Secretagogues and the somatotrope: signaling and proliferation.
Secretagogues and the somatotrope: signaling and proliferation.
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发表时间：
2000-12
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通讯作者：
L. Frohman;R. Kineman;J. Kamegai;S. Park;L. T. Teixeira;K. T. Coschigano;J. J. Kopchic-J.
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作者：
L. Frohman;R. Kineman;J. Kamegai;S. Park;L. T. Teixeira;K. T. Coschigano;J. J. Kopchic-J.
生长激素功能需要考虑生长激素 (GH) 分泌和细胞增殖。这些过程的调节在很大程度上由三种下丘脑激素控制：生长激素释放激素（GHRH）、生长抑素（SRIF）和尚未鉴定的生长激素促分泌素（GHS）。每个都与 G 蛋白连接的膜受体结合，通过该受体发生信号传导。我们的实验室使用了一系列对 GH 调节系统各个组成部分进行扰动的遗传和转基因模型来研究生长激素信号传导和增殖。 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，这意味着两个信号系统之间存在相互作用。自发性侏儒大鼠 (SDR) 的 GH 基因突变导致激素完全缺失，由于缺乏 GH 反馈和垂体受体表达的改变，下丘脑调节激素出现特征性变化。用 GHRH 和 GHS 处理 SDR 可以证明 GHRH 对 GHRH-R、GHS-R 和 SRIF 2 型受体 (SSTR-2) 表达的刺激作用以及对 SSTR-5 表达的抑制作用。生长激素也会改变这些受体的表达，尽管它的影响是在以后的时间段才会出现，而且似乎是间接的。总体而言，结果表明 GH 分泌存在复杂的调节，其中生长激素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 信号完整，但 SDR 和 GH-R 敲除 (ko) 小鼠的垂体较小且生长激素减少。将 hGHRH 转基因引入 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素增殖的因素提供了新的见解。
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.