Assessment of role of Kir6.1 subunit (ATP-sensitive K+ channel) in J wave syndrome

• Project/Area Number: 26460334
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Chiba University
• Principal Investigator: NAKAYA Haruaki 千葉大学, 理事 (60113594)
• Research Collaborator: Watanabe Yasuhiro 千葉大学, 医学薬学府 ; Matsumoto Akio 千葉大学, 大学院医学研究院, 准教授 (60437308)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: J波症候群 / 特発性心室細動 / ATP感受性K+チャネル / Kir6.1 / 遺伝子改変動物

Outline of Final Research Achievements

Clinical reports have indicated that the pathogenesis of J wave syndrome, which can lead to sudden cardiac death, partly associates with gain-of-function (GOF) mutation (S422L) of Kir6.1, a pore-forming subunit of ATP-sensitive K+ (KATP) channel. To test the hypothesis, we created Kir6.1 transgenic (TG) mouse strains over-expressing S422L (TGmt) or wild-type (TGWT) in cardiomyocytes and compared the cardiac electrophysiology. Although both TG mouse strains showed abnormal ECG, the density of KATP current was decreased in ventricular cells of TGmt and TGWT mice compared to ventricular cells of wild-type (WT) mice. In addition, the ATP sensitivity of single KATP channel in TGmt and TGWT ventricular cells were similar to that in WT ventricular cells.
Thus, the present study failed to support the hypothesis that the Kir6.1-S422L mutation is a direct cause of J wave syndrome.

