Inhibitory Effects of Ginsenoside Metabolites, Compound K and Protopanaxatriol, on GABA(C) Receptor-Mediated Ion Currents

Ginsenosides, one of the active ingredients of Panax ginseng, show various pharmacological and physiological effects, and they are converted into compound K (CK) or protopanaxatriol (M4) by intestinal microorganisms. CK is a metabolite derived from protopanaxadiol (PD) ginsenosides, whereas M4 is a metabolite derived from protopanaxatriol (PT) ginsenosides. The γ-aminobutyric acid receptor(C) (GABA(C)) is primarily expressed in retinal bipolar cells and several regions of the brain. However, little is known of the effects of ginsenoside metabolites on GABA(C) receptor channel activity. In the present study, we examined the effects of CK and M4 on the activity of human recombinant GABA(C) receptor (ρ1) channels expressed in Xenopus oocytes by using a 2-electrode voltage clamp technique. In oocytes expressing GABA(C) receptor cRNA, we found that CK or M4 alone had no effect in oocytes. However, co-application of either CK or M4 with GABA inhibited the GABA-induced inward peak current (I(GABA)). Interestingly, pre-application of M4 inhibited I(GABA) more potently than CK in a dose-dependent and reversible manner. The half-inhibitory concentration (IC(50)) values of CK and M4 were 52.1±2.3 and 45.7±3.9 µM, respectively. Inhibition of I(GABA) by CK and M4 was voltage-independent and non-competitive. This study implies that ginsenoside metabolites may regulate GABA(C) receptor channel activity in the brain, including in the eyes.