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First published on October 24, 2007; DOI: 10.1124/mol.107.040360

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Received for publication July 26, 2007.
Revised October 22, 2007.
Accepted for publication October 23, 2007.

Ginsenoside Rg3 Inhibits Human Kv1.4 Channel Currents by Interacting with the K531 Residue

Jun-Ho Lee 1, Byung-Hwan Lee 2, Sun-Hye Choi 2, In-Soo Yoon 2, Mi Kyung Pyo 2, Tea-Joon Shin 3, Woo-Sung Choi 2, Yoong-Ho Lim 2, Hyewhom Rhim 4, Kwang Hee Won 5, Young Whan Lim 5, Han Choe 5, Dong-Hyun Kim 6, Yang In Kim 7, Seung-Yeol Nah 8*

1 Bio/Molecular Informatics Center and College of Veterinary Medicine, Konkuk University, Seoul Korea 2 College of Veterinary Medicine, Konkuk University, Seoul Korea 3 College of College of Veterinary Medicine, Konkuk UniversityMedicine, Konkuk University, Seoul Korea 4 Life Science Division, KIST, Seoul Korea 5 University of Ulsan College of Medicine, Seoul, Korea 6 College of Pharmacy Kyung Hee University, 130-701, Korea 7 Department of Physiology, Korea University College of Medicine, Seoul 8 Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul Korea

* Address correspondence to: E-mail: synah{at}konkuk.ac.kr

Abstract

Recently we demonstrated 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 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). Mutation to K531Y of the K531 residue, which is known to be a key site for K+ activation and to be part of the extracellular tetraethylammonium (TEA) binding site, 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 (H507 to 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+]0 reduced the inhibitory effect of Rg3 on hKv1.4 channel currents, while 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 K531 residue 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 K531.


Key words: Ion channel regulation, Potassium, Mutagenesis/Chimeric approaches, Receptor-mediated




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