BETA 1 AND BETA 3 ADRENORECEPTORS

β 3肾上腺素能受体（AR）已被提出作为治疗剂。 治疗肥胖症和成人糖尿病的目标，最近 这项工作已经确定了人类β 3-AR基因的多态性， 与过度增重和胰岛素抵抗有关。 Beta3-AR 几乎只在脂肪细胞中表达， beta1-AR β 3-AR基因表达的组织特异性模式 它与β 1-AR在脂肪组织中的共存， 基本问题。 首先，β 1-和β 3-AR的共表达 这意味着β 3-AR亚型在脂肪细胞中起不同的作用， 脂肪细胞中的信号功能，最近的证据表明， β 1-和β 3-AR具有独特的信号传导特性， 受体激活脂肪细胞中的不同途径。 本组织 β 1-和β 3-AR信号在脂肪细胞中的作用将进一步 特征和具体的假设，关于生物化学和 该组织的细胞基础将受到考验。 第二，beta1和 β 3-AR表现出几种独特的药理学和生物化学特性， 适合分子分析的性质。 一组表位- 标记的、突变的和嵌合的受体已经产生， 验证在脂肪细胞中进行的观察，并进一步解剖 β 3-AR亚型特异性信号传导特性的分子基础。 这些分析将包括分子药理学检查 芳氧基普萘洛尔胺和苯乙醇胺激动剂， 作为选择性β 3-AR激动剂开发。 了解这些 化合物与β 3-AR亚型的相互作用不同， 相互作用对受体信号传导影响是理解 他们的生物行为。 具体目标是：目标1。探讨 脂肪细胞中β 3-AR信号的生化组织。 目标2. 为了进一步表征β 1- β 3-AR，并检查细胞和分子基础。 具体目标 3.研究β 3-AR选择性激动剂的分子药理学。

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.