CRITICAL CELLULAR EVENTS IN ALDOSTERONE SYNTHESIS

肾上腺肾小球细胞分泌醛固酮是 由许多促分泌素调节。 大多数特工 可能至少部分地通过钙来调节它们的作用， 信使系统 在AII的情况下，据认为， 激素结合会激活细胞膜 分解磷脂酰肌醇4，5的磷酸二酯酶 二磷酸到肌醇1，4，5三磷酸和二酰基甘油。 前者引起细胞内钙释放，从而激活细胞内钙离子通道。 钙调蛋白依赖性蛋白激酶，而后者被认为是 激活膜结合蛋白激酶C。关键事件 在三个层次上：1）受体-受体相互作用; 2） 膜相关事件，和3）细胞内事件。 的 本研究的目的是更全面地描述这些事件 并将它们整合到一个 激素作用的综合模型。关于荷尔蒙的研究- 受体的相互作用将首先集中在是否有鸟嘌呤 核苷酸结合蛋白，将受体连接到 磷酸二酯酶，如果是这样，我们将尝试分离， 描述这种蛋白质。 接下来，细胞基质和 磷脂酰肌醇周转的时间模式将 用放射性标记和色谱法测定 技术. 这些产品作为第二种产品可能有什么作用 信使也将被评估。 膜的研究- 相关事件将集中于确定是否存在Na+/H+ 肾小球细胞中的交换器，如果有，它起什么作用 在信号传导中。 膜相关C- 激酶将通过使用免疫细胞化学 本地化技术。 细胞内事件的研究将 重点介绍蛋白激酶（CaM/PK II、C-激酶、M-激酶）的作用 可能会影响信号传播。 使用32 P或35 S标记， 将记录“不稳定”蛋白质的存在， 将确定它是否是链接 蛋白激酶活性的变化和实际的 合成和分泌醛固酮。 这些的重要性 研究是双重的。 首先，醛固酮参与盐和 水平衡，从而发挥作用，在多种病理 states. 通过了解调节的机制， 醛固酮分泌，我们可能能够有利地改变他们的 当然了 第二，正在研究的受体-受体相互作用 不仅发生在肾上腺肾小球细胞， 各种各样的细胞遍布全身。 因此， 从这些研究也可能适用于激素调节， 这些组织中的细胞反应。

Aldosterone secretion from the adrenal glomerulosa cell is regulated by a number of secretagogues. Most of these agents probably mediate their effects, at least in part, via the calcium messenger system. In the case of AII, it is thought that upon hormone binding there is an activation of a membrane phosphodiesterase which breaks down phosphatidylinositol 4,5 bisphosphate to inositol 1,4,5 trisphosphate and diacylglycerol. The former causes intracellular calcium release, thus activating a calmodulin-dependent protein kinase, while the latter is thought to activate membrane bound, protein kinase C. Key events take place at three levels: 1) hormone-receptor interaction; 2) membrane-associated events, and 3) intracellular events. The goal of this study is to more fully characterize the events occurring at each of these levels and integrate them into a comprehensive model of hormone action. The studies on hormone- receptor interaction will first focus on whether there is a guanine nucleotide binding protein linking the receptor to the phosphodiesterase and, if so, we will attempt to isolate and characterize this protein. Next, the cellular substrates and temporal patterns of phsophatidylinositol turnover will be determined with radioactive labeling and chromatographic techniques. What role these products may have as second messengers will also be evaluated. The studies on membrane- associated events will focus on determining if there is a Na+/H+ exchanger in glomerulosa cells and if there is, what role it plays in signal transduction. The role of the membrane associated C- kinase will be evaluated by using immunocytochemical localization techniques. The studies on intracellular events will focus on what role protein kinase (CaM/PK II, C-kinase, M-kinase) may play in signal propagation. Using 32P or 35S labeling, the existence of a "labile" protein will be documented, and a determination will be made as to whether or not it is the link between the changes in protein kinase activity and actual synthesis and secretion of aldosterone. The importance of these studies is two-fold. First, aldosterone is involved in salt and water homeostasis and thus plays a role in multiple pathological states. By understanding the mechanisms of regulation of aldosterone secretion, we may be able to favorably alter their course. Second, the hormone-receptor interactions being studied take place not only in the adrenal glomerulosa cell but in a variety of cells throughout the body. Thus, principles derived from these studies may also apply to the hormonal regulation of cellular responses in these other tissues.