Stereospecificity of ginsenoside Rg₃ action on ion channels

Ginsenosides, active ingredients of Panax ginseng, exist as stereoisomers depending on the position of the hydroxyl group on carbon-20; i.e. 20(R)-ginsenoside and 20(S)-ginsenoside are epimers. We have shown previously that the mixture of 20(R)- and 20(S)-ginsenosides regulates ion channel activity. However, it was not clear which epimer was responsible. We investigated the structure-activity relationship of the ginsenoside Rg₃ stereoi-somers, 20-R-protopanaxatriol-3-[O-β-D-glucopyranosyl (1→2)-β-glucopyranoside], (20(R)-Rg₃) and 20-S-protopanaxatriol-3-[O-β-D-glucopyranosyl (1→2)-β-glucopyranoside], (20(S)-Rg₃) in regulating voltage-dependent Ca²⁺, K⁺ or Na⁺ channel currents and 5-HT_3A and α3β4 nicotinic acetylcholine (nACh) receptor channel currents expressed in Xenopus oocytes. 20(S)-Rg₃ but not 20(R)-Rg₃ inhibited the Ca²⁺, K⁺ and Na⁺ channel currents in a dose- and voltage-dependent manner. The fact that only 20(S)-Rg₃ is active indicates that its hydroxyl group may be geometrically better aligned with the hydroxyl acceptor group in the ion channels than that of 20(R)-Rg₃. However, both Rg₃ stereoisomers inhibited 5-HT_3A and α3β4 nACh receptor channel currents. These results indicate that the selectivity of action of the Rg₃ stereoisomers differs between voltage-dependent and ligand-gated ion channels.