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循環器疾患におけるイオンチャネル病に関する研究

Research Project

Project/Area Number07F07209
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field Circulatory organs internal medicine
Research InstitutionShiga University of Medical Science
Host Researcher 堀江 稔  Shiga University of Medical Science, 医学部, 教授
Foreign Research Fellow ZANKOV Dimitar Petrov  滋賀医科大学, 医学部, 外国人特別研究員
ZANKOV D. P.  
ZANKOV DimitarPetrov  滋賀医科大学, 医学部, 外国人特別研究員
Project Period (FY) 2007 – 2008
Project Status Completed(Fiscal Year 2008)
Budget Amount *help
¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 2008 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Fiscal Year 2007 : ¥1,100,000 (Direct Cost : ¥1,100,000)
KeywordsI_<Kr> / KCNH2 / LQT2 / α_1-受容体 / フェニレフリン / PI(4,5)P_2 / 機能喪失型変異 / 心室性不整脈 / I_<kr>
Research Abstract

イオンチャネルの機能変化により、発症する病気には、嚢胞性線維症をはじめ、多くが知られているが、循環器疾患では、1995以降、遺伝性不整脈の多くが、心筋電気活動を決定するイオンチャネルをコードする遺伝子の多様な変異により招来されることが分かってきた。中でも、遺伝性QT延長症候群は、心電図上の著しいQT延長とTorsade de pointesと呼ばれる特異な多形性心室頻拍による失神、さらにまれならず、心室細動による心臓性突然死をおこす重篤な疾患である。現在までに10個以上の責任遺伝子が同定されている。臨床的には、LQT1,2と命名されている膜電位依存性カリウムチャネルのαサブユニットをコードする遺伝子、KCNQ1とKCNH2の変異による場合が最も頻度が高い。研究代表者の堀江らは1996年から、QT延長症候群を含むあらゆる遺伝性不整脈患者から、ゲノムDNAを集積し、2009年3月の時点で、1430名のゲノム(約700家系)を集積した。内、約350家系がQT延長症候群であるが、その約55%の発端者で、遺伝子診断が可能であった。その遺伝型による臨床像の違いが、このような遺伝子検索を通して明らかとなってきた。その一つに、LQT2型と呼ばれるKCNH2遺伝子の変異により招来される病態では、Torsade de pointesの発作が、突然の驚きや電話や目覚まし時計の音など、いわゆるドキットしたときに起こることが判明した。一方、KCNQ1遺伝子の変異で起こるLQT1型では持続的な運動が誘因となることが分かってきた。そこで、研究分担者のZankovらは、これらの病像の違いが、交感神経のレスポンスではあるものの、そのMediatorが異なるためではないかと考え、持続運動時の活性化するβ受容体ではなく、α受容体刺激を介するイオンチャネル、すなわち、LQT2型で障害されるKCNH2遺伝子でおコードされるKv11.1蛋白におけるα受容体刺激作用を検討した。その結果α受容体刺激はGqを介して細胞膜内のPI(4,5)P_2レベルの減少を起こし、これがKv11.1チャネルの機能低下することがわかった。LQT2では、機能喪失型変異により、このチャネル機能がもとより減少しているため、さらなるα刺激の存在により、外向きK電流の低下を起こすことによりTorsade de pointesが発生しやすくなることを証明した。

Report

(2results)
  • 2008 Annual Research Report
  • 2007 Annual Research Report

Research Products

(70results)

All 2009 2008 2007 Other

All Journal Article Presentation Book Remarks

  • [Journal Article] Adrenergic regulation of the rapid component of delayed rectifier K+ current : Implications for arrhythmogenesis in LQT2 patients2009

    • Author(s)
      Zankov DP
    • Journal Title

      Heart Rhythm (掲載確定)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Angiotensin II type 1 receptor mediates partially hyposmotic-induced increase of IKs current in guinea pig atrium2009

    • Author(s)
      Zankov DP
    • Journal Title

      Pflugers Archiv-European Journal of Physiology (掲載確定)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel KCNE3 mutation reduces repolarizing potassium current and associated with long QT syndrome2009

