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 通过G蛋白调节效应器的受体，如 腺苷环化酶、磷脂酶C和离子通道控制 细胞内信号。300多种G蛋白的基因--排列 受体(GPLR)已经被克隆，这些基因的产物已经被 被证明可以调节重要的生理学。在GPLR中，突出的是 儿茶酚胺受体，如β2-肾上腺素能受体(β2AR)， 促进儿茶酚胺与细胞内信号通路的结合 与呼吸、心血管功能和新陈代谢有关。在……里面 尽管有大量关于初级序列的可用信息，我们的 了解这些受体的功能和丰度是如何 在分子水平上，受监管的基因仍然很大程度上是不完整的。激活 许多GPLR导致短期功能丧失(脱敏)，如 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Beta2AR(和其他GPLR)，但反应的分子生物学是 不知道。一种35,000米长的RNA结合蛋白(BetaARB)可与 经历失稳的β-2AR基因。激动剂的生物学- 诱导的、转录后的受体mRNA下调将是 探索使用涉及生物化学、分子和细胞的混合策略 生物学。胰岛素样的内源性酪氨酸激酶受体(TKRs) 受体，提供了第二个主要的信号模式。TRKs交叉监管 通过蛋白质磷酸化的GPLRs。Beta2AR作为底物 胰岛素受体催化的体内外磷酸化及其作用机制 对胰岛素的反应会使功能减弱。杂交的生物学-- 将探讨GPLR和TKR之间的监管，以实现结构性 终点，即确定磷酸化的位置和功能结果。 类似的实验将在更广泛的蛋白质主题上进行 激酶在GPLR生物学中的作用。一种特殊缺陷细胞的分析 蛋白激酶将提供一种新的方法来定义颞叶 GPLR磷酸化的序列和模式，认识到这些 多重磷酸化受体是几种不同的 肌动蛋白的类别。GPLR丰度和功能的变化 重要的医疗保健问题(充血性心脏病、肥胖和 其他)，并了解这些参数的机制 更改对于开发改进的临床管理和 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.