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Study of intracellular modulation mechanisms of cardiac ATP-sensitive K^+ channels and their pathophysiological implications.

Research Project

Project/Area Number 07457165
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionTokyo Medical and Dental University

Principal Investigator

HIRAOKA Masayasu  Tokyo Medical & Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (80014281)

Co-Investigator(Kenkyū-buntansha) HIRANO Yuji  Tokyo Medical & Dental University, Medical Research Institute, Assistant Profess, 難治疾患研究所, 助手 (00181181)
SAWANOBORI Tohru  Tokyo Medical & Dental University, Medical Research Institute, Associate Profess, 難治疾患研究所, 助教授 (00014217)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1996: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1995: ¥4,000,000 (Direct Cost: ¥4,000,000)
KeywordsATP-sensitive K^+ channel / rundown of the channel activity / intracellular ATP / ADP / actin cytoskeleton / adenosine / protein kinase C / プロティン・カイネース / ATPk感受性Kチャネル / 細胞内活性化因子 / チャネル活性の失活(rundown) / ATPの加水分解 / 再活性化 / アクチン細胞骨格
Research Abstract

The ATP-sensitive K^+ channels (K_<ATP>) are characterized by a strong inhibition by [ATP]_I but ATP is also necessary for the channels in an operative states. There are numerous factors to modulate the channel functions, which are difficult to attribute to real role for their openings during myocardial ischemia. We previously demonstrated that reactivation of after rundown by MgATP was caused by hydrolysis. Since ATP hydrolysis is also utilized in the process of actin cytoskeletal assembly, we examined the linkage between the K_<ATP> activity and the status of actin polymerization. Application of actin disrupters induced quick rundown. Actin stabilizers restored the channel activity in partially rundown channels, while they were ineffective in complete rundown or fully activated channels. MgATP plus F-actin restored the completely rundown channels. Therefore, the assembly and disassembly of actin cytoskeleton play a modulatory role for K_<ATP> Next, we examined whether or not K_<ATP> … More could be opened in the presence of milimor order of [ATP]_I. Using the trypsin-treated patches which showed least rundown, the presence of ADP plus Mg^<2+>, low pH increased the channel open probability in the presence of 1-2 mM [ATP]_I. From these results, we can conclude that K_<ATP> will be opened during early phase of myocardial ischemia where cellular ATP levels do not drop dramatically. This openings can be achieved with the presence of co-factors such as ADP and low pH,which are associated with ischemia. Another ischemic product, adenosine, is supposed to be an activator of K_<ATP> during myocardial ischemis, but its actual contribution in the whole-cell condition has not been demonstrated. We used a nystatin-perforated method which did not disturb the cellular condition. Using this technique, adenosine was shown to shorten K_<ATP> openings during metabolic inhibition, which was mediated through A2-receptor stimulation. The activation of PKC was also involved the K_<ATP> openings, but adenosine and PKC did not work synergistically as reported by the other groups. The intracellular mechanism between A2-receptor and PKC activation is under the extensive investigation. Less

