Ginsenoside Rg3 activates human KCNQ1 K+ channel currents through interacting with the K318 and V319 residues: a role of KCNE1 subunit
- Ginsenoside Rg3 activates human KCNQ1 K+ channel currents through interacting with the K318 and V319 residues: a role of KCNE1 subunit
- 최선혜; 신태준; 이병환; 추대현; 조한; 표미경; 황성희; 김보라; 이상목; 이준호; 김동현; 김형춘; 임혜원; 나승열
- Ginseng; Ginsenoside; KCNQ channel; Interaction site; Heart
- Issue Date
- European journal of pharmacology
- VOL 637, NO 1-3, 138-147
- The slowly activating delayed rectifier K+ channels (IKs) are one of the main pharmacological targets for
development of drugs against cardiovascular diseases. Cardiac IKs consists of KCNQ1 plus KCNE1 subunits.
Ginsenoside, one of the active ingredient of Panax ginseng, enhances cardiac IKs currents. However, little is
known about the molecular mechanisms of how ginsenoside interacts with channel proteins to enhance
cardiac IKs. In the present study, we investigated ginsenoside Rg3 (Rg3) effects on human IKs by co-expressing
human KCNQ1 plus KCNE1 subunits in Xenopus oocytes. Rg3 enhanced IKs currents in concentration- and
voltage-dependent manners. The EC50 was 15.2±8.7 μM. However, in oocytes expressing KCNQ1 alone, Rg3
inhibited the currents with concentration- and voltage-dependent manners. The IC50 was 4.8±0.6 μM. Since
Rg3 acts opposite ways in oocytes expressing KCNQ1 alone or KCNQ1 plus KCNE1 subunits, we examined Rg3
effects after co-expression of different ratios of KCNE1 and KCNQ1. The increase of KCNE1/KCNQ1 ratio
converted IKs inhibition to IKs activations. One to ten ratio of KCNE1 and KCNQ1 subunit is required for Rg3
activation of IKs. Mutations of K318 and V319 into K318Y and V319Y of KCNQ1 channel abolished Rg3 effects
on KCNQ1 or KCNQ1 plus KCNE1 channel currents. The docked modeling revealed that K318 residue plays a
key role in stabilization between Rg3 and KCNQ1 plus KCNE1 or KCNQ1 subunit. These results indicate that
Rg3-induced activation of IKs requires co-assembly of KCNQ1 and KCNE1 subunits and achieves this through
interaction with residues K318 and V319 of KCNQ1 subunit.
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