ANGIOTENSIN II RECEPTOR SIGNALING DOMAINS

描述：（改编自申请）血管紧张素II（angII）是 一种多效性激素， 与其受体激活相关的反应。 原型 血管紧张素Ⅱ受体（angII receptor，angII receptor）是血管平滑肌细胞（vascularsmoothmuscle，VSMC）的AT 1AR。 AT1AR VSMC中的激活与以下的顺序激活相关： 磷脂酶Cs（PLC）和磷脂酶D（PLD）。 最初的PLC 激活后迅速脱敏，随后立即发生PLD 蛋白偶联的AT 1AR也激活多种受体酪氨酸 激酶。 PI提出，这些不同的信号是由 与特定的时间和空间域相关联。 主要 本建议的一般目的是理解信令 通过提供对连接蛋白的偶联蛋白的深入了解， AT 1AR与效应分子的相互作用及受体调控机制 贩运到信号或再循环域。 初步证据 表明这个区域就是洞穴 一个主要的潜在假设 受体运输控制着信号的模式 一代 该计划最近的一项重要成就是， 发展和完善的技术， 针对特定信号成分的抗体进入VSMC。 这 例如，这一办法允许将关键作用分配给 Gg亚基在AT 1AR信号转导中的作用。 私家侦探已经发展出 一个通用模型，用于指导特定 关于血管平滑肌细胞中血管紧张素Ⅱ信号事件的机制假说。 到 对一般模型的检验，我们提出以下具体目标：1） 定义激活的AT 1AR所针对的特定膜结构域 激活后动员; 2）确定小窝的作用， 双相信号传导的紧张成分的激活位点 反应; 3）确定酪氨酸激酶的激活机制 4）检查小窝在氧化剂中的作用- 敏感的AT 1AR介导的信号转导; 5）使用杆状病毒 表达系统和来自细胞研究的信息，确定 AT 1AR信号通路的组分物理相互作用。 这些 研究应该提供新的见解的机制， 发挥其重要的生理和病理生理作用。

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.