Strategic evaluation of Receptor interaction using resonance energy transfer

使用共振能量转移对受体相互作用进行战略评估

基本信息

批准号：
17590058
负责人：
KOSHIMIZU Takaaki
金额：
$ 2.3万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Heteromultimerization of G-protein coupled receptors makes new class of drug targets. We evaluated systemic strategy to delineate functional properties of heteromer receptor, from their molecular level to whole animal level. Combinations of drug-oriented pharmacological method and genetic manipulation of receptor expression levels were equally effective for this purpose.To elucidate temporal and spacial receptor-receptor interactions in living cells, N-or C-terminus of the subunits were connected with either luciferase or green fluorescent proteins and transfer of bioluminescent resonance energy from luciferase to fluorescent proteins was monitored.Using gene targeting, physical and functional interactions of α 1-adrenergic receptor subtypes and V1 vasopressin subtypes were investigated. Elucidation of the physiological and pathophysiological roles of the specific α 1-adrenergic receptor subtype has been hampered, because the α 1-adrenergic receptor subtypes are co-expressed in the same arterial smooth muscles with different ratios, and that sufficiently subtype-selective agonists and antagonists have not been available. In addition, recent biochemical and pharmacological studies confirmed the potential role of dimerization of distinct α 1-adrenergic receptor subtypes in controlling their expression and pharmacological properties. Our data showed that α 1B-and α 1D-adrenergic receptors play distinctive contributions to the resting and agonist-stimulated BP regulations, particularly to the progression of hypertensive state. The V1a receptor, on the other hand, plays an important role in normal resting arterial BP regulation mainly by its regulation of circulating blood volume and baroreflex sensitivity.

G 蛋白偶联受体的异多聚化形成了新的药物靶标，从分子水平到整个动物水平，我们评估了描述异聚体受体功能特性的系统策略，并结合了药物导向的药理学方法和受体表达水平的遗传操作。为了阐明活细胞中的时间和空间受体-受体相互作用，亚基的 N 或 C 末端与荧光素酶或绿色荧光蛋白连接，并转移监测从荧光素酶到荧光蛋白的生物发光共振能量。利用基因靶向，研究了α1-肾上腺素能受体亚型和V1加压素亚型的物理和功能相互作用，阐明了特定α1-肾上腺素能受体亚型的生理和病理生理作用。受到阻碍，因为α1-肾上腺素能受体亚型在相同的动脉平滑肌中以不同的比例共表达，并且还没有足够的亚型选择性激动剂和拮抗剂。此外，最近的生化和药理学研究证实了不同α 1-肾上腺素受体亚型的二聚化在控制其表达和药理学特性方面的潜在作用。 -和α1D-肾上腺素能受体对静息和激动剂刺激的血压调节，特别是对高血压状态的进展发挥独特的作用。另一方面，主要通过调节循环血量和压力反射敏感性，在正常静息动脉血压调节中发挥重要作用。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Two alphal-adrenergic receptor subtypes regulating the vasopressor response have differential roles in blood pressure regulation.

调节血管加压反应的两种α-肾上腺素能受体亚型在血压调节中具有不同的作用。

DOI：
发表时间：
2005
期刊：
Mol.Pharm. 67
影响因子：
0
作者：
M.Isaji et al.;H.Wang et al.;N.Yamada et al.;H.Ueno et al.;H.Tanahashi et al.;Okuno Y;Adachi T;Ishida A;Hosoda C;Zhu S;Lazaro-Suarez ML;Kagaya S;Zacharia J;Sugimoto Y;Nagata N;Egashira N;Kagaya S;Chen Q;Erami C;Katsuma S;Adachi T;Katsuma S;Yamada M;Yamauchi J;Hosoda C
通讯作者：
Hosoda C

Vla Vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity.

Vla 加压素受体通过调节循环血量和压力反射敏感性来维持正常血压。

DOI：
发表时间：
期刊：
Proc.Natl.Acad.Sci.USA. (印刷中)
影响因子：
0
作者：
M.Isaji et al.;H.Wang et al.;N.Yamada et al.;H.Ueno et al.;H.Tanahashi et al.;Okuno Y;Adachi T;Ishida A;Hosoda C;Zhu S;Lazaro-Suarez ML;Kagaya S;Zacharia J;Sugimoto Y;Nagata N;Egashira N;Kagaya S;Chen Q;Erami C;Katsuma S;Adachi T;Katsuma S;Yamada M;Yamauchi J;Hosoda C;Adachi T;Katsuma S;Deighan C;Hirasawa A;Ami Y;Koshimizu T
通讯作者：
Koshimizu T