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Research Papers
Mutational Analysis of Block and Facilitation of HERG Current by A Class III Anti-Arrhythmic Agent, Nifekalant
Yukio Hosaka, Miki Iwata, Narutoshi Kamiya, Mitsuhiko Yamada, Kengo Kinoshita, Yoshifumi Fukunishi, Kenji Tsujimae, Hiroshi Hibino, Yoshihusa Aizawa, Atsushi Inanobe, Haruki Nakamura and Yoshihisa Kurachi
volume 1 | issue 3
May/June 2007Pages: 198 - 208
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Chemicals and toxins are useful tools to elucidate the structure-function relationship of various proteins including ion channels. The HERG channel is blocked by many compounds and this may cause life-threatening cardiac arrhythmia. Besides block, some chemicals such as the class III anti-arrhythmic agent nifekalant stimulate HERG at low potentials by shifting its activation curve towards hyperpolarizing voltages. This is called "facilitation". Here, we report mutations and simulations analyzing the association between nifekalant and channel pore residues for block and facilitation. Alanine-scanning mutagenesis was performed in the pore region of HERG. The mutations at the base of the pore helix (T623A), the selectivity filter (V625A) and the S6 helix (G648A, Y652A and F656A) abolished and S624A attenuated both block and facilitation induced by the drug. On the other hand, the mutation of other residues caused either an increase or a decrease in nifekalant-induced facilitation without affecting block. An open-state homology model of the HERG pore suggested that T623, S624, Y652 and F656 faced the central cavity, and were positioned within geometrical range for the drug to be able to interact with all of them at the same time. Of these, S649 was the only polar residue located within possible interaction distance from the drug held in its blocking position. Further mutations and flexible-docking simulations suggest that the size, but not the polarity, of the side chain at S649 is critical for drug induced facilitation.
Authors
Yukio Hosaka
Osaka University; Osaka, Japan
Miki Iwata
Osaka University; Osaka, Japan
Narutoshi Kamiya
Kobe University; Kobe, Japan
Mitsuhiko Yamada
Osaka University; Osaka, Japan
Kengo Kinoshita
Solution Oriented Research for Science and Technology; Tokyo, Japan
Yoshifumi Fukunishi
National Institute of Advanced Industrial Science and Technology; Tokyo, Japan
Kenji Tsujimae
University of Osaka; Osaka, Japan
Hiroshi Hibino
University of Osaka; Osaka, Japan
Yoshihusa Aizawa
Niigata University; Niigata, Japan
Atsushi Inanobe
Osaka University; Osaka, Japan
Haruki Nakamura
Osaka University; Osaka, Japan
Yoshihisa Kurachi
Osaka University Graduate School of Medicine
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.