Ventricular tachycardia triggered by augumented Ca leak through ryanodine receptor carrying point mutation: In vitro reconstruction of arrhythmogenicity

• Project/Area Number: 26460305
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Fukuoka University
• Principal Investigator: Uehara Akira 福岡大学, 医学部, 准教授 (60140745)
• Co-Investigator(Kenkyū-buntansha): 塩谷 孝夫 佐賀大学, 医学部, 助教 (20253594) ; 上原 清子 福岡大学, 医学部, 准教授 (00084244)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 心筋 / リアノジン受容体 / 不整脈 / Ca / calcium / 興奮収縮連関 / イオンチャネル / 筋生理学 / 心臓 / sarcoplasmic reticulum / arrythmia

Outline of Final Research Achievements

Mechanisms of Ca release from SR/ER through the cardiac RyR2 w a point mutation K4750Q linked to ventricular tachycardia VT were functionally examined by measuring Ca　signals and single RyR2 channel currents. The Ca signals were obtained from HEK293 and cardiac HL-1 cells expressing RyR channels. The single-channel currents were from RyR2 purified proteins. The mutation caused simultaneous functional defects in RyR2 function that include cytosolic Ca hyper-activation/sensitization, loss of cytosolic Ca/Mg-mediated inactivation, and luminal Ca hyper-activation/sensitization. The excessive SR Ca leak in K4750Q-expressing cells reduced [Ca]lum significantly lowering CPVT risk at rest. We thus show that the mutation markedly enhanced multiple RyR2 Ca regulatory mechanisms, which indicates that the K4750 residue resides at a pivotal structural point that synergizes cytosolic and luminal RyR2 control inputs.

Research Products

• [Journal Article] Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity. (2017)
  • Author(s): Akira Uehara, Takashi Murayama, Midori Yasukochi, Michael Fill, Minoru Horie,Toru Okamoto, Yoshiharu Matsuura, Kiyoko Uehara, Takahiro Fujimoto, Takashi Sakurai,and Nagomi Kurebayashi.
  • Journal Title: J Gen Physiol Volume: 149 Pages: 199-218
• [Journal Article] Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity. (2016)
  • Author(s): Uehara A, Horie M, et al.
  • Journal Title: Journal of General Physiology Volume: 149 Issue: 2 Pages: 199-218
  • DOI: 10.1085/jgp.201611624
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differentiated localizations of phosphorylated focal adhesion (2016)
  • Author(s): Uehara K and Uehara A
  • Journal Title: Cell Tiss Res Volume: 掲載確定 Issue: 3 Pages: 611-622
  • DOI: 10.1007/s00441-015-2350-1
  • Peer Reviewed
• [Journal Article] Integrin in endothelial cells of rat splenic sinus: an immunohistochemical and untrastructural study. (2014)
  • Author(s): Uehara K and Unhara A
  • Journal Title: Cell Tissue Research Volume: 356 Issue: 1 Pages: 183-189
  • DOI: 10.1007/s00441-014-1796-x
  • Peer Reviewed / Open Access
• [Presentation] リアノジン受容体チャネル催不整脈性変異によるカルシウム調節機構障害 (2016)
  • Author(s): 上原 明
  • Organizer: 日本生理学会
  • Place of Presentation: 北海道
  • Year and Date: 2016-03-20
• [Presentation] リアノジン受容体の催不整脈性変異によるチャネル不安定化機構 (2014)
  • Author(s): 上原 明
  • Organizer: 筋生理の集い
  • Place of Presentation: 慈恵医大
  • Year and Date: 2014-12-06