Report

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

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Hiraoka M,Sawanobori T. et al.: "Mechanism of openings and role of the ATP-sensitive K^+ channelsduring myocardial ischemia/reperfusion." pathophysiology of Heart Failure. 427-437 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Furukawa T,・・・,Hiraoka M. et al.: "Functional linkage of the cardiac ATP-sensitive K^+ channels to actin cytoskeleton." Pflugers Arch.431. 504-512 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ishihara,K,Hiraoka M.et al.: "The tetravalent organic cation spermine causes the gating of the IRK1channel expressed in marine fibroblast cells." J. Physiol.491. 367-382 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M"Sawanobori T,et al.: "Function of cardiac ion channels under normal and pathological conditions." Jpn. Heart J.37. 693-707 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M.: "Pathological functions of the ATP-sensitive K^+ channels in myocardial ischemia" Jpn. Heart J.38,(in press). (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M.,Furukawa T.: "Functional modulation of the cardiac ATP-sensitive K^+ channels." News in Physiological Science(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M,Furukawa T,et al.: "Molecular and Cellular Mechanisms of Cardiovascular Regulation" Regulation of rundown and reactivation of cardiac ATP-sensitive K^+ channels., 83-91 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 平岡 昌和: "細胞膜イオン電流-特にK電流を中心に。頻拍症" 西村書店, 51-66 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 平岡,昌和: "Kチャネルの機能と構造-最近の話題" 呼吸と循環, 113-120 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M,Sawanobori T,Adaniya H,Furukawa T: "Mechanism of openings and role of the ATP-sensitive K^+ channels during myocardial ischemia/reperfusion." Pathophysiology of Heart Failure. 427-437 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Furukawa T,Yamane T,Terai T,Katayama Y,Hiraoka M: "Functional linkage of the cardiac ATP-sensitive K^+ channels to actin cytoskeleton." Pflugers Arch. 431. 504-512 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ishihara K,Hiraoka M,Ochi R: "The tetravalent organic cation spermine causes the gating of the IRK1 channel expressed in marine fibroblast cells." J.Physiol.491. 367-382 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M,Sawanobori T,Kawano S,Hirano Y,Furukawa T: "Function of cardiac ion channels under normal and pathological conditions." Jpn Heart J.37. 693-707 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M,Furukawa T: "ATP-sensitive K^+ channels." News in Physiological Science. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M: "Pathological functions of the ATP-sensitive K^+ channels in myocardial ischemia." Jpn.Heart J.38 (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M,Furukawa T,Sawanobori T,Yamane T: "Regulation of rundown and reactivation of cardiac ATP-sensitive K^+ channels." Molecular and Cellular Mechanisms of Cardiovascular Regulation. Springer Verlag. 83-91 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiraoka M,Sawanobori T.etal.: "Mechanism of openings and role of the ATP-sensitive K^+ channels during myocardial ischemia/reperfusion." Pathophysiology of Heart Failure. 427-437 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Furukawa T,...Hiraoka H.et al.: "Functional linkage of the cardiac ATP-sensitive K^+ channels to actin cytoskeleton." Pflugers Arch.431. 504-512 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ishihara,K,Hiraoka M.et al.: "The tetravalent organic cation spermine causes the gating of the IRK1 channel expressed in marine fibroblast cells." J.Physiol.491. 367-382 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiraoka M.,Sawanobori T.et al.: "Function of cardiac ion channels under normal and pathological conditions." Jpn.Heart J.37. 693-707 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiraoka M.: "Pathological functions of the ATP-sensitive K^+ channels in myocardial ischemia" Jpn.Heart J.38(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiraoka M.,Furukawa T.: "Functional modulation of the cardiac ATP-sensitive K^+ channels." News in Physiological Science. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiraoka M,Furukawa T,et al.: "Molecular and Cellular Mechanisms of Cardiovascular Regulation" Regulation of rundown and reactivation of cardiac ATP-sensitive K^+ channels., 83-91 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平岡昌和: "細胞膜イオン電流-特にK電流を中心に。頻拍症" 西村書店, 51-66 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 平岡昌和: "Kチャネルの機能と構造-最近の話題" 呼吸と循環, 113-120 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sawanobori T,Hiraoka M.et al.: "Role of ATP-sensitive K^+ channel in the development of A-V block during hypoxia." J.Mol.Cell.Cardiol.27. 647-657 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yamane T,Furukawa T.& Hiraoka M.: "Characterization of 4-aminopyridine block of the noninactivating cloned K^+ channel,K_V1.5,expressed in Xenopus oocytes." Am.J.Physiol.269. H556-H564 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Furukawa T,Yamane T,Hiraoka M,et al.: "Negative charges that share important elements of function in cloned cardiac K^+ channel (K_V1.5)." Heart Vessels. Supp 9. 14-16 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 平岡昌和,沢登徹,他: "虚血病態におけるATP感受性K^+チャネル開口の役割" Jpn.Circ.J.Suppl.4. 1225-1231 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 山根禎一,古川哲史,平岡昌和: "電位依存性K^+チャネルクローンと固有のKチャネルとの機能相関" 心電図. 15. 114-123 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 山根禎一,古川哲史,平岡昌和: "膜電位依存性カリウムチャネル" 蛋白質・核酸・酵素. 40. 2280-2287 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hiraoka M.: "Recent Progress in Electropharmacology of the Heart,ed.by J.Toyama,M.Hiraoka,I.Kodama" CRC Press, 97-105 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hiraoka M,Furukawa T.et al.: "Potassium Channels in Normal and Pathological Conditions,ed.by J.Verooche,P.P.van Bogart & F.Verdonck." Leaven University Press, 103-107 (1995)

    • Related Report
      1995 Annual Research Report

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

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