BETA 1 AND BETA 3 ADRENORECEPTORS

β3肾上腺素能受体(AR)已被认为是一种治疗 肥胖症和成人糖尿病的治疗目标，以及最近 工作发现了人类β3-AR基因的一个多态性，即 与超重和胰岛素抵抗有关。Beta3-AR是 几乎只在脂肪细胞中表达，在脂肪细胞中它们共同表达 使用Beta1-AR。β3-AR基因表达的组织特异性模式 它与β1-AR在脂肪组织中的共存引起了几个 基本问题。第一，Beta1-和Beta3-AR的共表达 脂肪细胞中的β3-AR亚型具有不同的功能 在脂肪细胞中的信号功能，最近的证据表明 Beta1和Beta3-AR具有独特的信令属性，并且这些 受体激活脂肪细胞中不同的途径。该组织 脂肪细胞中Beta1和Beta3-AR信号的进一步 关于生物化学和生物化学的特征和具体假设 该组织的蜂窝基础将得到测试。第二，Beta1-和 β3-AR表现出几种独特的药理和生化 可用于分子分析的特性。一组表位- 标记、突变和嵌合的受体已经被创造出来，将使 对脂肪细胞观察的验证和进一步的解剖 β3-AR亚型特异性信号传递特性的分子基础。 这些分析将包括分子药理学的检查。 芳氧普萘醇胺和苯乙醇胺激动剂，化合物为 开发为选择性β3-AR激动剂。对这些问题的理解 化合物与β3-AR亚型有不同的相互作用，并且 这种相互作用对受体信号的影响是理解 他们的生物行为。具体目标是：目标1.调查 脂肪细胞中β3-AR信号的生化组织。目标2. 为了进一步表征Beta1-的差异信号特性- β3-AR，并检测其细胞和分子基础。特定目标 3.研究β_3-AR选择性激动剂的分子药理作用。

The beta3 adrenergic receptor (AR) has been proposed to be a therapeutic target for the treatment of obesity and adult-onset diabetes, and recent work has identified a polymorphism in the human beta3-AR gene that is associated with excess weight gain and insulin resistance. Beta3-AR are expressed almost exclusively in adipocytes where they are co-expressed with beta1-AR. The tissue-specific pattern of beta3-AR gene expression and its co-existence in adipose tissue with beta1-AR has raised several fundamental questions. First, the coexpression of beta1-and beta3-AR in fat cells implies that the beta3-AR subtypes serve different signaling functions in adipocytes, and recent evidence indicates that beta1- and beta3-AR have unique signaling properties and that these receptors activate distinct pathways in adipocytes. The organization of beta1- and beta3-AR signaling in adipocytes will be further characterized and specific hypotheses regarding the biochemical and cellular basis of that organization will be tested. Second, beta1- and beta3-AR exhibit several unique pharmacological and biochemical properties that are amenable to molecular analysis. A panel of epitope- tagged, mutated and chimeric receptors have been created that will allow validation of observations made in adipocyte and further dissection of the molecular bases of beta3-AR subtype-specific signaling properties. These analyses will include examination of the molecular pharmacology of aryloxypropranolamine and phenethanolamine agonists, compounds being developed as selective beta3-AR agonists. An understanding of how these compounds differentially interact with the beta 3-AR subtypes, and the impact of that interaction on receptor signaling is key to understanding their biological actions. Specific aims are: Aim 1. To investigate the biochemical organization of beta3-AR signaling in adipocytes. Aim 2. To further characterize the differential signaling properties of beta1- beta3-AR and to examine the cellular and molecular basis. Specific Aim 3. To examine the molecular pharmacology of beta3-AR-selective agonists.