BETA1 ADRENERGIC RECEPTOR ACTIVATION & EXPRESSION

肾上腺素能受体（AR）是肾上腺素能神经递质的重要调节剂。 交感神经控制中枢和 周围神经系统包括心脏 存在有限 了解调节-AR亚型的分子机制 在正常和失败的细胞中激活、表达和脱敏 心 1-肾上腺素能受体（1-AR）亚型定位于 主要在心脏，被认为是主要的 心脏收缩速度和力量的调节器。 我的实验室 已经克隆、测序并表达了大鼠和恒河猴 1-肾上腺素能受体基因 我们已经定义了1-AR转录 起始位点、启动子元件和多聚腺苷酸化位点用于 在C6胶质瘤细胞系中表达，并已确定潜在的 影响1-AR表达的增强子和阻遏子区域。 在 此外，我们已经确定了心脏中主要的1-AR启动子， 肌细胞，并已确定，1-AR转录在肌细胞， 心脏主要发生在下游起始部位。 此外，委员会认为， 我们已经证明，诱导型cAMP早期阻遏物（ICER）是 在C6细胞中由1-AR激动剂诱导，并且ICER与 1-AR启动子下调1-AR mRNA转录， 细胞表面受体减少。 目前，更多的研究 以鉴定1-AR的基因组元件和反式激活因子为中心 转录，使用1-AR内切酶-报告基因重组体， 转染测定、DNA迁移率改变和DNA酶足迹测定。 该项目的总体重点是准确识别功能 参与调节的调节要素和因素 1-肾上腺素能受体基因，并分析转录 1-肾上腺素能受体亚型的激活 脱敏和激素刺激。 研究将首先 在使用非人灵长类动物组织之前， 1-AR反式激活因子的鉴定。

The -adrenergic receptors ( -ARs) are important modulators in the sympathetic control of various metabolic processes in the central and peripheral nervous system, including the heart. There is a limited understanding of the molecular mechanisms that regulate -AR subtype activation, expression, and desensitization in the normal and failing heart. The 1-adrenergic receptor ( 1-AR) subtype is localized predominantly in the heart and is believed to be the principal modulator of the rate and force of cardiac contraction. My laboratory has cloned, sequenced, and expressed the rat and rhesus macaque 1-adrenergic receptor genes. We have defined the 1-AR transcriptional start sites, promoter elements, and polyadenylation sites used for expression in the C6 glioma cell line, and have identified potential enhancer and repressor regions that influence 1-AR expression. In addition, we have defined the primary 1-AR promoter in cardiac myocytic cells, and have determined that 1-AR transcription in the heart occurs predominantly from downstream start sites. Furthermore, we have demonstrated that the inducible cAMP early repressor (ICER) is induced in C6 cells by 1-AR agonists, and that ICER interacts with the 1-AR promoter to down-regulate 1-AR mRNA transcription, with resultant diminution of cell surface receptor. Additional research is now centered on identifying genomic elements and trans-activators of 1-AR transcription, with the use of 1-AR luciferase-reporter recombinants, transfection assays, DNA mobility shift and DNase footprinting assays. The overall focus of this project is to precisely identify functional regulatory elements and factors involved in the regulation of the 1-adrenergic receptor gene, and to analyze the transcriptional activation of the 1-adrenergic receptor subtype during receptor desensitization and hormonal stimulation. Research will initially utilize rodent tissues, prior to the use of nonhuman primate tissues, in the identification of 1-AR transactivators.