RT Journal Article
SR Electronic
T1 Characteristics of Ginsenoside Rg<sub>3</sub>-Mediated Brain Na<sup>+</sup> Current Inhibition
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1114
OP 1126
DO 10.1124/mol.105.015115
VO 68
IS 4
A1 Jun-Ho Lee
A1 Sang Min Jeong
A1 Jong-Hoon Kim
A1 Byung-Hwan Lee
A1 In-Soo Yoon
A1 Joon-Hee Lee
A1 Sun-Hye Choi
A1 Dong-Hyun Kim
A1 Hyewhon Rhim
A1 Sung Soo Kim
A1 Jai-Il Kim
A1 Choon-Gon Jang
A1 Jin-Ho Song
A1 Seung-Yeol Nah
YR 2005
UL http://molpharm.aspetjournals.org/content/68/4/1114.abstract
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.