2001 Fiscal Year Final Research Report Summary
Polymorphism of cardiac K^+ channel gene and hyperactivity of drugs
| Project/Area Number |
12670656
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Nagoya University |
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Principal Investigator |
KAMIYA Kaichiro Nagoya University, Research Institute of Environmental Medicine, Professor, 環境医学研究所, 教授 (50194973)
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| Co-Investigator(Kenkyū-buntansha) |
KODAMA Itsuo Nagoya University, Research Institute of Environmental Medicine, Professor, 環境医学研究所, 教授 (30124720)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Long QT syndrome / Arrhythmias / K+channel / Sudden Cardiac Death / genes |
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| Research Abstract |
Acquired long QT syndrome is most caused by block of cardiac HERG K^+ channels by commonly used medications. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. To determine the structural basis for high-affinity drug block of HERG channels, determined the important residues for drug binding of class III antiarrhythmic agents ; vesnarinone (cardiotonic agent), E-403 1 and dofetilide(a methanesulfonanilide antiarrhythmic drug), MS55 1 (a non-methanesulfonanilide antiarrhythmic drug) and bepridil (multi-channel blocker). We mutated to alanine individual residues of S6 (L646-Y667) and the few residues of the pore helix (L622-V625) predicted to line the channel cavity and inner pore regions based on homology with the solved crystal structure of the KcsA channel (Doyle et al., 1998). Vesnarinone bound to six specific residues within the channel cavity. This result was published in Molecular Pharmacology (Kamiya et al., 2001). In addition, acute application of amiodarone, an antiarrhythmic agent, was found to inhibit HERG current, whereas long-term treatment of amiodarone decreased Iks (Kamiya et al. Circulation 001). Dofetilide caused less block in six channels with Ala missense mutations located in the pore helix (T623A, S624A and V625A) and the S6 domain (G648A, F656A and V659A). These six residues are identical to those reported on MK-499. In addition to these mutants, MS-551 caused less block on 1655A. Bepridil did not block any of S6 mutants except F656A. These results suggest that 1) methanesulfonanilide drugs have common and identical binding sites, 2) class III drugs binds to different residues of HERG channels, hereby producing different pharmacological effects.
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Research Products
(9 results)
