Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue

Jun Ho Lee, Byung Hwan Lee, Sun Hye Choi, In Soo Yoon, Kyung Pyo Mi, Tae Joon Shin, Woo Sung Choi, Yoongho Lim, Hyewhon Rhim, Hee Won Kwang, Whan Lim Yong, Han Choe, Dong Hyun Kim, Yang In Kim, Seung Yeol Nah

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Abstract

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 (Rg 3). 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 Rg 3 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.

Original languageEnglish
Pages (from-to)619-626
Number of pages8
JournalMolecular Pharmacology
Volume73
Issue number3
DOIs
Publication statusPublished - 2008 Mar 1

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Tetraethylammonium
Ginsenosides
Mutation
Xenopus laevis
Point Mutation
Oocytes
Hydrogen
Binding Sites
ginsenoside Rg3
Amino Acids
Membranes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Lee, J. H., Lee, B. H., Choi, S. H., Yoon, I. S., Mi, K. P., Shin, T. J., ... Nah, S. Y. (2008). Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue. Molecular Pharmacology, 73(3), 619-626. https://doi.org/10.1124/mol.107.040360

Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue. / Lee, Jun Ho; Lee, Byung Hwan; Choi, Sun Hye; Yoon, In Soo; Mi, Kyung Pyo; Shin, Tae Joon; Choi, Woo Sung; Lim, Yoongho; Rhim, Hyewhon; Kwang, Hee Won; Yong, Whan Lim; Choe, Han; Kim, Dong Hyun; Kim, Yang In; Nah, Seung Yeol.

In: Molecular Pharmacology, Vol. 73, No. 3, 01.03.2008, p. 619-626.

Research output: Contribution to journalArticle

Lee, JH, Lee, BH, Choi, SH, Yoon, IS, Mi, KP, Shin, TJ, Choi, WS, Lim, Y, Rhim, H, Kwang, HW, Yong, WL, Choe, H, Kim, DH, Kim, YI & Nah, SY 2008, 'Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue', Molecular Pharmacology, vol. 73, no. 3, pp. 619-626. https://doi.org/10.1124/mol.107.040360
Lee, Jun Ho ; Lee, Byung Hwan ; Choi, Sun Hye ; Yoon, In Soo ; Mi, Kyung Pyo ; Shin, Tae Joon ; Choi, Woo Sung ; Lim, Yoongho ; Rhim, Hyewhon ; Kwang, Hee Won ; Yong, Whan Lim ; Choe, Han ; Kim, Dong Hyun ; Kim, Yang In ; Nah, Seung Yeol. / Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue. In: Molecular Pharmacology. 2008 ; Vol. 73, No. 3. pp. 619-626.
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abstract = "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 (Rg 3). 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 Rg 3 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.",
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AU - Lee, Byung Hwan

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AU - Yoon, In Soo

AU - Mi, Kyung Pyo

AU - Shin, Tae Joon

AU - Choi, Woo Sung

AU - Lim, Yoongho

AU - Rhim, Hyewhon

AU - Kwang, Hee Won

AU - Yong, Whan Lim

AU - Choe, Han

AU - Kim, Dong Hyun

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