MOLECULAR PROPERTIES OF CARDIAC ADRENERGIC RECEPTORS

我们请求支持一个基础研究项目，旨在阐明 在分子水平上，该基因的性质和功能模式 儿茶酚胺的β肾上腺素能受体。儿茶酚胺，如 去甲肾上腺素和肾上腺素在荷尔蒙中是至关重要的。 对整个循环的控制。这些化合物通过刺激 膜结合酶腺苷环化酶，它是由 结合特定的β-肾上腺素能受体。虽然我们的动力 研究一直渴望阐明基本的生物化学 肾上腺素能控制循环的基本过程，它已经成为 越来越清楚的是，研究β受体的最佳模型 循环酶系统是简单、均一的细胞群体。相应地，很多 我们的大部分工作都是用这样简单的模型系统进行的。这项建议具有 三个密切相关的主要目标，都涉及主要关注 β-肾上腺素能受体作为一种增进理解的途径 生理过程中正常和不正常的荷尔蒙控制。 这些目标是：1)获得有关该基因的详细分子信息 包括完整的β-肾上腺素能受体的生化性质 从cDNA克隆推导出的氨基酸序列以及 整个基因；2)了解受体的功能方式 为了翻译激动剂配体在细胞外表面的结合 细胞激活鸟嘌呤核苷酸调节蛋白和 质膜内的腺苷酸环化酶。这将通过以下方式完成 在人工膜中进行重建研究，其中纯化 受体和纯化的效应器成分重组并发挥其功能 所研究的相互作用。3)了解受体的功能方式 都是在质膜中调节的，例如通过共价 修改，并在核水平上，在速度方面 受体的细胞基因转录。主要焦点将是 腺苷环化酶对药物的脱敏作用 β-肾上腺素能刺激。这种脱敏是一种常见的 β-肾上腺素能等药物在高血压病治疗中的应用 激动剂。这些研究将提供第一个全面的情况 腺苷环化酶偶联受体的功能模式 有关受体结构的详细信息为 了解受体功能和受体调节。

We request support for a program in basic research directed at elucidating at a molecular level the nature and mode of functioning of the Beta-adrenergic receptors for catecholamines. Catecholamines such as norepinephrine and epinephrine are of vital importance in the hormonal control of the entire circulation. These compounds act via stimulation of the membrane-bound enzyme adenylate cyclase which is in turn mediated by binding to specific Beta-adrenergic receptors. Although the impetus to our studies has been the desire to shed light on the basic biochemical processes underlying adrenergic control of the circulation, it has become increasingly clear that the best models for study of the Beta-receptor cyclase system are simple, homogeneous cell populations. Accordingly, much of our work is conducted with such simple model systems. This proposal has three major intimately linked goals, all involving primary focus on the Beta-adrenergic receptor as an approach to gaining increased understanding of the normal and abnormal hormonal control of physiological processes. These goals are: 1) to obtain detailed molecular information about the biochemical nature of the Beta-adrenergic receptor including the complete amino acid sequence as deduced from cDNA clones as well as the sequence of the entire gene; 2) to understand the way in which the receptor functions to translate the binding of an agonist ligand on the outer surface of the cell into activation of the guanine nucleotide regulatory protein and the enzyme adenylate cyclase within the plasma membrane. This will be done by performing reconstitution studies in artificial membranes wherein purified receptor and purified effector components are reunited and their functional interactions studied. 3) To understand the way in which receptor function is regulated both in the plasma membrane, as for example by covalent modification, and at the nuclear level in terms of the rate of transcription of the cellular gene for the receptor. The major focus will be on the problem of desensitization of adenylate cyclase to Beta-adrenergic stimulation. Such desensitization is a common result of the therapeutic application of Beta-adrenergic and other types of agonists. These studies will provide the first comprehensive picture of the mode of functioning of an adenylate cyclase-coupled receptor in which detailed information about receptor structure provides the basis for understanding receptor function and receptor regulation.