Mutations of Arginine 222 in Pre-transmembrane Domain I of Mouse 5-HT_<3A> Receptor Abolish 20(R)- But Not 20(S)-Ginsenoside Rg_3 Inhibition of 5-HT-Mediated Ion Currents(Pharmacology)

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Ginsenosides, active ingredients of Panax ginseng, exist as stereoisomers depending on the position of the hydroxyl group on carbon-20; i.e. 20(R)-ginsenoside and 20(S)-ginsenoside are epimers. We previously investigated the structure-activity relationship of the ginsenoside Rg_3 stereoisomers, 20-R-protopanaxatriol-3-[O-β-D-glucopyranosyl (1→2)-β-glucopyranoside], (20(R)-Rg_3) and 20-S-protopanaxatriol-3-[O-β-D-glucopyranosyl (1→2)-β-glucopyranoside], (20(S)-Rg_3) in regulating 5-HT_<3A> receptor-mediated ion currents (I_<5_HT>) expressed in Xenopus oocytes and found that 20(S)-Rg_3 rather than 20(R)-Rg_3 was more stronger inhibitor of I_<5_HT>. In the present study, we further investigated the effects of 20(R)-Rg_3 and 20(S)-Rg_3 on mouse 5-HT_<3A> receptor channel activity after site-directed mutations of 5-HT3A receptor facilitation site, which is located at pre-transmembrane domain I (pre-TM1). 5-HT_<3A> receptor was expressed in Xenopus oocytes, and I_<5_HT> was measured using two-electrode voltage clamp technique. In wild-type, both 20(R)-Rg_3 and 20(S)-Rg_3 inhibited I_<5_HT> with concentration-dependent and reversible manner. Induction of 5-HT_<3A> receptor facilitation by point mutations of pre-TM1 amino acid residue R222 to R222A, R222D, R222E or R222T not only decreased EC_<50> values for I_<5_HT> compared to wild-type but also abolished 20(R)-Rg_3-induced inhibition of I_<5_HT>. Those mutations also shifted the IC_<50> values by 20(S)-Rg_3 into right direction by 2- to 4-folds compared with wild-type. These results indicate that 5-HT_<3A> receptor facilitation differentially affects 20(R)-Rg_3- and 20(S)-Rg_3-mediated 5-HT_<3A> receptor channel regulation.
社団法人日本薬学会の論文
2007-09-01

Mutations of Arginine 222 in Pre-transmembrane Domain I of Mouse 5-HT_<3A> Receptor Abolish 20(R)- But Not 20(S)-Ginsenoside Rg_3 Inhibition of 5-HT-Mediated Ion Currents(Pharmacology)

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