| Project/Area Number |
10307056
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
NAGAO Taku Graduate School of Pharmaceutical Sciences, Laboratory of Pharmacology and Toxicology, University of Tokyo Professor, 大学院・薬学系研究科, 教授 (30217971)
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| Co-Investigator(Kenkyū-buntansha) |
ADACHI-AKAHANE Satomi Graduate School of Pharmaceutical Sciences, Laboratory of Pharmacology and Toxicology, University of Tokyo Assistant professor, 大学院・薬学系研究科, 助手 (00184185)
KUROSE Hitoshi Graduate School of Pharmaceutical Sciences, Laboratory of Pharmacology and Toxicology, University of Tokyo Associate Professor, 大学院・薬学系研究科, 助教授 (10183039)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥32,700,000 (Direct Cost: ¥32,700,000)
Fiscal Year 2000: ¥9,600,000 (Direct Cost: ¥9,600,000)
Fiscal Year 1999: ¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 1998: ¥13,400,000 (Direct Cost: ¥13,400,000)
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| Keywords | Heart failure / Excitation-contraction coupling / Cardiac muscle / Ca^<2+> transients / L-type Ca^<2+> channel / Ca^<2+> handling / β adrenergic receptors / Myocardial infarction model / 梗塞モデル / 心肥大 / カルシウム シグナリング / カルシウム チャネル / 細胞骨格 / 洞房結節 / カルシウム トランジェント / 過分極活性型(If)チャネル |
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| Research Abstract |
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.
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