Ginsenoside Rg3 activates human KCNQ1 K+ channel currents through interacting with the K318 and V319 residues: a role of KCNE1 subunit.
The slowly activating delayed rectifier K(+) channels (I(Ks)) are one of the main pharmacological targets for development of drugs against cardiovascular diseases. Cardiac I(Ks) consists of KCNQ1 plus KCNE1 subunits. Ginsenoside, one of the active ingredient of Panax ginseng, enhances cardiac I(Ks) currents. However, little is known about the molecular mechanisms of how ginsenoside interacts with channel proteins to enhance cardiac I(Ks). In the present study, we investigated ginsenoside Rg(3) (Rg(3)) effects on human I(Ks) by co-expressing human KCNQ1 plus KCNE1 subunits in Xenopus oocytes. Rg(3) enhanced I(Ks) currents in concentration- and voltage-dependent manners. The EC(50) was 15.2+/-8.7 microM. However, in oocytes expressing KCNQ1 alone, Rg(3) inhibited the currents with concentration- and voltage-dependent manners. The IC(50) was 4.8+/-0.6 microM. Since Rg(3) acts opposite ways in oocytes expressing KCNQ1 alone or KCNQ1 plus KCNE1 subunits, we examined Rg(3) effects after co-expression of different ratios of KCNE1 and KCNQ1. The increase of KCNE1/KCNQ1 ratio converted I(Ks) inhibition to I(Ks) activations. One to ten ratio of KCNE1 and KCNQ1 subunit is required for Rg(3) activation of I(Ks). Mutations of K318 and V319 into K318Y and V319Y of KCNQ1 channel abolished Rg(3) effects on KCNQ1 or KCNQ1 plus KCNE1 channel currents. The docked modeling revealed that K318 residue plays a key role in stabilization between Rg(3) and KCNQ1 plus KCNE1 or KCNQ1 subunit. These results indicate that Rg(3)-induced activation of I(Ks) requires co-assembly of KCNQ1 and KCNE1 subunits and achieves this through interaction with residues K318 and V319 of KCNQ1 subunit.
Choi
Sun-Hye
SH
Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea.
Shin
Tae-Joon
TJ
Lee
Byung-Hwan
BH
Chu
Dae-hyun
DH
Choe
Han
H
Pyo
Mi-Kyung
MK
Hwang
Sung-Hee
SH
Kim
Bo-Ra
BR
Lee
Sang-Mok
SM
Lee
Jun-Ho
JH
Kim
Dong-Hyun
DH
Kim
Hyoung-Chun
HC
Rhim
Hye-whon
HW
Nah
Seung-Yeol
SY
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D004305:Dose-Response Relationship, Drug; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051657:KCNQ1 Potassium Channel / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D005894:Panax / Q000737:chemistry; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014633:Valine / Q000378:metabolism; D014982:Xenopus laevis
D036145:Ginsenosides; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; C097367:ginsenoside Rg3; D014633:Valine; D008239:Lysine