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Evidence that the tertiary structure of 20(S)-ginsenoside Rg3 with tight hydrophobic packing near the chiral center is important for Na+ channel regulation

2005; Elsevier BV; Volume: 333; Issue: 4 Linguagem: Inglês

10.1016/j.bbrc.2005.06.026

1090-2104

Dongil Kang, Jee‐Young Lee, Ji‐Young Yang, Sang Min Jeong, Jun‐Ho Lee, Seung‐Yeol Nah, Yangmee Kim,

Pharmacological Effects of Natural Compounds

Ginsenosides are the active ingredients of Panax ginseng. Ginsenoside Rg3 exists as two stereoisomers of carbon-20: 20-S-protopanaxatriol-3-[O-β-d-glucopyranosyl (1 → 2)-β-glucopyranoside] (20(S)-Rg3) and 20-R-protopanaxatriol-3-[O-β-d-glucopyranosyl (1 → 2)-β-glucopyranoside] (20(R)-Rg3). Recently, we reported that 20(S)-Rg3 regulates voltage-dependent Ca2+ channel activity and several types of ligand-gated ion channels, whereas 20(R)-Rg3 does not have this activity. In this study, we investigated the structure–activity relationship of these two stereoisomers by NMR spectroscopy and by measurement of the current in Xenopus oocytes expressing the mouse cardiac voltage-dependent Na+ channel (Nav1.5). We found that 20(S)-Rg3 but not 20(R)-Rg3 inhibited Na+ channel current in a dose- and voltage-dependent manner. The difference between Rg3 epimers in voltage-dependent ion channel regulation indicates that the structure of 20(S)-Rg3 may be geometrically better aligned than that of 20(R)-Rg3 for interaction with receptor regions in Na+ channels. The 1H and 13C NMR chemical shifts, including all hydroxyl protons of 20(S)-Rg3 and 20(R)-Rg3, were completely assigned, and their tertiary structures were determined. 20(S)-Rg3 has more tight hydrophobic packing near the chiral center than 20(R)-Rg3. Tertiary structures and activities of 20(S)-Rg3 and 20(R)-Rg3 indicate that 20(S)-Rg3 may have stronger interactions with the receptor region in ion channels than 20(R)-Rg3. This may result in different stereoselectivity of Rg3 stereoisomers in the regulation of voltage-dependent Na+ channel activity. This is the first structural approach to ginsenoside action on ion channel.