    • Author(s)
      Ohno S
    • Journal Title

      Hum Mutat 30

      Pages : 557-563

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel mutation associated with Jervell and Lange-Nielsen syndrome in a Japanese family2008

    • Author(s)
      Ohno S
    • Journal Title

      Circ J (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overlap Between LQT3 and Brugada Syndrome:Clinical Features in a Common Mutation and Underlying Biophysical Mechanisms2008

    • Author(s)
      Makita N
    • Journal Title

      Journal of Clinical Investigation (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel KCNE3mutations interact with KCNQland cause long QT syndrome2008

    • Author(s)
      Ohno S
    • Journal Title

      Human Mutation (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Age-and genotype-specific triggers for life-threatening arrhythmia in the genotyped long-QT syndrome2008

    • Author(s)
      Sakaguchi T
    • Journal Title

      Journal of Cardiovascular Electrophysiology (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutation site dependent variability of cardiac events in LQT2 form of congenital long-QT syndrome2008

    • Author(s)
      Nagaoka I
    • Journal Title

      Circulation Journal (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel SCN5Again-of-function mutation M1875T associated with familial atrial fibrillation2008

    • Author(s)
      Makiyama T
    • Journal Title

      Journal of American College of Cardiology (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] N-and C-terminal KCNEl mutations cause distinct phenotypes of long QT syndrome2007

    • Author(s)
      Ohno S
    • Journal Title

      Heart Rhythm 4

      Pages : 332-340

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stimulatory action of protein kinase Cvarepsilon isoform on the slow component of delayed rectifier K(+)current in guinea-pig atrial myocytes2007

    • Author(s)
      Toda H
    • Journal Title

      Br J Pharmacol 150

      Pages : 1011-1021

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanistic basis for the pathogenesis of long QT syndrome associated with a common splicing mutation in KCNQ1 gene2007

    • Author(s)
      Tsuji K
    • Journal Title

      J Mol Cell Cardiol 42

      Pages : 662-669

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A paradoxical effect of lidocaine for the N406S mutation of SCN5A associated with Brugada syndrome2007

    • Author(s)
      Itoh H
    • Journal Title

      Int J Cardiol 121

      Pages : 249-252

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Disorders of Cardiac Repolarization-Long QT and Short QT Syndromes2007

    • Author(s)
      Horie M
    • Journal Title

      Circ J 71

      Pages : 50-53

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protective mechanism of adenosine to the rat arterial endothelial dysfunction induced by hydrogen peroxide2007

    • Author(s)
      Lu J
    • Journal Title

      Biol Pharm Bull 30

      Pages : 1206-1211

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Common Long QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients with Different Ethnic Backgrownds:Toward a Mutation-specific Risk Stratification2007

    • Author(s)
      Crotti L
    • Journal Title

      Circulation 116

      Pages : 2366-2375

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with brugada syndrome2007

    • Author(s)
      Takagi M
    • Journal Title

      Journal of cardiovascular electrophysiology 18

      Pages : 1244-1251

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ablation for AF:Techniques,Results and Risks2007

    • Author(s)
      堀江 稔
    • Journal Title

      AHA Highlights2006

      Pages : 174-179

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Brugada症候群と遺伝子病-Brugada症候群とQT延長症候群など他の遺伝子病との関連について-2007

    • Author(s)
      牧山 武
    • Journal Title

      Heart View 11

      Pages : 54-61

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 心房筋細胞におけるAT1受容体を介した緩徐活性型遅延整流性K+電流(IKs)の増大と活動電位の短縮-心房細動治療におけるAT1受容体遮断薬の有効性との関連2007

    • Author(s)
      松浦 博
    • Journal Title

      心電図 27

      Pages : 145-153

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 心臓イオンチャネル遺伝子の転写制御機構〜エピジェネティックスと機能分化2007

