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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：
NAGAO Taku
金额：
$ 20.93万
依托单位：
University of Tokyo
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.

本项目的目的是为心力衰竭的治疗基础开辟一个新的概念。1998年至2000年，我们开展了心力衰竭早期心脏E-C偶联中Ca^2+信号转导、心肌缺血保护的分子基础、L型Ca^2+通道门控调控的分子机制、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）在心肌缺血保护的分子基础方面，我们发现活性氧（ROS）直接激活Gi和Go，从而导致细胞外信号调节激酶（ERK）的激活。我们开辟了一个新的概念，ROS也参与了导致心脏保护的信号转导途径。2)通过比较哺乳动物对DHP敏感的Ca^<2+>通道α_<1C>亚基和海洋动物对DHP不敏感的Ca^<2 +>通道α_1亚基的氨基酸序列，我们确定L型Ca^<2 +>通道α_亚基孔结构域中的Ser 1115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<1C>。我们的发现为电压依赖性Ca^<2+>通道的门控机制提供了新的概念。我们还发现L型Ca^2+通道α亚基羧基端的Ser 1901<1C>是PKA调节的靶点。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的Ca^<2+>处理机制，尤其是Na^<+-> Ca^<2+>交换活性上调。4)阐明了β_1肾上腺素能受体对β受体激动剂耐受内化的分子基础，部分解释了β_1肾上腺素能受体下调速度较慢的原因。