotective, anti-inflammatory, and life-prolonging effects. However, relatively little is known about the effects of resveratrol on the regulation of ligand-gated ion channels. We have previously reported that resveratrol regulates subsets of homomeric ligand-gated ion channels such as those of 5-HT3A receptors. The γ-aminobutyric acidC (GABAC) receptor is mainly expressed in retinal bipolar cells and plays an important role in visual processing. In the present study, we examined the effects of resveratrol on the channel activity of homomeric GABAC receptor expressed in Xenopus oocytes injected with cRNA encoding human GABAC ρ subunits. Our data show that the application of GABA elicits an inward peak current (IGABA ) in oocytes that express the GABAC receptor. Resveratrol treatment had no effect on oocytes injected with H2O or with GABAC receptor cRNA. Co-treatment with resveratrol and GABA inhibited IGABA in oocytes with GABAC receptors. The inhibition of IGABA by resveratrol was in a reversible and concentration-dependent manner. The IC50 of resveratrol was 28.9±2.8 µM in oocytes expressing GABAC receptor. The inhibition of IGABA by resveratrol was in voltage-independent and non-competitive manner. These results indicate that resveratrol might regulate GABAC receptor expression and that this regulation might be one of the pharmacological actions of resveratrol on the nervous system.
Fig. 1. Chemical structure of resveratrol and effect of resveratrol (Res) on GABAC receptors expressing oocytes. (A). Application of resveratrol (100 µM) for 1 min had no effect on IGABA expression in oocytes expressing GABAC receptors (B).
Fig. 2. Effect of Res on IGABA expression in oocytes that express GABAC receptors. (A) GABA (2 µM) was first applied and then GABA was co- or pre-applied with Res (100 µM). Thus, co- and pre-application of Res with GABA inhibited IGABA. The resting membrane potential of oocytes was approximately -35 mV, and oocytes were voltage clamped at a holding potential of -80 mV prior to drug application. Traces are representative of 6 separate oocytes from 3 frogs. (B) Pre-application of Res inhibited IGABA more potently than that inhibited by co-treatment. (C) IGABA in GABAC receptors expressing oocytes was elicited at -80 mV holding potential, with indicated time in the presence of 2 µM GABA and with the indicated pre-treatment concentration of Res that was applied before GABA application. (D) IGABA % inhibition induced by Res treatment was calculated using the average of peak that the inward current elicited by GABA treatment before Res application and of the peak inward current elicited by GABA treatment after pre-treatment of Res before GABA. The continuous line shows the curve fitted according to the equation. Each point represents the mean±S.E.M. (n=9~12 from 3 frogs).
Fig. 3. Time-dependent effects of pre-application of Res on IGABA in oocytes that express GABAC receptors. (A) Res (100 µM)-mediated inhibition on IGABA is pre-application-time dependent. Traces represent 6 separate oocytes from 3 frog batches. IGABA in GABAC receptor-expressing oocytes was elicited at a holding potential of -80 mV for the indicated Res pre-application time prior to drug application. (B) Res-mediated inhibition of IGABA was almost saturated after 30 s of pre-application. The resting membrane potential of the oocytes was approximately -35 mV, and the oocytes were voltage-clamped at a holding potential of -80 mV. Each point represents the mean±S.E.M. (n=9~12/group).
Fig. 4. Current-voltage relationship and voltage-independent inhibition by Res. (A) Current-voltage relationships of IGABA inhibition by Res in GABAC receptor-expressing oocytes. Representative current-voltage relationships were obtained using voltage ramps of -100 to +40 mV for 300 ms at a holding potential of -80 mV. Voltage steps were applied before and after application of 2 µM GABA in the absence or presence of 100 µM Res. (B) Voltage-independent inhibition of IGABA in the GABAC receptors by Res. Inset; the values were obtained from the receptors in the presence or absence of 100 µM Res at the indicated membrane holding potentials.
Fig. 5. Concentration-dependent effects of GABA on Res-mediated inhibition of IGABA. (A) The representative traces were obtained from the GABAC receptor-expressing oocytes. IGABA expression shown in the upper and lower panels were elicited at a holding potential of -80 mV by GABA at concentrations of 1 µM and 30 µM GABA respectively. (B) Concentration-response relationship of GABA with GABAC receptors treated with GABA (0.3~30 µM) alone or with GABA plus pre-application of 30 µM or 100 µM Res. The IGABA of oocytes expressing the GABAC receptors was measured using the indicated concentration of GABA in the absence (â¡) or presence of 30 µM (â) or 100 µM (âµ) Res. Oocytes were exposed to GABA alone or to GABA with Res. Oocytes were voltage-clamped at a holding potential of -80 mV. Each point represents mean±S.E.M. (n=9~12/group).
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