Molecular Determinants of hERG Channel Block by Terfenadine and Cisapride
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概要
- 論文の詳細を見る
Block of cardiac hERG K+ channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160–3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.
- 2008-11-20
著者
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NIWA Ryoko
Department of Humoral Regulation Division of Regulation of Organ Function Research Institute of Envi
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KAMIYA Kaichiro
Department of Humoral Regulation Division of Regulation of Organ Function Research Institute of Envi
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Niwa Ryoko
名古屋大学環境医学研究所 心・血管
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Niwa R
Department Of Cardiovascular Research Research Institute Of Enviromental Medicine Nagoya University
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Niwa Ryoko
名古屋大学環境医学研究所
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Honjou Haruo
名古屋大学 循環器内科学
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Honjou Haruo
Department Of Humoral Regulation Research Institute Of Environmental Medicine Nagoya University
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Honjo Haruo
名古屋大学環境医学研究所
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Honjo Haruo
Department Of Cardiovascular Research Research Institute Of Environmental Medicine Nagoya University
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Kamiya Kaichiro
静岡済生会総合病院 不整脈科
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Kamiya K
Division Of Cardiovascular Research Reseearch Institute Of Environmental Medicine Nagoya University
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Kamiya Kaichiro
名古屋大学環境医学研究所 循環器学
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Kamiya K
Nagoya Univ. Nagoya Jpn
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Kamiya Kaichiro
Department Of Humoral Regulation The Research Institute Of Environmental Medicine Nagoya University
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Morishima Mikio
Department of Cardiovascular Research, Research Institute of Environmental Medichine, Nagoya Univers
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Honjo Haruo
Department Of Applied Physics Faculty Of Engineering
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Morishima Mikio
Department Of Cardiovascular Research Research Institute Of Enviromental Medicine Nagoya University
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SANGUINETTI Michael
Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute, Univ
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Kamiya Kaichiro
Department Of Cardiovascular Research Research Institute Of Environmental Medicine Nagoya University
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Kamiya Kaichiro
Division Of Circulation And Respiration Research Institute Of Environmental Medicine Nagoya Universi
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Sanguinetti Michael
Department Of Medicine Division Of Cardiology Eccles Institute Of Human Genetics University Of Utah
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Kamiya K
Nagoyauniv. Nagoya Jpn
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Niwa Ryoko
Department Of Cardiovascular Research Research Institute Of Enviromental Medicine Nagoya University
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Sanguinetti Michael
Department Of Physiology And Nora Eccles Harrison Cardiovascular Research & Training Institute U
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本荘 晴朗
Department Of Cardiovascular Research Research Institute Of Environmental Medicine Nagoya University
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Kamiya kaichiro
Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University
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