MECHANISM OF ACTION OF GROWTH HORMONE

除了通过运动促进身体的全面发育之外 胰岛素样生长因子、生长激素直接作用于终末 脂肪组织、肌肉、肝脏和胰腺中的分化细胞 胰岛调节能量代谢。对肌肉和脂肪的影响 组织是复杂的，在生长激素缺乏时包括胰岛素样刺激 组织，然后诱导不耐药以进一步刺激 这一模式和胰岛素的反作用，如加速脂肪分解 和葡萄糖代谢的拮抗作用。这三个截然不同的动作似乎 由单独的激素-受体相互作用产生。可用 有关生长激素受体的信息不能解释这种多重 相互作用，对生长激素受体信号如何改变知之甚少 细胞活动。生长激素受体基因是复杂的，至少有2 受体蛋白的异构体通过交替剪接表达 它在脂肪细胞、肝脏，可能还有其他组织中都有表达。的一个目标 拟议的研究是为了评估不同的假设 生长激素受体亚型介导不同类型的反应 脂肪细胞。我们将确定是否表达更多的异构体 在脂肪细胞中，无论它们是更大的受体复合体的亚单位， 无论它们是独立调节的，无论是不同的异构体还是 复合体可以与特定的反应联系在一起，以及 受体对生长激素的反应在细胞表面重新排列、簇状或帽状。 另一个目标是探索生长激素受体的早期影响 相互作用，以努力确定信号转导的机制。 为此，我们将研究突变的生长激素与 受体，但不能发出信号，而是充当竞争性的 生长激素拮抗剂。我们将继续研究新发现的 生长激素增加细胞内钙浓度的作用，并在 尤其是，将重点放在最早的 已知的生长激素受体相互作用的表达。实现这些目标 目标将要求应用生物化学和分子生物学 方法以及数字成像显微镜。这些研究应该 提供对生长激素调节机制的基本见解 分化细胞的代谢行为，并协调其 维持生物体整体能量平衡的活动。

In addition to promoting overall-bodily growth through the actions of the insulin-like growth factors, GH acts directly on terminally differentiated cells in adipose tissue, muscle, liver, and pancreatic islets to regulate energy metabolism. The effects on muscle and adipose tissue are complex and include insulin-like stimulation in GH deprived tissues followed by induction of refractoriness to further stimulation in this mode and by such contra insulin actions as acceleration of lipolysis and antagonism of glucose metabolism. These 3 distinct actions appear to result from separate hormone-receptor interactions. Available information on the GH receptor cannot account for such multiple interactions, and little is known of how the GH receptor signals altered cellular activity. The GH receptor gene is complex, and at least 2 isoforms of receptor protein are expressed through alternate splicing of its mRNA in adipocytes, liver, and probably other tissues. One goal of the proposed studies is to evaluate the hypothesis that different isoforms of the GH receptor mediate different classes of response in adipocytes. We will determine whether additional isoforms are expressed in adipocytes, whether they are subunits of larger receptor complexes, whether they are independently regulated, whether different isoforms or complexes can be associated with particular responses and whether receptors realign, cluster or cap on the cell surface in response to GH. Another goal is to explore the early consequences of GH-receptor interaction in an effort to define the mechanisms of signal transduction. To this end we will study the interactions of a mutated GH which binds to the receptor, but fails to signal and acts instead as a competitive antagonist of GH. We will continue our studies of the newly discovered actions of GH to increase intracellular calcium concentrations, and, in particular, will focus on the mechanisms that underlie this earliest known expression of GH-receptor interaction. Accomplishment of these goals will require application of biochemical and molecular biological approaches as well as digital imaging microscopy. These studies should provide fundamental insights into the mechanisms by which GH modulates the metabolic behavior of differentiated cells and coordinates their activities in support of the overall energy balance of the organism.