Mayo K E, Miller T, DeAlmeida V, Godfrey P, Zheng J, Cunha S R
Department of Biochemistry, Molecular Biology & Cell Biology, Northwestern University, Evanston, Illinois 60208, USA.
Recent Prog Horm Res. 2000;55:237-66; discussion 266-7.
Hormones from the hypothalamus mediate interactions between the nervous and endocrine systems by controlling the activity of specific target cells in the anterior pituitary gland. The hypothalamic peptide, growth hormone-releasing hormone (GHRH), acts on pituitary somatotroph cells to stimulate their proliferation during development and to regulate their ability to produce and secrete growth hormone (GH). These actions are mediated by a recently identified receptor for GHRH that belongs to family B-III of the G protein-coupled receptor superfamily. The rat GHRH receptor is expressed predominantly in the pituitary gland and in somatotroph cells. To investigate this tissue- and cell-specific expression, the receptor gene has been cloned and characterized. The receptor gene promoter is selectively expressed in pituitary cells and is regulated by the pituitary-specific transcription factor Pit-1. There is a sexual dimorphism in GHRH receptor expression in the rat pituitary, suggesting regulation by gonadal steroids. In addition, glucocorticoids are potent positive regulators of GHRH receptor gene expression. Substantial evidence points to an important role for GHRH in regulating the proliferation and functional activity of the somatotroph cell. This is best observed in the dwarf little mouse, which harbors a mutation in the extracellular domain of the GHRH receptor that abolishes the receptor's hormone-binding and signaling properties, resulting in severe somatotroph hypoplasia. Complementary studies in transgenic mice overexpressing the ligand GHRH reveal corresponding somatotroph hyperplasia. Consistent with these observations, GHRH potently activates the MAP kinase pathway in pituitary somatotroph cells. To better understand the hormone-binding and signaling properties of the GHRH receptor, mutant and chimeric receptors have been analyzed to define domains important for GHRH interaction. The GHRH receptor signals predominantly through cAMP-dependent pathways; however, a variant form of the GHRH receptor with an insertion into the third intracellular domain, generated through alternative RNA processing, binds GHRH but fails to signal, suggesting potential modulation of receptor function at a post-transcriptional level. This chapter will integrate these basic investigations of GHRH and its receptor with current information on the involvement of the GHRH signaling system in human diseases of GH secretion and growth.
下丘脑分泌的激素通过控制腺垂体中特定靶细胞的活性来介导神经和内分泌系统之间的相互作用。下丘脑肽，即生长激素释放激素（GHRH），作用于垂体生长激素细胞，在发育过程中刺激其增殖，并调节其产生和分泌生长激素（GH）的能力。这些作用是由最近鉴定出的一种GHRH受体介导的，该受体属于G蛋白偶联受体超家族的B-III家族。大鼠GHRH受体主要在垂体和生长激素细胞中表达。为了研究这种组织和细胞特异性表达，已克隆并鉴定了该受体基因。该受体基因启动子在垂体细胞中选择性表达，并受垂体特异性转录因子Pit-1调控。大鼠垂体中GHRH受体表达存在性别差异，提示受性腺类固醇调节。此外，糖皮质激素是GHRH受体基因表达的有效正调节因子。大量证据表明GHRH在调节生长激素细胞的增殖和功能活性中起重要作用。这在矮小的小鼠中表现得最为明显，该小鼠的GHRH受体细胞外结构域发生突变，消除了受体的激素结合和信号传导特性，导致严重的生长激素细胞发育不全。在过表达配体GHRH的转基因小鼠中进行的补充研究揭示了相应的生长激素细胞增生。与这些观察结果一致，GHRH能有效激活垂体生长激素细胞中的MAP激酶途径。为了更好地理解GHRH受体的激素结合和信号传导特性，已对突变型和嵌合型受体进行了分析，以确定对GHRH相互作用重要的结构域。GHRH受体主要通过cAMP依赖性途径发出信号；然而，通过可变RNA加工产生的一种在第三个细胞内结构域插入的GHRH受体变体形式，能结合GHRH但无法发出信号，提示在转录后水平可能对受体功能进行调节。本章将把这些关于GHRH及其受体的基础研究与目前关于GHRH信号系统参与人类生长激素分泌和生长疾病的信息整合起来。
