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Molecular analysis of the structural function of angiotensin II receptors for new therapeutic strategy

血管紧张素 II 受体结构功能的分子分析以制定新的治疗策略

基本信息

批准号：
15590871
负责人：
MIURA Shin-ichiro
金额：
$ 2.18万
依托单位：
Fukuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Two distinct subtypes of angiotensin II (Ang II) receptors, type 1(AT1) and type 2 (AT2), which are members of the G-protein-coupled receptor superfamily (GPCRs), have been identified.Multiple signaling pathways link AT1 receptor to Gq-dependent inositol phosphate (IP) production and Gq-independent phospho-extracellular signal-activated kinase(p-ERK)1/2 by Ang II in the regulation of cardiovascular vasoconstriction and cell growth, respectively. An Ang II analogue, [Sar^1, Ile^4, Ile^8]Ang II, did not stimulate Gq-dependent IP production, but still activated Gq-independent p-ERK1/2 in human coronary artery smooth muscle cells as well as in a cell line that stably expressed AT^1 receptor. This activation was mostly mediated by [Sar^1, Ile^4, Ile^8]Ang II-induced Gq-independent epidermal growth factor receptor transactivation. We found that AT^1 receptor signaling shows bifurcation into functionally separate pathways.In addition, members of the GPCRs undergo homo- and/or hetero-oligomeri … More zation to induce cell signaling. Although some of these show constitutive activation, it is not clear how such GPCRs undergo homo-oligomerization with transmembrane (TM) helix movement. We previously reported that AT2 receptor showed constitutive activation and induced apoptosis independent of its ligand, Ang II. Therefore, we analyzed the translocation and oligomerization of AT2 receptor with TM movement when the receptor induces cell signaling. Constitutively active homo-oligomerization, which was due to disulfide bonding between Cys35 in one AT2 receptor and Cys290 in another AT2 receptor, was localized in the cell membrane without Ang II stimulation and induced apoptosis without changes in receptor conformation. These results provide the direct evidence that the constitutive active homo-oligomeric GPCRs by intermolecular interaction in two extracellular loops is translocated to the cell membrane and induces cell signaling independent of receptor conformation and ligand stimulation.Based on molecular biological studies, we found new findings on the structure and function of Ang II receptors and possible new therapeutic strategies for targeting these receptors. Less

血管紧张素II（Ang II）受体的两种不同亚型，1型（AT 1）和2型（AT 2），它们是G蛋白偶联受体超家族（GPCR）的成员，多种信号通路将AT 1受体与Gq依赖性磷酸肌醇（IP）产生和Gq非依赖性磷酸化细胞外信号激活激酶（p-ERK）1/2通过Ang II调节心血管收缩和细胞生长。在人冠状动脉平滑肌细胞以及稳定表达AT^1受体的细胞系中，血管紧张素II类似物[Sar ^1，Ile ^4，Ile ^8]血管紧张素II不能刺激Gq依赖性IP的产生，但仍能激活Gq非依赖性p-ERK 1/2。这种激活主要由[Sar ^1，Ile ^4，Ile ^8]Ang II诱导的Gq非依赖性表皮生长因子受体反式激活介导。我们发现，AT^1受体信号通路分为功能独立的通路，此外，GPCR的成员经历同源和/或异源寡聚体， ...更多信息诱导细胞信号传导。尽管其中一些显示出组成性激活，但尚不清楚此类GPCR如何经历具有跨膜（TM）螺旋运动的同源寡聚化。我们以前报道，AT 2受体表现出组成性激活，并诱导凋亡独立于其配体，血管紧张素Ⅱ。因此，我们分析了AT 2受体在诱导细胞信号传导时的易位和寡聚化。组成型活性的同源寡聚化，这是由于在一个AT 2受体和Cys 290在另一个AT 2受体之间的二硫键，是本地化在细胞膜上没有血管紧张素II刺激和诱导细胞凋亡，而不改变受体构象。这些结果提供了直接的证据表明，组成型活性同源寡聚GPCRs通过两个细胞外环的分子间相互作用被转运到细胞膜上，并诱导细胞信号传导，而不依赖于受体的构象和配体的刺激。少