    • Author(s)
      鷹野 誠
    • Journal Title

      心電図 27

      Pages : 15-28

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 家族性心房細動を識る2007

    • Author(s)
      堀江 稔
    • Journal Title

      Heart View 11

      Pages : 84-86

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] QT延長症候群(先天性、後天性)2007

    • Author(s)
      坂口 知子
    • Journal Title

      臨床検査 51

      Pages : 764-768

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Jervell and Lange-Nielsen症候群2007

    • Author(s)
      堀江 稔
    • Journal Title

      日本臨床 別冊4

      Pages : 205-208

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Romano-Ward症候群2007

    • Author(s)
      堀江 稔
    • Journal Title

      日本臨床 別冊4

      Pages : 230-233

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 先天性QT延長症候群2007

    • Author(s)
      堀江 稔
    • Journal Title

      Long QT Syndrome

      Pages : 1-6

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RASが電気生理学的特性と線維化に与える影響2007

    • Author(s)
      堀江 稔
    • Journal Title

      心房細動

      Pages : 98-105

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] QT延長症候群2007

    • Author(s)
      伊藤 英樹
    • Journal Title

      QT間隔の診かた・考え方

      Pages : 131-132

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 心房リモデリングの予防と改善は可能か2007

    • Author(s)
      堀江 稔
    • Journal Title

      日本内科学会雑誌 96

      Pages : 109-111

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 薬剤性QT延長症候群2007

    • Author(s)
      堀江 稔
    • Journal Title

      Long QT Syndrome

      Pages : 1-6

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] チャネル病の修飾因子総論2007

    • Author(s)
      伊藤 英樹
    • Journal Title

      心臓 39

      Pages : 576-579

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] Negative Regulation of LQT2-Associated Kv11. 1 Mutant Channels by Alpha(1A)-Adrenoceptors in Mammalian Cell Line2009

    • Author(s)
      Zankov DP
    • Organizer
      Biophysical Society 53rd Annual Meeting
    • Place of Presentation
      Boston, U.S.A.
    • Related Report
      2008 Annual Research Report
  • [Presentation] Mutant KCNE3 Reduces Repolarizing Potassium Current And Causes Long QT Syndrome2008

    • Author(s)
      Ohno S
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Molecular Pathogenesis of Genotyped Drug-Induced Long QT Syndrome2008

    • Author(s)
      Itoh H
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Overlap Between LQT3 and Brugada Syndrome:Clinical Features in a Common Mutation and Underlying Biophysical Mechanisms2008

    • Author(s)
      Makita N
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Brugada Syndrome and Diverse Phenotypes of Cardiac Sodium Channelopathies2008

    • Author(s)
      Makiyama T
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] TA novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation2008

    • Author(s)
      Makiyama T
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Familial Dilated Cardiomyopathy with Conduction Disease Caused by Lamin A/C Mutations:Efficacy of the Cardiac Resynchronization Therapy with a Defibrillator2008

    • Author(s)
      Makiyama T
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Cardiac sodium channel gene mutations are prevalent in Japanese patients with familial sick sinus syndrome2008

    • Author(s)
      Makiyama T
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] A Common KCNEl Polymorphism,D85N,is a Genetic Modifier of Long QT Syndrome2008

    • Author(s)
      Nishio Y
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Mutation Analysis of the Glycerol-3 Phosphate Dehydrogenase-1 Like(GP_D1L)Gene in Japanese Patients with Brugada Syndrome2008

    • Author(s)
      Makiyama T
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Different Response to Exercise Testing between LQT7 Form of Congenital Long QT Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia2008

    • Author(s)
      Yamada Y
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Impact of Frameshift Mutation and Nonsense-mediated mRNA Decay on Clinical Phenotype in LQT2 Form of Congenital Long QT Syndrome2008

    • Author(s)
      Noda T
    • Organizer
      第72回日本循環器学会・学術集会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Involvement of AT1 receptor in swelling-induced regulation of IKS current in guinea pig atrium2008

    • Author(s)
      Zankov DP
    • Organizer
      第25回 国際心臓研究学会(ISHR)日本部会
    • Place of Presentation
      神奈川
    • Year and Date
      2008-12-05
    • Related Report
      2008 Annual Research Report
  • [Presentation] Angiotensin II type l receptor partially mediates stretch-induced potentiation of the slow component of delayed rectifier potassium current in guinea pig atrium2007

