STRUCTURE AND BIOLOGY OF BETA ADRENERGIC RECEPTORS

许多激素、神经递质和治疗药物与细胞表面结合 受体通过G蛋白调节效应物， 腺苷酸环化酶、磷脂酶C和离子通道控制 胞内信号传导 超过300种G蛋白的基因 受体（GPLR）的基因已经被克隆，并且这些基因的产物已经被 被证明是重要的生理调节器 GPLR中最突出的是 肾上腺素能受体（β 2 AR）， 传播与细胞内信号通路结合的儿茶酚胺 涉及呼吸、心血管功能和新陈代谢。 在 尽管有大量关于原生序列的可用信息， 了解这些受体的功能和丰度是如何 调控在分子水平上仍然很不完整。 激活 许多GPLR导致短期功能丧失（脱敏）， 以及受体丰度的长期损失（下调）。 激动剂诱导的受体下调发生在转录后 对于β 2AR（和其他GPLR），但反应的分子生物学是 不知道。 一种35，000 M的RNA结合蛋白（betaARB）特异性结合 β 2 AR mRNA，其经历去稳定化。 激动剂的生物学- 诱导的，受体mRNA的转录后下调将是 使用生物化学、分子和细胞的混合策略进行探索 生物学 内源性酪氨酸激酶受体（TKRs），如胰岛素 受体，提供了第二个主要的信号传导模式。 TRKs交叉调节 GPLRs通过蛋白质磷酸化。 β 2AR作为底物， 胰岛素受体催化磷酸化的体内和体外研究 功能在对胰岛素的反应中减弱。 交叉的生物学- GPLRs和TKRs之间的调节将被探索到结构 端点，即，确定磷酸化位点和功能结果。 类似的实验将在更广泛的蛋白质主题上进行 GPLR生物学中激酶作用。 分析缺乏特异性抗体的细胞 蛋白激酶将提供一种新的方法来定义时间 GPLR磷酸化的序列和模式，认识到这些 多磷酸化受体是几种不同的 激酶类。 GPLR丰度和功能的改变是 重要的医疗保健问题（充血性心脏病，肥胖， 其他），并了解这些参数的机制 改变是至关重要的发展改善临床管理， 治疗

Many hormones, neurotransmitters and therapeutic drugs bind to cell-surface receptors that function via G-proteins to regulate effectors such as adenylylcyclase, phospholipase C, and ion channels controlling intracellular signaling. The genes for more than 300 G-protein-lined receptors (GPLRs) have been cloned and products of these genes have been shown to mediate vital physiology. Prominent among the GPLRs are catecholamine receptors like the beta2-adrenergic receptor (beta2AR) that propagates catecholamine binding to intracellular signaling pathways involved with respiration, cardiovascular function, and metabolism. In spite of the wealth of available information on primary sequence, our understanding of how the function and abundance of these receptors are regulated remains largely incomplete at the molecular level. Activation of many GPLRs results in a short-term loss of function (desensitization) as well as a longer-term loss in receptor abundance (down-regulation). Agonist-induced down-regulation of receptor occurs post-transcriptionally for beta2AR (and other GPLRs), but the molecular biology of the response is not known. A 35,000M, RNA-binding protein (betaARB) specifically binds to beta2AR mRNA which undergoes destabilization. The biology of agonist- induced, post-transcriptional down-regulation of receptor mRNA will be explored using a hybrid strategy involving biochemistry, molecular and cell biology. Intrinsic tyrosine kinase receptors (TKRs) like the insulin receptor, provide a second major signaling paradigm. TRKs cross-regulate GPLRs via protein phosphorylation. The beta2AR acts as a substrate for insulin receptor-catalyzed phosphorylation in vivo and in vitro and its function is attenuated in response to insulin. The biology of cross- regulation between GPLRs and TKRs will be explored to the structural endpoint, i.e., defining sites of phosphorylation and functional outcome. Similar experiments will be conducted on the broader theme of protein kinase action in GPLR biology. Analysis of cells deficient in a specific protein kinase will provide a novel approach to defining the temporal sequence and pattern of GPLR phosphorylation, recognizing that these multiply-phosphorylated receptors are substrates for several distinct classes of kinases. Alterations in GPLR abundance and function underlie important health care problems (congestive heart disease, obesity, and others) and understanding the mechanisms by which these parameters are altered is critical to developing improved clinical management and therapies.