title: Characteristics of ginsenoside Rg3-mediated brain Na+ current inhibition.
abstract: We demonstrated previously that ginsenoside Rg(3) (Rg(3)), an active ingredient of Panax ginseng, inhibits brain-type Na(+) channel activity. In this study, we sought to elucidate the molecular mechanisms underlying Rg(3)-induced Na(+) channel inhibition. We used the two-microelectrode voltage-clamp technique to investigate the effect of Rg(3) on Na(+) currents (I(Na)) in Xenopus laevis oocytes expressing wild-type rat brain Na(V)1.2 alpha and beta1 subunits, or mutants in the channel entrance, the pore region, the lidocaine/tetrodotoxin (TTX) binding sites, the S4 voltage sensor segments of domains I to IV, and the Ile-Phe-Met inactivation cluster. In oocytes expressing wild-type Na(+) channels, Rg(3) induced tonic and use-dependent inhibitions of peak I(Na). The Rg(3)-induced tonic inhibition of I(Na) was voltage-dependent, dose-dependent, and reversible, with an IC(50) value of 32 +/- 6 microM. Rg(3) treatment produced a 11.2 +/- 3.5 mV depolarizing shift in the activation voltage but did not alter the steady-state inactivation voltage. Mutations in the channel entrance, pore region, lidocaine/TTX binding sites, or voltage sensor segments did not affect Rg(3)-induced tonic blockade of peak I(Na). However, Rg(3) treatment inhibited the peak and plateau I(Na) in the IFMQ3 mutant, indicating that Rg(3) inhibits both the resting and open states of Na(+) channel. Neutralization of the positive charge at position 859 of voltage sensor segment domain II abolished the Rg(3)-induced activation voltage shift and use-dependent inhibition. These results reveal that Rg(3) is a novel Na(+) channel inhibitor capable of acting on the resting and open states of Na(+) channel via interactions with the S4 voltage-sensor segment of domain II.
authors: Research Laboratory for the Study of Ginseng Signal Transduction, Dept. of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Korea.
authors: Jun-Ho
authors: JH
authors: Lee
authors: Sang Min
authors: SM
authors: Jeong
authors: Jong-Hoon
authors: JH
authors: Kim
authors: Byung-Hwan
authors: BH
authors: Lee
authors: In-Soo
authors: IS
authors: Yoon
authors: Joon-Hee
authors: JH
authors: Lee
authors: Sun-Hye
authors: SH
authors: Choi
authors: Dong-Hyun
authors: DH
authors: Kim
authors: Hyewhon
authors: H
authors: Rhim
authors: Sung Soo
authors: SS
authors: Kim
authors: Jai-Il
authors: JI
authors: Kim
authors: Choon-Gon
authors: CG
authors: Jang
authors: Jin-Ho
authors: JH
authors: Song
authors: Seung-Yeol
authors: SY
authors: Nah
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018076:DNA, Complementary; D036145:Ginsenosides / Q000494:pharmacology*; D008012:Lidocaine / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D015222:Sodium Channels / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D018076:DNA, Complementary; D036145:Ginsenosides; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568253:Scn2A protein, rat; D015222:Sodium Channels; C097367:ginsenoside Rg3; D008012:Lidocaine