    • Author(s)
      Dimitar P Zankov
    • Organizer
      American Heart Association, Scientific Sessions2007
    • Place of Presentation
      Orlando,Florida,USA
    • Related Report
      2007 Annual Research Report
  • [Presentation] Cardiac arrhythmias and ion channel diseases2007

    • Author(s)
      Horie M
    • Organizer
      East Asia International Cardiovascular Symposium
    • Place of Presentation
      Harbin,China
    • Related Report
      2007 Annual Research Report
  • [Presentation] Bradycardia before beta-blocker therapy as an arrhythmic risk in LQT2 form of congenital long-QT syndrome2007

    • Author(s)
      Nagaoka I
    • Organizer
      ESC Congress2007
    • Place of Presentation
      Vienna,Austria
    • Related Report
      2007 Annual Research Report
  • [Presentation] Diagnostic criteria for the long QT syndrome2007

    • Author(s)
      Horie M
    • Organizer
      World Congress on Cardiac Pacing and Electrophysiology
    • Place of Presentation
      Rome,Italy
    • Related Report
      2007 Annual Research Report
  • [Presentation] 心房リモデリングの予防と改善は可能か2007

    • Author(s)
      堀江 稔
    • Organizer
      第104回日本内科学会
    • Place of Presentation
      大阪
    • Related Report
      2007 Annual Research Report
  • [Presentation] KCNQ1遺伝子上の高頻度スプライス変異によるQT延長症候群発症のメカニズム2007

    • Author(s)
      辻 啓子
    • Organizer
      第9回日本RNA学会
    • Place of Presentation
      名古屋
    • Related Report
      2007 Annual Research Report
  • [Presentation] Brugada症候群とLQT3のオーバーラップ:SCN5A変異の臨床的特徴と分子メカニズム2007

    • Author(s)
      蒔田 直昌
    • Organizer
      第55回日本心臓病学会学術集会
    • Place of Presentation
      東京
    • Related Report
      2007 Annual Research Report
  • [Presentation] 心筋Naチャネルの遺伝子異常と薬剤誘発性不整脈2007

    • Author(s)
      蒔田 直昌
    • Organizer
      第24回日本心電学会学術集会
    • Place of Presentation
      愛知
    • Related Report
      2007 Annual Research Report
  • [Presentation] 家族性洞不全症候群の1家系に認めた心臓Naチャネル(SCN5A)遺伝子異常の電気生理学的機能解析2007

    • Author(s)
      牧山 武
    • Organizer
      第24回日本心電学会学術集会
    • Place of Presentation
      愛知
    • Related Report
      2007 Annual Research Report
  • [Presentation] 低浸透圧刺激による心筋緩徐活性型遅延整流性K+電流(IKs)の増大におけるAT1受容体の関与について2007

    • Author(s)
      Dimitar P Zankov
    • Organizer
      第24回日本心電学会学術集会
    • Place of Presentation
      愛知
    • Related Report
      2007 Annual Research Report
  • [Presentation] P2Y-受容体アイソフォームによる心筋GIRK1/G工RK4チャネルの調節2007

    • Author(s)
      丁 維光
    • Organizer
      第24回日本心電学会学術集会
    • Place of Presentation
      愛知
    • Related Report
      2007 Annual Research Report
  • [Presentation] 心房細動の診断と治療を巡る最近の話題2007

    • Author(s)
      堀江 稔
    • Organizer
      The 2nd meet the Expert in Toyohashi
    • Place of Presentation
      愛知
    • Year and Date
      2007-12-15
    • Related Report
      2007 Annual Research Report
  • [Presentation] 心室細動後の心肺蘇生に成功し、遺伝子診断により確定した先天性QT延長症候群(LQT1)の1例2007

    • Author(s)
      松本 真
    • Organizer
      第20回心臓性急死研究会
    • Place of Presentation
      東京
    • Year and Date
      2007-12-15
    • Related Report
      2007 Annual Research Report
  • [Presentation] 薬剤性QT延長症候群の遺伝的背景2007

