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Ginsenoside Rg₃ Inhibits Human Kv1.4 Channel Currents by Interacting with the Lys531 Residue

Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine (J.-H.L., B.-H.L., S.-H.C., I.-S.Y., M.K.P., T.-J.S., W.-S.C., S.-Y.N.) and Bio/Molecular Informatics Center (Y.-H.L), Konkuk University, Seoul, Korea; Life Science Division, Korea Institute of Science and Technology, Seoul, Korea (H.R.); Department of Physiology and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Seoul, Korea (K.H.W., Y.W.L., H.C.); College of Pharmacy, Kyung Hee University, Seoul, Korea (D.-H.K); and Department of Physiology, Korea University College of Medicine, Seoul, Korea (Y.I.K.)

We have demonstrated previously that the 20(S) but not the 20(R) form of ginsenoside Rg₃ inhibited K⁺ currents flowing through Kv1.4 (hKv1.4) channels expressed in Xenopus laevis oocytes, pointing to the presence of specific interaction site(s) for Rg₃ in the hKv1.4 channel. In the current study, we sought to identify this site(s). To this end, we first assessed how point mutations of various amino acid residues of the hKv1.4 channel affected inhibition by 20(S)-ginsenoside Rg₃ (Rg₃). Lys531 residue is known to be a key site for K⁺ activation and to be part of the extracellular tetraethylammonium (TEA) binding site; the mutation K531Y abolished the Rg₃ effect and made the Kv1.4 channel sensitive to TEA applied to the extracellular side of the membrane. Mutations of many other residues, including the pH sensitive-site (H507Q), were without any significant effect. We next examined whether K⁺ and TEA could alter the effect of Rg₃ and vice versa. We found that 1) raising [K⁺]_o reduced the inhibitory effect of Rg₃ on hKv1.4 channel currents, whereas Rg₃ shifted the K⁺ activation curve to the right, and 2) TEA caused a rightward shift of the Rg₃ concentration-response curve of wild-type hKv1.4 channel currents, whereas Rg₃ caused a rightward shift of the TEA concentration-response curve of K531Y mutant channel currents. The docked modeling revealed that Lys531 plays a key role in forming hydrogen bonds between Rg₃ and hKv1.4 channels. These results indicate that Rg₃ inhibits the hKv1.4 channel current by interacting with residue Lys531.

Address correspondence to: Prof. Seung-Yeol Nah, Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 143-701 Korea. E-mail: synah{at}konkuk.ac.kr