Ginseng saponins, major active components of ginseng root used by folk medicine in the treatment of various diseases, produce multiple pharmacological responses having many effects on the central and peripheral nervous system. Specifically, ginsenoside Rg(2) has been shown to block the nicotinic acetylcholine receptors in bovine chromaffin cells. We have studied the effect of Rg(2) on different types of human neuronal nicotinic acetylcholine receptors (nAChRs), both homomeric and heteromeric, expressed in Xenopus oocytes. Rg(2) did not affect the acetylcholine (ACh)-induced currents in alpha(7) human receptors, however Rg(2) affected the peak currents, and mainly the desensitization of heteromeric receptors alpha(3)beta(4), alpha(3)beta(2), alpha(4)beta(4), and alpha(4)beta(2). Both effects, a diminution of peak current and an increase of desensitization, are dose-dependent and are very similar for all the receptors. The mechanism of action has been studied in more detail in alpha(3)beta(4) and alpha(4)beta(2) receptors where we found a negligible shift in the ACh dose-response curves and a persistence of the Rg(2) effects at high ACh concentrations, indicative of a noncompetitive antagonism. A lack of voltage dependence on the reduction of the peak currents induced by ACh also suggests that Rg(2) does not act as an open channel blocker of human nAChR. The results indicate that Rg(2) acts specifically on heteromeric human nAChRs modulating their desensitization and suggest a possible mechanism by which this saponin contributes to the multiple therapeutic effects of ginseng.