    • Author(s)
      堀江 稔
    • Organizer
      第28回日本聯床薬理学会年会
    • Place of Presentation
      栃木
    • Year and Date
      2007-11-29
    • Related Report
      2007 Annual Research Report
  • [Presentation] 遺伝子変異が固定された不整脈源性右室心筋症(ARVC)の1剖検例2007

    • Author(s)
      長岡 伊織
    • Organizer
      第64回滋賀県循環器疾患研究会
    • Place of Presentation
      滋賀
    • Year and Date
      2007-11-10
    • Related Report
      2007 Annual Research Report
  • [Presentation] Age-Related Triggers for Life-Threatning Arrhythmia in the Genotyped Long QT Syndrome2007

    • Author(s)
      Sakaguchi T
    • Organizer
      The American Heart Association Scientific Sessions2007
    • Place of Presentation
      U.S.A
    • Year and Date
      2007-11-06
    • Related Report
      2007 Annual Research Report
  • [Presentation] Overlap Between LQT3 and Brugada Syndrome:Clinical Features in a Common Mutation and Underlying Biophysical Mechanisms2007

    • Author(s)
      Makita N
    • Organizer
      The American Heart Association Scientific Sessions2007
    • Place of Presentation
      U.S.A
    • Year and Date
      2007-11-05
    • Related Report
      2007 Annual Research Report
  • [Presentation] Familial Dilated Cardiomyopathy with Conduction Disease Caused by a Lamin A/C Mutation:Efficacy of the Cardiac Resynchronization Therapy with a Defibrillator2007

    • Author(s)
      Makiyama T
    • Organizer
      The American Heart Association Scientific Sessions2007
    • Place of Presentation
      U.S.A
    • Year and Date
      2007-11-05
    • Related Report
      2007 Annual Research Report
  • [Presentation] The same genetics for Brugada syndrome and AF2007

    • Author(s)
      Horie M
    • Organizer
      The 3rd Asia-Pacific Atrial Fibrillation Symposium
    • Place of Presentation
      TAIWAN
    • Year and Date
      2007-10-20
    • Related Report
      2007 Annual Research Report
  • [Presentation] 先天性2型QT延長症候群の不整脈発症リスク評価:遺伝子検索から臨床へ2007

    • Author(s)
      長岡 伊織
    • Organizer
      第12回京滋不整脈研究会
    • Place of Presentation
      京都
    • Year and Date
      2007-10-13
    • Related Report
      2007 Annual Research Report
  • [Presentation] QT延長症候群の遺伝的背景〜先天性と後天性の比較検討2007

    • Author(s)
      伊藤 英樹
    • Organizer
      第27回近畿循環器疾患治療研究会
    • Place of Presentation
      大阪
    • Year and Date
      2007-08-25
    • Related Report
      2007 Annual Research Report
  • [Presentation] QT延長症候群の診断と治療-最近の知見を中心に2007

    • Author(s)
      堀江 稔
    • Organizer
      第27回日本ホルター・ノンインベイシブ心電学研究会
    • Place of Presentation
      大分
    • Year and Date
      2007-07-07
    • Related Report
      2007 Annual Research Report
  • [Book] Annual Review循環器2007

    • Author(s)
      伊藤 英樹
    • Publisher
      中外医学社
    • Related Report
      2007 Annual Research Report
  • [Book] 新心臓病診療プラクチイス2007

    • Author(s)
      蔦本 尚慶
    • Publisher
      文光堂
    • Related Report
      2007 Annual Research Report
  • [Book] 循環器症候群(II)-その他の循環器疾患を含めて2007

    • Author(s)
      松本 鉄也
    • Publisher
      日本臨牀
    • Related Report
      2007 Annual Research Report
  • [Remarks]

    • URL
      http://www.shiga-med.ac.jp/~hqmedl/shiga_image/top.html
    • Related Report
      2008 Annual Research Report

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Published : 2007-04-01   Modified : 2016-04-21  

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