Characteristics of ginsenoside Rg(3)-mediated brain Na+ current inhibition
- Authors
- Lee, Jun-Ho; Jeong, Sang Min; Kim, Jong-Hoon; Lee, Byung-Hwan; Yoon, In-Soo; Lee, Joon-Hee; Choi, Sun-Hye; Kim, Dong-Hyun; Rhim, Hyewhon; Kim, Sung Soo; Kim, Jai-Il; Jang, Choon-Gon; Song, Jin-Ho; Nah, Seung-Yeol
- Issue Date
- Oct-2005
- Publisher
- AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
- Citation
- MOLECULAR PHARMACOLOGY, v.68, no.4, pp 1114 - 1126
- Pages
- 13
- Journal Title
- MOLECULAR PHARMACOLOGY
- Volume
- 68
- Number
- 4
- Start Page
- 1114
- End Page
- 1126
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/24505
- DOI
- 10.1124/mol.105.015115
- ISSN
- 0026-895X
1521-0111
- 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 beta 1 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 IC50 value of 32 +/- 6 mu M. 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.
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