Frohman L A, Kineman R D, Kamegai J, Park S, Teixeira L T, Coschigano K T, Kopchic J J
Department of Medicine, University of Illinois at Chicago, 60612, USA.
Recent Prog Horm Res. 2000;55:269-90; discussion 290-1.
Somatotrope function requires consideration of both growth hormone (GH) secretion and cellular proliferation. The regulation of these processes is, to a large extent, controlled by three hypothalamic hormones: GH-releasing hormone (GHRH), somatostatin (SRIF), and an as-yet-unidentified GH secretagogue (GHS). Each binds to G protein-linked membrane receptors through which signaling occurs. Our laboratory has used a series of genetic and transgenic models with perturbations of individual components of the GH regulatory system to study both somatotrope signaling and proliferation. Impaired GHRH signaling is present in the lit mouse, which has a GHRH receptor (R) mutation, and the dw rat, which has a post-receptor signaling defect. Both models also have impaired responses to a GHS, implying an interaction between the two signaling systems. The spontaneous dwarf rat (SDR), in which a mutation of the GH gene results in total absence of the hormone, shows characteristic changes in the hypothalamic regulatory hormones due to an absence of GH feedback and alterations in the expression of each of their pituitary receptors. Treatment of SDRs with GHRH and a GHS has allowed demonstration of a stimulatory effect of GHRH on GHRH-R, GHS-R, and SRIF type 2 receptor (SSTR-2) expression and an inhibitory effect on SSTR-5 expression. GH also modifies the expression of these receptors, though its effects are seen at later time periods and appear to be indirect. Overall, the results indicate a complex regulation of GH secretion in which somatotrope receptor, as well as ligand expression, exerts an important physiological role. Both the SDR and the GH-R knockout (ko) mouse have small pituitaries and decreased somatotropes, despite elevated GHRH secretion and intact GHRH-R signaling. Introduction of the hGHRH transgene into GH-R ko mice confirmed that the proliferative effects of GHRH require GH/insulin-like growth factor-I (IGF-I) action. The results offer new insights into factors participating in somatotrope proliferation.
生长激素细胞功能需要同时考虑生长激素（GH）分泌和细胞增殖。这些过程的调节在很大程度上受三种下丘脑激素控制：生长激素释放激素（GHRH）、生长抑素（SRIF）和一种尚未明确的生长激素促分泌素（GHS）。每种激素都与G蛋白偶联膜受体结合，通过这些受体进行信号传导。我们实验室使用了一系列对GH调节系统各个成分进行扰动的遗传和转基因模型，来研究生长激素细胞信号传导和增殖。GHRH信号传导受损存在于具有GHRH受体（R）突变的lit小鼠和具有受体后信号缺陷的dw大鼠中。这两种模型对GHS的反应也受损，这意味着两种信号系统之间存在相互作用。自发性侏儒大鼠（SDR）中，GH基因突变导致该激素完全缺失，由于缺乏GH反馈以及其垂体受体各自表达的改变，下丘脑调节激素出现特征性变化。用GHRH和GHS治疗SDRs已证实GHRH对GHRH-R、GHS-R和生长抑素2型受体（SSTR-2）表达具有刺激作用，对SSTR-5表达具有抑制作用。GH也会改变这些受体的表达，不过其作用在较晚时期才出现，且似乎是间接的。总体而言，结果表明GH分泌存在复杂调节，其中生长激素细胞受体以及配体表达发挥着重要的生理作用。尽管GHRH分泌增加且GHRH-R信号传导完整，但SDR和GH-R基因敲除（ko）小鼠的垂体都较小，生长激素细胞数量减少。将hGHRH转基因导入GH-R ko小鼠证实，GHRH的增殖作用需要GH/胰岛素样生长因子-I（IGF-I）的作用。这些结果为参与生长激素细胞增殖的因素提供了新的见解。