Research Products

• [Journal Article] A novel diphenylthiosemicarbazide is a potential insulin secretagogue for anti-diabetic agent (2016)
  • Author(s): Sugawara k, Honda K, Reien Y, Yokoi N, Seki C, Takahashi H, Minami K, Mori I, Matsumoto A, Nakaya H, Seino S
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0164785-e0164785
  • DOI: 10.1371/journal.pone.0164785
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regeneration of the Cardiac Conduction System by Adipose Tissue-Derived Stem Cells (2015)
  • Author(s): Takahashi T, Nagai T, Kanda M, Liu ML, Kondo N, Naito AT, Ogura T, Nakaya H, Lee JK, Komuro I, Kobayashi Y.
  • Journal Title: Circulation Journal Volume: 79 Issue: 12 Pages: 2703-2712
  • DOI: 10.1253/circj.CJ-15-0400
  • NAID: 130005110933
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Experimental assessment of effects of antiproliferative drugs of drug-eluting stents on endothelial cells (2015)
  • Author(s): Miura K, Nakaya H, Kobayashi Y.
  • Journal Title: Cardiovascular Revascularization Medicine Volume: 16 Issue: 6 Pages: 344-347
  • DOI: 10.1016/j.carrev.2015.07.002
  • Peer Reviewed
• [Journal Article] Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters (2015)
  • Author(s): Kurokawa, J., Sasano, T., Kodama, M., Li, M., Ebana, Y., Harada, N., Honda, S.-I., Nakaya, H., & Furukawa, T.
  • Journal Title: J. Toxicol. Sci. Volume: 40 Issue: 3 Pages: 339-348
  • DOI: 10.2131/jts.40.339
  • NAID: 130005068413
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A protective role of Nox1/NADPH oxidase in a mouse model with hypoxia-induced bradycardia. (2015)
  • Author(s): Kojima A, Matsumoto A, Nishida H, Reien Y, Iwata K, Shirayama T, Yabe-N C, Nakaya H.
  • Journal Title: J Pharmacol Sci Volume: 127 Issue: 3 Pages: 370-376
  • DOI: 10.1016/j.jphs.2015.02.007
  • Peer Reviewed / Open Access
• [Journal Article] Termination of Aconitine-Induced Atrial Fibrillation by the K_ACh-Channel Blocker Tertiapin: Underlying Electrophysiological Mechanism (2014)
  • Author(s): Suzuki K, Matsumoto A, Nishida H, Reien Y, Maruyama H, Nakaya H.
  • Journal Title: Journal of Pharmacological Sciences Volume: 125 Issue: 4 Pages: 406-414
  • DOI: 10.1254/jphs.14023FP
  • NAID: 130004677795
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed / Open Access
• [Journal Article] Effects of selective KAch channel blocker NTC-801 on atreal fibrillation in a canine model of atrial tachpacing: comparison with class Ic and III drugs. (2014)
  • Author(s): Yamamoto W, Hashimoto N, Matsuura J, Machida T, Ogino Y, Kobayashi T, Yamanaka Y, Ishiwata N, Yamashita Y, Tanimoto K, Miyoshi S, Fukuda K, Nakaya H, Ogawa S.
  • Journal Title: J Cardiovasc Pharmacol Volume: 63 Issue: 5 Pages: 421-427
  • DOI: 10.1097/fjc.0000000000000065
  • Peer Reviewed
• [Journal Article] Role of K_<ATP> channels in cardiac arrhythmias (2013)
  • Author(s): Nakaya H
  • Journal Title: J Cardiovasc Pharmacol Ther Volume: 19(3) Issue: 3 Pages: 237-243
  • DOI: 10.1177/1074248413515078
  • Peer Reviewed
• [Presentation] Electrophysiological changes in the transgenic mouse heart of Kir6.1-S422L (2017)
  • Author(s): 渡部恭大、三木隆司、清野進、安西尚彦、松本明郎、中谷晴昭
  • Organizer: 第90回 日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] Can overexpression of a gain-of-function mutation in Kir6.1 mimic electrophysiological changes simulating J wave syndrome in mice? (2016)
  • Author(s): 渡部恭大、三木隆司、清野進、安西尚彦、松本明郎、中谷晴昭
  • Organizer: 第63回 日本不整脈心電学会学術大会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-07-14
• [Presentation] Can overexpression of a gain-of-function mutation in Kir6.1 mimic electrophysiological changes simulating J wave syndrome in mice? (2016)
  • Author(s): 渡部恭大、三木隆司、清野進、安西尚彦、松本明郎、中谷晴昭
  • Organizer: 第11回 トランスポーター研究会年会
  • Place of Presentation: 京都大学宇治キャンパスきはだホール（京都府京都市）
  • Year and Date: 2016-07-02
• [Presentation] NOによるマウス腸内細菌叢の安定化機構 (2016)
  • Author(s): 松本明郎、清水建、霊園良恵、立花知子、渡部恭大、野田公俊、中谷晴昭
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-03-09
• [Presentation] マウス腸管内におけるNO産生の可視化による殺菌機構の解析 (2015)
  • Author(s): 松本明郎、霊園良恵、立花知子、清水健、渡部恭大、野田公俊、中谷晴昭
  • Organizer: 第133回日本薬理学会関東部会
  • Place of Presentation: 柏の葉カンファレンスセンター （千葉県・柏市）
  • Year and Date: 2015-10-10
• [Presentation] マウス腸管におけるNO依存性殺菌機構の解析 (2015)
  • Author(s): 渡部恭大、霊園良恵、立花知子、清水健、中谷晴昭、松本明郎
  • Organizer: 132回日本薬理学会関東部会
  • Place of Presentation: 明海大学浦安キャンパス（千葉県・浦安市）
  • Year and Date: 2015-07-04
• [Presentation] マウス心電図J 波の解析 －J波症候群におけるKATP チャネルの役割の評価の試み－ （ECG analysis of J-wave in mice: Evaluation of role of KATP channels in J wave Syndrome） (2015)
  • Author(s): 渡部 恭大、松本 明郎、三木 隆司、中谷 晴昭
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Book] 難治性不整脈診療 エキスパートのアプローチ (2016)
  • Author(s): 中谷晴昭
  • Total Pages: 332
  • Publisher: 中外医学社
• [Book] 循環器急性診療 Critical Care Cardiology (2015)
  • Author(s): 中谷晴昭
  • Total Pages: 864
  • Publisher: メディカル・サイエンス・インターナショナル