PT  - JOURNAL ARTICLE
AU  - Jun-Ho Lee
AU  - Sang Min Jeong
AU  - Jong-Hoon Kim
AU  - Byung-Hwan Lee
AU  - In-Soo Yoon
AU  - Joon-Hee Lee
AU  - Sun-Hye Choi
AU  - Dong-Hyun Kim
AU  - Hyewhon Rhim
AU  - Sung Soo Kim
AU  - Jai-Il Kim
AU  - Choon-Gon Jang
AU  - Jin-Ho Song
AU  - Seung-Yeol Nah
TI  - Characteristics of Ginsenoside Rg<sub>3</sub>-Mediated Brain Na<sup>+</sup> Current Inhibition
AID  - 10.1124/mol.105.015115
DP  - 2005 Oct 01
TA  - Molecular Pharmacology
PG  - 1114--1126
VI  - 68
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/68/4/1114.short
4100  - http://molpharm.aspetjournals.org/content/68/4/1114.full
SO  - Mol Pharmacol2005 Oct 01; 68
AB  - We demonstrated previously that ginsenoside Rg3 (Rg3), an active ingredient of Panax ginseng, inhibits brain-type Na+ channel activity. In this study, we sought to elucidate the molecular mechanisms underlying Rg3-induced Na+ channel inhibition. We used the two-microelectrode voltage-clamp technique to investigate the effect of Rg3 on Na+ currents (INa) in Xenopus laevis oocytes expressing wild-type rat brain NaV1.2 α and β1 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, Rg3 induced tonic and use-dependent inhibitions of peak INa. The Rg3-induced tonic inhibition of INa was voltage-dependent, dose-dependent, and reversible, with an IC50 value of 32 ± 6 μM. Rg3 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 Rg3-induced tonic blockade of peak INa. However, Rg3 treatment inhibited the peak and plateau INa in the IFMQ3 mutant, indicating that Rg3 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 Rg3-induced activation voltage shift and use-dependent inhibition. These results reveal that Rg3 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.