CRITICAL CELLULAR EVENTS IN ALDOSTERONE SYNTHESIS

肾上腺肾小球细胞分泌的醛固酮 受多个分泌物的调节。大多数这样的特工 可能至少部分地通过钙离子来调节它们的作用。 信使系统。在AII的情况下，人们认为 荷尔蒙结合有一种膜的激活 分解磷脂酰肌醇4，5的磷酸二酯酶 二磷酸为肌醇1，4，5三磷酸和二酰甘油。 前者导致细胞内钙释放，从而激活一种 钙调蛋白依赖的蛋白激酶，而后者被认为是 激活膜结合，蛋白激酶C关键事件采取 在三个层面上放置：1)激素-受体相互作用；2) 膜相关事件；3)细胞内事件。这个 这项研究的目的是更全面地描述事件的特征 在每个级别上发生，并将它们集成到 荷尔蒙作用的综合模型。关于激素的研究-- 受体的相互作用首先集中在是否存在鸟嘌呤 核苷酸结合蛋白将受体连接到 磷酸二酯酶，如果是这样，我们将尝试分离和 描述这种蛋白质的特征。接下来，细胞底物和 磷酸肌醇周转的时间模式将是 放射性标记法和层析法测定 技巧。这些产品作为第二个产品可能起到什么作用 还将对信使进行评估。关于膜的研究-- 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以及如果有，它扮演什么角色 在信号转导方面。膜结合C-的作用 将使用免疫细胞化学方法来评估激酶 本地化技术。对细胞内事件的研究将 关注蛋白激酶(CaM/PK II、C-K、M-K)的作用 可能在信号传播中发挥作用。使用32P或35S标记， “不稳定”蛋白质的存在将被记录在案，并且 将确定它是否是链接 在蛋白激酶活性的变化和实际 醛固酮的合成和分泌。这些因素的重要性 学习是双重的。首先，醛固酮与盐和 水的动态平衡，从而在多种病理变化中发挥作用 各州。通过了解生物多样性的调节机制 我们也许能够有利地改变它们的 当然了。第二，正在研究的激素-受体相互作用 不仅发生在肾上腺小球细胞中，而且发生在 遍及全身的各种细胞。因此，衍生出的原则 来自这些研究的结果也可能适用于激素调节 这些其他组织中的细胞反应。

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.