Study on regulatory mechanism for cardiac contraction : seeking for therapeutic basis of heart failure.

心脏收缩调节机制的研究:寻找心力衰竭的治疗基础。

基本信息

  • 批准号:
    10307056
  • 负责人:
  • 金额:
    $ 20.93万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (A).
  • 财政年份:
    1998
  • 资助国家:
    日本
  • 起止时间:
    1998 至 2000
  • 项目状态:
    已结题

项目摘要

The aim of this project was to open up a novel concept for therapeutic basis of heart failure. In the past three years from 1998 through 2000, we have carried out the research project by focusing on Ca^<2+> signaling in cardiac E-C coupling at the early stage of heart failure, molecular basis for cardiac protection against ischemia, molecular mechanism underlying modulation of L-type Ca^<2+> channel gating, cellular mechanism for desensitization of β adrenergic receptors. Our research products are summarized as follows :1) With respect to the molecular basis for cardiac protection against ischemia, we found that ROS (reactive oxygen species) directly activates Gi and Go, which results in the activation of ERK (extracellular signal-regulated kinase). We opened up a novel concept that ROS is also involved in the signal transduction pathway leading to cardiac protection. 2) We identified Ser1115 in the pore domain of L-type Ca^<2+> channel α_<1C> subunit as the critical determinant for modulation of L-type Ca^<2+> channel gating by Ca^<2+> channel agonists by comparing the amino acid sequences between DHP-sensitive mammalian α_<1C> subunit and DHP-insensitive Ca^<2+> channel α_1 subunit of sea animals. Our finding opened up a novel concept in the gating mechanism of voltage-dependent Ca^<2+> channels. We also found that Ser1901 in the carboxy terminal of L-type Ca^<2+> channel α_<1C> subunit is the target for the PKA-modulation. 3) We found that, in the early adaptive stage of heart failure, the Ca^<2+> handling mechanism, especially Na^<+-> Ca^<2+> exchange activity, is up-regulated in ventricular myocytes of coronary artery ligation model rats. 4) We clarified the molecular basis for the tolerance of β_1 adrenergic receptors against internalization on exposure to β adrenergic agonists, which partially explains the reason for the slower rate of down regulation β_1 adrenergic receptors.
该项目的目的是为心力衰竭的治疗基础开辟一个新的概念。从1998年到2000年,我们开展了心衰早期Ca^<2+>信号在心脏E-C偶联中的作用、心脏缺血保护的分子基础、l型Ca^<2+>通道门控调节的分子机制、β肾上腺素能受体脱敏的细胞机制等方面的研究。我们的研究成果总结如下:1)关于心肌缺血保护的分子基础,我们发现活性氧(ROS)直接激活Gi和Go,从而激活ERK(胞外信号调节激酶)。我们开辟了一个新的概念,即ROS也参与导致心脏保护的信号转导途径。2)通过比较dhp敏感的哺乳动物α_<1C>亚基与dhp不敏感的海洋动物Ca^<2+>通道α_1亚基的氨基酸序列,发现l型Ca^<2+>通道α_<1C>亚基孔域Ser1115是Ca^<2+>通道激动剂调节l型Ca^<2+>通道门控的关键决定因素。我们的发现为电压依赖性Ca^<2+>通道的门控机制开辟了一个新的概念。我们还发现l型Ca^<2+>通道α_<1C>亚基羧基端的Ser1901是pka调制的靶点。3)我们发现,在心力衰竭的早期适应阶段,冠状动脉结扎模型大鼠心室肌细胞中Ca^<2+>处理机制,特别是Na^<+-> Ca^<2+>交换活性上调。4)阐明了β_1肾上腺素能受体内化耐受的分子基础,部分解释了β_1肾上腺素能受体下调速率较慢的原因。

项目成果

期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sato, K.et al.: "Modulatory role of endothelial Calcium Level in vasculor tension of canine depolarized coronary actories." American Journal of Physiology. 43 (2). H494-H499 (1998)
Sato, K.等人:“内皮钙水平对犬去极化冠状动脉血管张力的调节作用。”
  • DOI:
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  • 影响因子:
    0
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  • 通讯作者:
Naguro, I. et al.: "Ser^<1901> of α1c subunit is required for the PKA-mediated enhancement of L-type Ca^<2+> channel currents but not for the negative shift of activation"FEBS Letters. 489. 87-91 (2001)
Naguro, I. 等人:“α1c 亚基的 Ser^<1901> 对于 L 型 Ca^2+ 通道电流的 PKA 介导的增强是必需的,但对于激活的负向转移则不需要”FEBS Letters 489。 .87-91 (2001)
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    0
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Takesono,A., et al: "Negative regulation of α_2-adrenergic receptor-mediated G_i signaling by a novel pathway."Biochem.J.. 343. 77-85 (1999)
Takesono, A. 等人:“通过新途径对 α_2-肾上腺素能受体介导的 G_i 信号传导进行负调节。”Biochem.J. 343. 77-85 (1999)
  • DOI:
  • 发表时间:
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  • 影响因子:
    0
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  • 通讯作者:
Nishida,M., et al: "G_<iα> and G_<oα> are target proteins of reactive oxygen species."Nature. 408. 492-495 (2000)
Nishida, M., 等人:“G_<iα> 和 G_<oα> 是活性氧的靶蛋白。”Nature,408. 492-495 (2000)。
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    0
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NAGAO Taku其他文献

NAGAO Taku的其他文献

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{{ truncateString('NAGAO Taku', 18)}}的其他基金

Novel Therapeutic Strategy for Heart Failure : Molecular Mechanism underlying the Regulation of Ca^<2+> Signaling in the Heart
心力衰竭的新治疗策略:心脏中 Ca^<2> 信号传导调节的分子机制
  • 批准号:
    13307065
  • 财政年份:
    2001
  • 资助金额:
    $ 20.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Role of receptor kinase in β1-adrenergic receptor signaling, and hypertrophy/heart failure
受体激酶在 β1-肾上腺素能受体信号传导和肥厚/心力衰竭中的作用
  • 批准号:
    11557189
  • 财政年份:
    1999
  • 资助金额:
    $ 20.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
Establishment of Functional Analysis by Expressing Antibody Molecule in the Cells
细胞内表达抗体分子功能分析的建立
  • 批准号:
    07557151
  • 财政年份:
    1995
  • 资助金额:
    $ 20.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Analysis of effects of Ca-antagonists in pathophysiological models
Ca2+拮抗剂在病理生理模型中的作用分析
  • 批准号:
    04454530
  • 财政年份:
    1992
  • 资助金额:
    $ 20.93万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Regulation by beta-adrenoceptor subtypes of cardiac function : Analysis by selective beta agonists
β-肾上腺素受体亚型对心脏功能的调节:选择性β激动剂的分析
  • 批准号:
    02454485
  • 财政年份:
    1990
  • 资助金额:
    $ 20.93万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)

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