MECHANISM OF ACTION OF GROWTH HORMONE

除了促进整体身体的增长，通过行动的 胰岛素样生长因子，GH直接作用于 脂肪组织、肌肉、肝脏和胰腺中的分化细胞 调节能量代谢。 对肌肉和脂肪的影响 组织是复杂的，包括胰岛素样刺激GH剥夺 组织，然后诱导对进一步刺激的不应性， 这种模式和胰岛素的作用相反， 和葡萄糖代谢的拮抗作用。 这三种不同的行为似乎 是由不同的受体相互作用引起的。 可用 关于GH受体的信息不能解释这种多重性， 相互作用，很少有人知道GH受体信号如何改变 细胞活动 GH受体基因是复杂的，至少有2 受体蛋白的同种型通过选择性剪接 它的mRNA在脂肪细胞、肝脏和可能的其他组织中。 的一个目标 拟议的研究是评估不同的假设， GH受体的亚型介导不同类型的反应， 脂肪细胞 我们将确定是否有其他亚型表达 在脂肪细胞中，无论它们是较大受体复合物的亚基， 它们是否是独立调节的，是否是不同的同种型或 复合物可以与特定的反应相关联， 受体在细胞表面重新排列、聚集或覆盖以响应GH。 另一个目标是探索生长激素受体的早期后果， 相互作用，以确定信号转导的机制。 为此，我们将研究一种突变的生长激素的相互作用， 受体，但未能发出信号，而是作为一个竞争性的 GH的拮抗剂。 我们将继续研究新发现的 GH增加细胞内钙离子浓度的作用， 特别是，将重点放在这一最早的基础机制， 已知GH-受体相互作用的表达。 完成这些 目标将需要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 提供了基本的见解的机制，生长激素调节 分化细胞的代谢行为，并协调它们的 支持机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.