Physiological and pathophysiological roles of casein kinase 2 in the regulation of cardiac L-type Ca channels

• Project/Area Number: 26860145
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Shinshu University
• Principal Investigator: KASHIHARA Toshihide 信州大学, 学術研究院医学系, 助教 (20552334)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Ｌ型カルシウムチャネル / 心筋 / タンパク質リン酸化酵素 / 心筋興奮収縮連関 / アンジオテンシンⅡ / 陽性変力作用 / βアレスチン / カゼインキナーゼ２ / L型カルシウムチャネル

Outline of Final Research Achievements

CaV1.2 L-type Ca2+ channels (LTCC) play an essential role in cardiac excitation-contraction coupling. We recently found that LTCC activity is regulated by casein kinase 2 (CK2) α’β in immature cardiac myocytes. Here, we examined the molecular mechanism underlying the regulation of LTCC activity by CK2α’β. In this study, we revealed that CK2α’β determines LTCC activity through phosphorylating threonine 1704 of CaV1.2, and that angiotensin II strongly activates LTCC through AT1 receptor/β-arrestin2/Src/CK2α’β in immature but not adult cardiac myocytes.

Research Products

• [Journal Article] Transplantation of adipose tissue-derived stem cells improves cardiac contractile function and electrical stability in a rat myocardial infarction model. (2015)
  • Author(s): Gautam M., Fujita D., Kimura K., Ichikawa H., Izawa A., Hirose M., Kashihara T., Yamada M., Takahashi M., Ikeda U., Shiba Y.
  • Journal Title: Journal of molecular and cellular cardiology Volume: 81 Pages: 139-149
  • DOI: 10.1016/j.yjmcc.2015.02.012
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac overexpression of constitutively active Gαq causes angiotensin II type1 receptor activation, leading to progressive heart failure and ventricular arrhythmias in transgenic mice (2014)
  • Author(s): Matsushita N, Kashihara T, Shimojo H, Suzuki S, Nakada T, Takeishi Y, Mende U, Taira E, Yamada M, Sanbe A, Hirose M
  • Journal Title: PLoS One Volume: 9 Issue: 8 Pages: e106354-e106354
  • DOI: 10.1371/journal.pone.0106354
  • Peer Reviewed / Open Access
• [Presentation] Angiotensin II activates L-type Ca2+ channels through removing inhibition of casein kinase 2α’β by p27KIP1 in immature cardiac myocytes (2016)
  • Author(s): Toshihide Kashihara, Tsutomu Nakada, Mitsuhiko Yamada
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 神奈川県横浜市西区 パシフィコ横浜会議センター
  • Year and Date: 2016-03-09
• [Presentation] カゼインキナーゼ2による幼若心筋細のL型Ca2+チャネル活性化の分子機構 (2015)
  • Author(s): 柏原俊英、中田勉、山田充彦
  • Organizer: 第25回日本循環薬理学会
  • Place of Presentation: 奈良県奈良市水門町 東大寺総合文化センター金鐘ホール
  • Year and Date: 2015-12-04
• [Presentation] Regulation of L-type Ca2+ channels by angiotensin II type 1 receptor/beta-arrestin-2 biased signaling through casein kinase 2 in immature cardiomyocytes (2015)
  • Author(s): Toshihide Kashihara, Tsutomu Nakada, Xiaoguang Guo, Mitsuhiko Yamada
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸市中央区 神戸国際会議場
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Angiotensin II type 1 receptor/betaarrestin2 biased signaling activates L-type Ca2+ channels in immature cardiac myocytes (2015)
  • Author(s): Toshihide Kashihara, Tsutomu Nakada, Xiaoguang Guo, Mitsuhiko Yamada
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋市熱田区 名古屋国際会議場
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] AT1アンジオテンシンⅡ受容体／βアレスチン2バイアスシグナルはα’β型カゼインキナーゼ2の活性化を介して幼弱心筋細胞のL型Ca2+チャネルを活性化させる (2014)
  • Author(s): 柏原俊英、中田勉、郭暁光、山田充彦
  • Organizer: 第24回日本循環薬理学会
  • Place of Presentation: 山形市双葉町 山形テルサ
  • Year and Date: 2014-12-05
• [Presentation] Failure to deactivate ventricular L-type Ca2+ channels in the phase 3 hyperpolarization is the direct cause of early afterdepolarization and torsade de pointes (2014)
  • Author(s): Toshihide Kashihara, Mitsuhiko Yamada
  • Organizer: 第29回日本不整脈学会学術大会／第31回日本心電学会学術集会 合同学術大会
  • Place of Presentation: 東京都港区 ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-22 – 2014-07-25
• [Remarks] 信州大学医学部・分子薬理学教室
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/chair/i-yakuri/index.html