Effects of ginsenosides and their metabolites on voltage-dependent Ca²⁺ channel subtypes

In previous reports we demonstrated that ginsenosides, active ingredients of Panax ginseng, affect some subsets of voltage-dependent Ca²⁺ channels in neuronal cells expressed in Xenopus laevis oocytes. However, the major component(s) of ginseng that affect cloned Ca²⁺ channel subtypes such as α_1C (L)-, α_1B (N)-, α_1A (P/Q)-, α _1E (R)- and α_1G (T) have not been identified. Here, we used the two-microelectrode voltage clamp technique to characterize the effects of ginsenosides and ginsenoside metabolites on Ba²⁺ currents (I_Ba) in Xenopus oocytes expressing five different Ca²⁺ channel subtypes. Exposure to ginseng total saponins (GTS) induced voltage-dependent, dose-dependent and reversible inhibition of the five channel subtypes, with particularly strong inhibition of the α_1G-type. Of the various ginsenosides, Rb₁, Rc, Re, Rf, Rg₁, Rg₃, and Rh₂, ginsenoside Rg₃ also inhibited all five channel subtypes and ginsenoside Rh₂ had most effect on the α_1C- and α_1E-type Ca²⁺ channels. Compound K (CK), a protopanaxadiol ginsenoside metabolite, strongly inhibited only the α_1G-type of Ca²⁺ channel, whereas M4, a protopanaxatriol ginsenoside metabolite, had almost no effect on any of the channels. Rg₃, Rh₂, and CK shifted the steady-state activation curves but not the inactivation curves in the depolarizing direction in the α_1B- and α_1A-types. These results reveal that Rg₃, Rh₂ and CK are the major inhibitors of Ca²⁺ channels in Panax ginseng, and that they show some Ca²⁺ channel selectivity.