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Establishment of molecular targeting therapy for duonic heart failure bystabilizmgryanodine receptor

Research Project

Project/Area Number 18390234
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionYamaguchi University

Principal Investigator

YANO Masafumi  Yamaguchi University, Hospital, Associate Professor (90294628)

Co-Investigator(Kenkyū-buntansha) YAMAMOTO Takeshi  Yamaguchi University, Graduate School of Medicine, Assistant Professor (50363122)
IKEDA Yasuhiro  Yamaguchi University, School of Medicine, Associate Professor (00260349)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥15,570,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2007: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2006: ¥10,500,000 (Direct Cost: ¥10,500,000)
Keywordssarcoplasmic reticulum / scalcium / rvanodine receptor / heart failure / lethal arrhythmia / point mutation
Research Abstract

Two domains within the ryanodine receptor (RyR2) of sarcoplasmic reticulum (SR) {N-terminal (0-600) and central (2000-2500) domains} was found to interact with each other as a regulatory switch for channel gating. We previously reported that K201 (JTV519) inhibits Ca^<2+> leak by correcting the defective inter-domain interaction between the two domains in failing hearts. Here, we identified the K201-binding domain and diaracterizedtherole ofthis novel domain on RyR2 channel gating.
An assay using a quartz-crystal microbalance revealed that K201 specifically bound to recornbinant RyR2 fragment: 1741. 2270 in the 1-2750 region. By further analysis of the fragnent1741-2270, 201 was found to specifically bind to its sub-fragment2114-2149. Using the peptide matching this sub-fragment (DP2114-2149)as a carrier, the RyR2 was specifically labeled with methylcoumarin acetate(MCA). Moreover, of several recombinant RyR2 fragments, only fragment 2234-2750 was specifically MCA-labeled; this suggests that the K201 binding domain2114-2149 binds with domain 2234-2750. Addition of DP2114-2149 to the MCA-labeled SR interfered with the interaction between domain2114-2149 and domain2234-2750 causing domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. In failing cardiomyocytes, the frequency of spontaneous Ca^<2+> spark (CaSF) was much higher than normal cardiomyocytes (p<0.01), whereas incorporation of DP2114-2149 markedly decreased CaSF to normal level; the same effect as that produced by K201.
In conclusion, we first identified the K201-binding site as domain2114-2149 of RyR2 Interruption of the inter-domain interaction between the domain2114-2149 and central domain2234-2750 seems to mediate stabilization of RyR2 in failing hearts, which may lead to a novel therapeutic strategy against heart failure and perhaps lethal arrhythmia.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (13 results)

All 2008 2007 2006

All Journal Article (10 results) (of which Peer Reviewed: 6 results) Presentation (3 results)

  • [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts2008

    • Author(s)
      Takeshi Yamamoto
    • Journal Title

      Circulation 117

      Pages: 762-72

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Ryanodine receptor as a new therapeutic target of heart failure and lethal arrhythmia.2008

    • Author(s)
      Masafumi Yano
    • Journal Title

      Circulation Journal 72

      Pages: 509-14

    • NAID

      110006656889

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Ryanodine receptor as a new therapeutic target of heart failure and lethal arrhythmia2008

    • Author(s)
      Yano, M
    • Journal Title

      Circ J 72(4)

      Pages: 509-14

    • NAID

      110006656889

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts2008

    • Author(s)
      Yamamoto, T, Yano, M, Xu, X, Uchinoumi, H, Tateishi, H, Mochizuki, M, Oda, T, Kobayashi, S, Ikemoto, N, Matsuzaki, M
    • Journal Title

      Circulation 117(6)

      Pages: 762-72

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Identification of target domains of the cardiac ryanodine receptor tocorrect channel disorder in failing hearts2008

    • Author(s)
      Takeshi Yamamoto
    • Journal Title

      Circulation 117

      Pages: 762-72

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ryanodine receptor as a new therapeutic target of heart failure and lethalarrhythmia2008

    • Author(s)
      Masafumi Yano
    • Journal Title

      Circulation Journal 72

      Pages: 509-514

    • NAID

      110006656889

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure.2007

    • Author(s)
      Mamoru Mochizuki
    • Journal Title

      Journal of American College of Cardiology. 49

      Pages: 1722-1732

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary 2006 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 「研究成果報告書概要(欧文)」より2007

    • Author(s)
      Mochizuki, M, Yano, M, Oda, T, Tateishi, H, Kobayashi, S, Yamamoto, T, Ikeda, Y, Ohkusa, T, Ikemoto, N, Matsuzaki, M
    • Journal Title

      JAm Coll Cardiol 49(16)

      Pages: 1722-32

    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] ATI receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+ -leak induced by oxidative stress.2006

    • Author(s)
      Takahiro Tokuhisa
    • Journal Title

      Circulation Journal 70

      Pages: 777-786

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] ATI receptor antagonist restores cardiac ryanodine receptor function, rendering isoproterenol-induced failing heart less susceptible to Ca2+-leak induced by oxidative stress.2006

    • Author(s)
      Takahiro Tokuhisa
    • Journal Title

      Circulation Journal 70

      Pages: 777-786

    • Related Report
      2006 Annual Research Report
  • [Presentation] Identification of therapeutic domain within the cardiac ryanodine receptor to correct abnormal Ca2+ release in failing hearts2008

    • Author(s)
      Masafumi Yano
    • Organizer
      The 72st Annual Scientific Meeting of the Japanese Circulation Society:Plenary Session 5
    • Place of Presentation
      Fukuoka, Japan
    • Year and Date
      2008-03-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Ryanodine Receptor as a new therapeutic target of heart failure and lethal arrhythmia2007

    • Author(s)
      Masafumi Yano
    • Organizer
      The 71st Annual Scientific Meeting of the Japanese Circulation Society:Japan Heart Foundation Satoh Memorial Award Lectore
    • Place of Presentation
      Kobe, Japan
    • Year and Date
      2007-03-16
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Role of ryanodine receptor in heart failure2007

    • Author(s)
      Masafumi Yano
    • Organizer
      The 71st Annual Scientific Meeting of the Japanese Circulation Society: AHA-JCS joint Symposium
    • Place of Presentation
      Kobe, Japan
    • Year and Date
      2007-03-15
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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