Differential effect of ginsenoside metabolites of the 5-HT_3A receptor-mediated ion current in Xenopus oocytes

Ginsenosides are major active ingredients of Panax ginseng. They have a number of pharmacological and physiological actions, and are transformed into compound K (CK) or M4 by intestinal microorganisms. CK is derived from protopanaxadiol (PD) ginsenosides, whereas M4 is derived from protopanaxatriol (PT) ginsenosides. Recent reports show that ginsenosides act as pro-drugs for these metabolites. In previous work we demonstrated that the ginsenoside Rg₂ regulates human 5-hydroxytryptamine_3A (5-HT_3A) receptor channel activity [Choi et al. (2003)]. In the present study, we investigated the effect of CK and M4 on the activity of the human 5-HT_3A receptor channel. The 5-HT_3A receptor was expressed in Xenopus oocytes, and the current was measured using the two-electrode voltage clamp technique. Treatment with CK or M4 had no effect on oocytes injected with 5-HT_3A receptor cRNA. However pretreatment with M4 or CK followed by injection of 5-HT_3A receptor cRNA led to reversible inhibition of the 5-HT-induced inward peak current (I_5-HT). Half maximal inhibitory concentrations (IC₅₀) of CK and M4 were 36.9 ± 9.6 and 7.3 ± 2.2 μM, respectively. Inhibition by M4 was non-competitive and voltage-independent. These results indicate that M4, a metabolite of PT ginsenosides, acts primarily on 5-HT_3A receptors and further, that ginsenosides as well as ginsenoside metabolites can influence 5-HT_3A receptor channel activity in Xenopus oocytes.