Angiotensin II Receptor Signaling Domains

血管紧张素 II 受体信号传导域

• 批准号: 6603390
• 负责人: Robert WAYNE ALEXANDER
• 金额: $ 34.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-18 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603390
• 关键词: angiotensin II; angiotensin receptor; biological signal transduction; caveolas; enzyme activity; free radical oxygen; hormone regulation /control mechanism; intracellular transport; membrane activity; membrane structure; mitogen activated protein kinase; molecular assembly /self assembly; protein localization; protein structure function; protein tyrosine kinase; receptor binding; receptor expression; renin angiotensin system; tissue /cell culture; vascular smooth muscle

DESCRIPTION: (Verbatim from the application): The renin-angiotensin system is important in normal physiology and the diseases hypertension and atherosclerosis. Angiotensin II (Ang II), interacts with, among others, the Ang II type 1A receptor (AT, AR) of vascular smooth muscle cells (VSMCs), leading to activation of several phospholipases (PL). The second or tonic phase of signaling requires endocytosis or sequestration of the AT1 4R to an undefined discrete signaling domain, a major focus of this proposal. Additionally, Ang II increases intracellular calcium, and activates protein kinase C, Src family kinases and Jak kinases, as well as mitogen activated protein kinases that mediate VSMC hypertrophy and growth. Importantly, Mg II induces robust generation of reactive oxygen species (ROS) that are major modifiers of signal generation. Calcium-dependent transactivation of the epidermal growth factor receptor (EGF R) serves as a "scaffold" for the assembly of a signaling complex including cSrc, Pyk2, and downstream adaptors (Shc, Grb2, Sos), leading to ERK1/2 and protein kinase B/Akt activation. Little is known of the spatial-temporal organization of AT,A R signaling in the VSMC membrane and how specificity is achieved. Evidence suggests that receptors and associated signaling molecules are not randomly distributed but are localized in specialized domains. Functionally distinct microdomains with characteristic lipid composition, "lipid rafts," have been identified in plasma membranes. "Rafts" localize signaling molecules including receptors, G-protein subunits, adaptor molecules, and a host of signal generating proteins. They serve as scaffolds to facilitate interactions among pathways and signaling proteins. Caveolae are cell membrane invaginations that contain the major structural protein caveolin and are specialized forms of rafts. We have shown that Ang II stimulation of VSMCs causes movement of the AT, A R into caveolae-enriched membrane fractions. Its original, basal location is undefined. Another major signaling domain is the focal adhesion or complex, which contains integrin receptors and many associated signaling molecules as well as caveolin. The EGF R has been associated with both caveolae and focal adhesions. Our preliminary data indicate that the Mg Il-induced transmodulation of the EGF-R and certain downstream pathways are dependent upon ROS and suggest involvement of both caveolin and focal adhesion associated molecules. We hypothesize that the full repertoire of Ang 11-induced signals in VSMC is dependent upon several major "scaffolds" and discrete signaling domains. To gain insight into these issues we propose three Specific Aims involving: 1) the basal location and mechanisms by which AT1ARS move to caveolae-enriched fractions; 2) determination of the functional consequences of this movement or sequestration; and 3) determination of the role of ROS in affecting the related signaling pathways. Insights gained in understanding of the mechanisms of Ang II signaling will lead to increased understanding of the pathogenesis and potential treatment of hypertension and atherosclerosis.

描述：（逐字化的应用程序）：肾素 - 血管紧张素系统是 在正常生理学和疾病中重要的高血压和 动脉粥样硬化。血管紧张素II（ANG II）与Ang相互作用 II血管平滑肌细胞（VSMC）的1A型受体（AT，AR），领先 激活几种磷脂酶（PL）。第二或滋补阶段 信号传导需要AT1 4R的内吞或隔离到不确定的 离散信号域，这是该提案的主要重点。另外，Ang II 增加细胞内钙，并激活蛋白激酶C，SRC家族 激酶和JAK激酶，以及有丝分裂原激活的蛋白激酶 介导VSMC肥大和生长。重要的是，MG II诱导了鲁棒 活性氧（ROS）的产生是信号的主要修饰符 一代。表皮生长因子的钙依赖性反式激活 受体（EGF R）用作信号复合物组装的“支架” 包括CSRC，PYK2和下游适配器（SHC，GRB2，SOS），导致 ERK1/2和蛋白激酶B/AKT激活。对 AT的时空组织，VSMC膜中的R信号传导以及如何 达到了特异性。有证据表明受体和相关 信号分子不是随机分布的，而是位于 专业领域。具有特征性的功能不同的微域 在质膜中已经鉴定出脂质组成，“脂质筏”。 “筏”定位信号分子，包括受体，G蛋白亚基， 衔接子分子和许多信号产生蛋白质。他们用作 脚手架以促进途径和信号蛋白之间的相互作用。 小窝是细胞膜的起伏，包含主要结构 蛋白质小窝蛋白，是筏子的特殊形式。我们已经证明了Ang II VSMC的刺激导致AT的运动，A r进入小窝富集 膜分数。它的原始基础位置不确定。另一个专业 信号域是局灶性粘附或复合物，其中包含整联蛋白 受体和许多相关的信号分子以及小窝蛋白。 EGF R与小窝和局灶性粘连有关。我们的初步 数据表明MG IL诱导的EGF-R的透射和某些 下游途径取决于ROS，并暗示两者的参与 小窝蛋白和局灶性粘附相关分子。我们假设完整 VSMC中ANG 11引起的信号的曲目取决于几个主要 “脚手架”和离散信号域。了解这些问题 我们提出了三个涉及的特定目标：1）基础位置和机制 AT1ARS通过它转移到富含小菜的分数； 2）确定 这种运动或隔离的功能后果； 3）决心 ROS在影响相关信号通路中的作用。洞察力获得了 在理解ANG II信号的机制时，将导致增加 了解高血压的发病机理和潜在治疗 动脉粥样硬化。