Regulation of L-type calcium channel by intracellular subunit in cardiac hypertrophy and failure.

• Project/Area Number: 23390212
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: NAKAYAMA HIROYUKI 大阪大学, 薬学研究科(研究院), 准教授 (40581062)
• Co-Investigator(Kenkyū-buntansha): ASAHI Michio 大阪医科大学, 薬理学, 教授 (10397614) ; FUJIO Yasushi 大阪大学, 薬学研究科, 教授 (20359839)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: カルシウム / チャネル / 心肥大 / 心不全 / カルモデュリン依存性キナーゼ / マイクロドメイン / シグナリング / カルシウムチャネル / プロテインキナーゼA / 細胞死

Research Abstract

L-type calcium channel (LTCC) localizes at T-tubules and caveolae in cardiomyocytes, and plays major roles in excitation-contraction coupling and cardiac hypertrophy. The expression of b2a subunit of LTCC (b2a) is increased in human failing heart. Phosphorylation of b2a by CaMKII enhanced LTCC activity. In the present study, we examined the pathological role of b2a phosphorylation in cardiac hypertrophy. We developed a method to examine caveolae-specific activation of CaMKII and found that b2a phosphorylation occurs specifically in caveolae and elicit myocyte hypertrophy in a1 adrenergic stimulation. Thus, we generated transgenic mice (TG) overexpressing non phosphorylated mutant of b2a.The expressions of b2a in both mutant and wild-type TG were similar. a1 adrenergic stimulation induced cardiac hypertrophy was attenuated in mutant TG compared to wild-type TG mice. In conclusion, we revealed that phosphorylated b2a localized at caveolae and exaggerates cardiac hypertrophy.

