ANGIOTENSIN II RECEPTOR SIGNALING DOMAINS

描述：(改编自应用)血管紧张素II(AngII)是 一种具有非凡信号转导能力的多效性激素 与其受体激活相关的反应。原型机 血管紧张素Ⅱ受体是血管平滑肌的AT1AR。AT1AR VSMC中的激活与顺序激活相关 磷脂酶Cs(PLC)和磷脂酶D(PLD)。最初的PLC 激活后迅速脱敏，随后立即出现PLD 蛋白偶联AT1AR还激活多种受体酪氨酸 激活剂。PI建议这些不同的信号按以下方式组织 与特定的时间和空间领域相关联。少校 本建议的总体目标是理解信令 通过提供对连接 AT1AR到效应分子和控制受体的机制 贩运到信令或回收领域。初步证据 这表明这个领域就是洞穴。一个重要的潜在假设 受体交易控制着信号的模式 一代。该计划最近的一个重要成就是 电输送技术的发展与完善 针对特定信号组件进入VSMC的抗体。这 例如，方法允许将关键角色分配给 AT1AR信号转导中的GG亚基。PI已经开发出 指导特定应用程序的开发和测试的通用模型 血管平滑肌细胞中血管紧张素Ⅱ信号事件的机械论假说。至 对通用模型的检验我们提出了以下具体目标：1) 定义激活的AT1AR所属的特定膜结构域 激活后动员；2)确定小窝作为 双相信号紧张性成分的激活部位 反应；3)确定酪氨酸激酶的激活机制 通过AT1AR在小窝中；4)检测小窝在氧化剂中的作用- 敏感的AT1AR介导的信号转导；5)利用杆状病毒 表达系统和来自细胞研究的信息，确定 AT1AR信号通路的组件在物理上相互作用。这些 研究应该为血管紧张素转换酶II的机制提供新的见解 发挥其关键的生理学和病理生理学作用。

DESCRIPTION: (Adapted from the application) Angiotensin II (angII) is a pleiotropic hormone with an extraordinary repertoire of signaling responses associated with activation of its receptors. The prototype ang II receptor is the AT1AR of vascular smooth muscle (VSMC). AT1AR activation in VSMC is associated with the sequential activation of phospholipase Cs (PLC) and phospholipase D (PLD). The initial PLC activation rapidly desensitizes and is followed immediately by PLD protein coupled AT1AR also activates a variety of receptor tyrosine kinase. The PIs propose that these various signals are organized by being associated with specific temporal and spatial domains. The major general object of this proposal is to understand the signaling repertoire by providing insights into the coupling protein linking the AT1AR to effector molecules and into the mechanisms controlling receptor trafficking into signaling or recycling domains. Preliminary evidence suggests that this domain is the caveola. A major underlying hypothesis is that the receptor trafficking controls the pattern of signal generation. An important recent accomplishment of the program is the development and refinement of the technique of electroportation of antibodies against specific signaling components into VSMC. This approach, for example, has permitted assignment of a pivotal role for the Gg subunit in transducing AT1AR signaling. The PIs have developed a general model that guides development and testing of specific mechanistic hypotheses concerning angII signaling events in VSMC. To test the general model we propose the following specific aims: 1) Define the specific membrane domains to which the activated AT1AR is mobilized after activation; 2) Determine the role of caveolae as the site of activation of the tonic component of the biphasic signaling response; 3) Determine the mechanism of activation of tyrosine kinase by the AT1AR in caveolae; 4) Examine the role of caveolae in oxidant- sensitive AT1AR-mediated signal transduction; 5) Using the baculovirus expression system and information from cell studies, determine which components of the AT1AR signaling pathways physically interact. These studies should provide new insights into the mechanisms by which ang II fulfills its pivotal physiologic and pathophysiologic roles.