BETA1 AND BETA3 ADRENORECEPTORS

Beta1 和 Beta3 肾上腺素受体

• 批准号: 2016648
• 负责人: James G Granneman
• 金额: $ 22.16万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2016648
• 关键词: adenylate cyclase; adipocytes; animal genetic material tag; beta adrenergic agent; beta adrenergic receptor; brown fat; cyclic AMP; gene expression; gene induction /repression; genetic promoter element; human genetic material tag; immunocytochemistry; introns; isoproterenol; laboratory rat; lipolysis; molecular cloning; protein isoforms; protein purification; protein structure function; receptor binding; receptor coupling; receptor expression; receptor sensitivity; reporter genes; tissue /cell culture

The beta3 adrenergic receptor has been proposed to be a therapeutic target for the treatment of obesity and adult-onset diabetes, yet very little is known about the biochemical and pharmacological properties of these receptors. Pharmacological and molecular data indicate that adipose tissues contain both beta1 and beta3 receptors, yet it is unclear why fat cells make both receptor subtypes. Our preliminary data, however, indicate that beta1 and beta3 receptors have distinct signal- transducing properties and are differentially regulated by agonist exposure. We propose to further characterize these differences and examine the molecular bases of those differences. We have discovered that he human beta3 receptor gene contains an intron and a second protein-coding exon. All previous work with the recombinant human beta3 receptor was conducted on a protein that lacked the sequence from the second exon, and thus was incomplete. Furthermore, preliminary data indicates that the newly-discovered exon may play an important role in the pharmacological and regulatory properties of the human receptor. We have also discovered that the rat beta3 receptor gene also contains multiple exons and introns. The sequence of the first intron of the rat gene suggest that it may play a role in fat-specific expression. Our specific aims are: 1. To characterize, for the first time, the pharmacological properties of the recombinant full-length human beta3 receptor. To further characterize the differential signalling properties of beta1 and beta 3 receptors. 2. To characterize the differential regulation of beta1 and beta3 receptors by agonist exposure and to examine the molecular basis. 3. To evaluate the impact of the differential signalling properties of beta1 and beta3 receptors on physiological responses in adipocytes. 4. To determine the genetic elements that confer adipose tissue-specific expression of the rat beta3 receptor, with a initial focus on the potential role of the first intron. To determine whether the human beta3 receptor gene contains similar elements.

β3肾上腺素能受体已被认为是一种治疗性 治疗肥胖症和成人糖尿病的靶标 关于生化和药理学特性知之甚少 这些受体。 药理和分子数据表明 脂肪组织既包含beta1和beta3受体，但尚不清楚 为什么脂肪细胞会形成两种受体亚型。 我们的初步数据， 但是，表明beta1和beta3受体具有不同的信号 - 转导特性，并受动物差异调节 接触。 我们建议进一步描述这些差异， 检查这些差异的分子碱基。 我们发现他的人beta3受体基因包含一个内含子 和第二个蛋白质编码外显子。 重组的所有以前的工作 人β3受体是在缺乏序列的蛋白质上进行的 从第二个外显子开始，因此不完整。 此外，初步 数据表明，新发现的外显子可能起重要作用 在人体受体的药理和调节特性中。 我们还发现大鼠beta3受体基因也包含 多个外显子和内含子。 大鼠第一内含子的序列 基因表明它可能在脂肪特异性表达中起作用。 我们的 具体目的是： 1。首次表征药理特性 重组全长的人β3受体的。 进一步 表征beta1和beta 3的差分信号传导特性 受体。 2。表征beta1和beta3的差分调节 受动力学暴露的受体并检查分子基础。 3。评估差分信号传导特性的影响 脂肪细胞中生理反应的β1和β3受体。 4。确定赋予脂肪组织特异性的遗传元素 大鼠β3受体的表达，最初的重点 第一个内含子的潜在作用。 确定人beta3是否 受体基因包含相似的元素。