Research Products

• [Journal Article] Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2 (2014)
  • Author(s): Shintani Y, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, 他3名
  • Journal Title: EMBO Rep Volume: 15(4) Pages: 438-45
• [Journal Article] Genetic modulation of the SERCA activity does not affect the Ca2+ leak from the cardiac sarcoplasmic reticulum (2014)
  • Author(s): Morimoto S, Hongo K, Kusakari Y, Komukai K, Kawai M, O-Uchi J, Nakayama H, 他4名
  • Journal Title: Cell Calcium Volume: 55(1) Pages: 17-23
• [Journal Article] Genetic modulation of the SERCA activity does not affect the Ca2+ leak from the cardiac sarcoplasmic reticulum. (2014)
  • Author(s): Morimoto S, Hongo K, Kusakari Y, Komukai K, Kawai M, O-Uchi J, Nakayama H, Asahi M, Otsu K, Yoshimura M, Kurihara S.
  • Journal Title: Cell Calcium. Volume: 55 Issue: 1 Pages: 17-23
  • DOI: 10.1016/j.ceca.2013.10.005
  • Peer Reviewed / Open Access
• [Journal Article] Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2. (2014)
  • Author(s): Shintani Y, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, Takashima S, Yashiro K, Suzuki K.
  • Journal Title: EMBO Reports Volume: 15 Issue: 4 Pages: 438-445
  • DOI: 10.1002/embr.201337945
  • Peer Reviewed / Open Access
• [Journal Article] Calcium dependent signaling in cardiac hypertrophy and cell death (2013)
  • Author(s): Nakayama H, Fujio Y, Yamaguchi O
  • Journal Title: Clin Calcium Volume: 23(4) Pages: 505-15
• [Journal Article] Ras Homologue Enriched in Brain (Rheb) -dependent mTORC1 Activation Becomes Indispensable for Cardiac Hypertrophic Growth after Early Postnatal Period (2013)
  • Author(s): Tamai T, Yamaguchi O, Hikoso S, Takeda T, Taneike M, Oka T, Oyabu J, Murakawa T, Nakayama H, 他6名
  • Journal Title: J Biol Chem Volume: 288(5) Pages: 10176-87
• [Journal Article] Cathelicidin antimicrobial peptide inhibits fibroblast migration via P2X7 receptor signaling. (2013)
  • Author(s): Kumagai, S., Matsui, K., Kawaguchi, H., Yamashita, T., Mohri, T., Fujio, Y., Nakayama, H.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 437 Issue: 4 Pages: 609-614
  • DOI: 10.1016/j.bbrc.2013.07.010
  • Peer Reviewed
• [Journal Article] Autophagy-mediated degradation is necessary for regression of cardiac hypertrophy during ventricular unloading. (2013)
  • Author(s): Oyabu J, Yamaguchi O, Hikoso S, Takeda T, Oka T, Murakawa T, Yasui H, Ueda H, Nakayama H, Taneike M, Omiya S, Shah AM, Nishida K, Otsu K.
  • Journal Title: Biochemical and Biophysical Research Communication Volume: 441 Issue: 4 Pages: 787-792
  • DOI: 10.1016/j.bbrc.2013.10.135
  • Peer Reviewed
• [Journal Article] Ca2+依存性の心肥大・心筋細胞死誘導シグナル (2013)
  • Author(s): 中山博之、山口修、藤尾慈
  • Journal Title: Clinical Calcium Volume: 23 Pages: 505-515
• [Journal Article] Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy. (2011)
  • Author(s): Chen X
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 50 Issue: 3 Pages: 460-470
  • DOI: 10.1016/j.yjmcc.2010.11.012
  • Peer Reviewed
• [Journal Article] Autophagy-mediated degradation is necessary for regression of cardi ac hypertrophy during ventricular unloading
  • Author(s): Oyabu J, Yamaguchi O, Hikoso S, Takeda T, Oka T, Murakawa T, Yasui H, Ueda H, Nakayama H, 他5名
  • Journal Title: Biochem Biophys Res Commun Volume: 441(4) Pages: 787-92
• [Journal Article] Cathelicidin antimicrobial peptide inhibits fibroblast migration via P2X7 receptor signaling
  • Author(s): Kumagai S, Matsui K, Kawaguchi H, Yamashita T, Mohri T, Fujio Y, Nakayama H
  • Journal Title: Biochem Biophys Res Commun Volume: 437(4) Pages: 609-14
• [Journal Article] Requirement of SLD5 for early embryo-genesis
  • Author(s): Mohri T, Ueno M, Nagahama Y, Gong ZY, Asano M, Oshima H, Oshima M, Fujio Y, Takakura N
  • Journal Title: PLoS One Volume: 8(11)
• [Presentation] Caveolae- specific phosphorylation of L-type calcium channel b2a subunit exaggerates cardiac hypertrophic responses after a1 adrenergic stimulation in mice (2014)
  • Author(s): Hiroyuki Nakayama
  • Organizer: American Heart Association
  • Place of Presentation: Las Vegas
• [Presentation] Phosphorylation of L-type Ca2+ channel b2a subunit induce cardiomyocyte hypertrophy (2014)
  • Author(s): 早水菜緒
  • Organizer: 第87回日本薬理学会
  • Place of Presentation: 仙台
• [Presentation] Excessive BIN1 expression results in adverse remodeling through cardiomyocyte death (2014)
  • Author(s): 舎川洸太
  • Organizer: 第87回日本薬理学会
  • Place of Presentation: 仙台
• [Presentation] Excessive BIN1 expression results in adeverse remodeling through cardiomyocyte death (2014)
  • Author(s): Kota Tonegawa, Sachi Matsunami, Daisuke Tsuchiyama, Hiroyuki Nakayama, Yasushi Fujio
  • Organizer: 日本薬理学会
  • Place of Presentation: 仙台国際センター（仙台）
• [Presentation] Phosphorylation of L-type Ca2+ channel b2a subunit induces cardiomyocyte hypertrophy (2014)
  • Author(s): Nao Hyamizu, Shohei Kumagai, Sachi Matsunami, Hiroyuki Nakayama, Yasushi Fujio
  • Organizer: 日本薬理学会
  • Place of Presentation: 仙台国際センター（仙台）
• [Presentation] Caveolae-specific phosphorylation of L-type calcium channel 2a subunit exaggerates cardiac hypertrophic responses after 1 adrenergic stimulation in mice. (2014)
  • Author(s): Hiroyuki Nakayama, Shohei Kumagai, Sachi Matsunami, Nao Hayamizu Wataru Otsuka and Yasushi Fujio.
  • Organizer: Basic Cardiovascular Sciences/American Heart Association
  • Place of Presentation: Paris Las Vegas (ラスベガス）
• [Presentation] Inhibition of P2X7 Receptor Signaling Promote Adverse Cardiac Remodeling after Myocardial Infarction thorough Enhanced Cardiac Fibroblast Migration (2013)
  • Author(s): Shohei Kumagai
  • Organizer: American Heart Association
  • Place of Presentation: Dallas
• [Presentation] Inhibition of P2X7 Receptor Signaling Promote Adverse Cardiac Remodeling after Myocardial Infarction thorough Enhanced Cardiac Fibroblast Migration (2013)
  • Author(s): 熊谷渉平
  • Organizer: 第21回血管生物学会
  • Place of Presentation: 大阪
• [Presentation] Inhibition of P2X7 receptor signaling promotes adverse cardiac remodeling after myocardial infarction through enhanced cardiac fibroblast migration (2013)
  • Author(s): 熊谷渉平 中山博之 宮脇昭光 毛利友美 藤尾慈
  • Organizer: 日本血管生物医学会
  • Place of Presentation: 千里国際阪急ホテル（大阪）
• [Presentation] Inhibition of P2X7 Receptor Signaling Promotes Adverse Cardiac Remodeling after Myocardial Infarction through Enhanced Cardiac Fibroblast Migration (2013)
  • Author(s): Kumagai Shohei, Nakayama Hiroyuki, Miyawaki Akimitsu, Mohri Tomomi, Fujio Yasushi,
  • Organizer: American Heart Association
  • Place of Presentation: ダラス
• [Presentation] The myocardial activation of CaMKIIb leads to heart failure (2013)
  • Author(s): 輪島こまゆ
  • Organizer: 第86回 日本薬理学会年会
  • Place of Presentation: 福岡
• [Presentation] Development of a novel tool for analysis of PKA and CaMKII activities in caveolae (2013)
  • Author(s): 松浪佐知
  • Organizer: 第86回 日本薬理学会年会
  • Place of Presentation: 福岡
• [Presentation] Cathelicidin antimicrobial peptide inhibits fibroblasts migration via P2X7 receptor signaling (2013)
  • Author(s): 熊谷渉平
  • Organizer: 第86回 日本薬理学会年会
  • Place of Presentation: 福岡
• [Presentation] オートファジーを免れたミトコンドリアDNAの蓄積は心臓において炎症と心不全を惹起する (2012)
  • Author(s): 中山博之
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Calcium-mediated pathogenesis in heart (2012)
  • Author(s): 中山 博之
  • Organizer: 日本薬理学会年回
  • Place of Presentation: 京都
  • Invited
• [Book] 遺伝子医学MOOK別冊 細胞死研究の今 –疾患との関わり、創薬に向けてのアプローチ− (2013)
  • Author(s): 中山博之、大津欣也
  • Total Pages: 6
  • Publisher: メディカルドゥ
• [Book] 遺伝子医学MOOK別冊細胞死研究の今
  • Author(s): 中山博之, 他
  • Publisher: メディカルドウ