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Reconstruction of native K^+ channels by use of cloned K^+ channels and its application to the development of antiarrhythmic agents.

Research Project

Project/Area Number 07557170
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field 応用薬理学・医療系薬学
Research InstitutionYamagata University (1996-1997)
Tohoku University (1995)

Principal Investigator

ISHII Kuniaki  Yamagata University, School of Medicine, Associate Professor, 医学部, 助教授 (10184459)

Co-Investigator(Kenkyū-buntansha) NUNOKI Kazuo  Tohoku University, School of Medicine, Lecturer, 医学部, 講師 (10172743)
平 則夫  (文部省)学位授与機構, 教授 (60004553)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 1996: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1995: ¥6,900,000 (Direct Cost: ¥6,900,000)
KeywordsK^+ channel clones / antiarrhythmic drugs / quinidine / MS-551 / verapamil / Herg / サブユニット / 内向き整流
Research Abstract

We had reported that the class III antiarrhythmic drugs had no effects on the currents of cloned K^+ channels (Kv family). Lack of auxiliary subunit (S) which affects the sensitivity of K^+ channel clones to drugs was one of the possibilities. However, recently two (three) K^+ channel genes that are responsible for I_<kr> (Herg) and I_<ks> (KvLQT1+minK) have been identified. Mutation of these genes causes long QT syndrome. Since, I_<kr> is a target for typical class III drugs, we had decided to study Herg channel not Kv channels. Effects of quinidine (class I), MS-551 (class III) and verapamil (class IV) on the currents flowing through Herg channel were investigated using a X enopus oocyte expression system. The three drugs blocked Herg currents in a concentration-dependent manner. The concentration required to reduce tail-current by 50% (IC50) was about 3.2muM for quinidine, 8.8muM for MS-551 and 7.3muM for verapamil at 0 mV.IC50 for quinidine and verapamil did not vary significantly with test potential, while that for MS-551 seemed to be smaller with larger depolarizing test pulse. When MS-551 or verapamil was applied, repetitive pulsing to 0 mV caused a slight cumulative decrease of Herg currents. When quinidine was applied, a cumulative decrease in Herg currents was not evident with repetitive pulsing. Quinidine is known to act as open channel blocker of native K^+ currents. Therefore it might be possible that quinidine blocks open Herg channel very rapidly. Recovery of Herg currents from the block by the drugs were also investigated. After a 10-min washout, Herg currents recovered 80% from the block by MS-551 (30muM), but hardly recovered from the block by verapamil (30muM). Several point mutants were constructed to study the binding sites of the antiarrhythmic drugs. Preliminary results indicate that the sixth transmembrane is probably involved in the binding of the drugs.

Report

(3 results)
  • 1997 Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] S., Kondoh et al.: "A mammalian transient type K^+ channel,rat Kvl.4,has two potential domains that could produce rapid inactivation" J.Biol.Chem.272. 19333-19338 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M., Nagashima et al.: "Unitary current through inward rectifier K^+ channel cloned from rabbit heart - Comparison with the native K^+ channel" J.Mol.Cell.Cardiol.28. 957-965 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] N., Taira et al.: "Molecular and cellular mechanisms of cardiovasular regulation" Springer-Verlag, 11(452) (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Kondoh et al.: "A mammalian transient type K^+ channel, rat Kv 1.4, has two potential domains that could produce rapid inactivation." J.Biol.Chem.vol.272. 19333-19338 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Nagashima et al.: "Unitary current through the inward rectifier K^+ channel cloned from rabbit heart-Comparison with the native K^+ channel." J.Mol.Cell Cardiol.vol.28. 957-965 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T.Taira et al.: "Artificial modulation of potassium channels." Molecular and Cellular Mechanisms of Cardiovascular Regulation. 3-13 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Nagashima: "Umitary current through the in ward rectifier K^+ channel cloned from rabbit heart --Comparison with the native K^+ channel" J.Mol.Cell.Cardial.28. 957-965 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] N.Taira: "Molecular and cellular mechanisms of cardiovascular regulation" Springer-Verlag, 11(452) (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] M. Nagashima et al.: "Unitary current through the inward rectifier potassium channel cloned from rabbit heart-Comparison with the native potassium channel-" J. Mol. Cell. Cardiol.(in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y. Sasaki et al.: "Voltage-dependent K^+ channel(Kv1.5) cloned from rabbit heart and facilitation of inactivation of the delayed rectifier current by rat B subunit" FEBS Lett.372. 20-24 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] H. Murakoshi et al.: "Determination of K_A values by controlled receptor expression in Xenopus oocytes" Br. J. Pharmacol.116. 2062-2066 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] T. Yamagishi et al.: "Antiarrhythmic and bradycardic drugs inhibit currents of cloned K^+ channels, Kv1.2 and Kv1.4" Eur. J. Pharmacol.281. 151-159 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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