Camiña Jesus P, Carreira Marcos C, Micic Dragan, Pombo Manuel, Kelestimur Fahrettin, Dieguez Carlos, Casanueva Felipe F
Department of Medicine, Research Area, Molecular Endocrinology Laboratory, School of Medicine and Complejo Hospitalario Universitario de Santiago, University of Santiago de Compostela, E-15780 Santiago de Compostela, Spain.
Endocrine. 2003 Oct;22(1):5-12. doi: 10.1385/ENDO:22:1:5.
The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHSR1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK- 293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3- dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels (store-operated calcium channels). Upon repeated administration, ghrelin showed a marked suppression of ghrelin-mediated elevations of intracellular calcium. This homologous desensitization represents an important physiological mechanism that modulates receptor responsiveness and acts as an information filter for intracellular signaling system. The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis.
垂体前叶生长激素（GH）的脉冲式释放受至少两种下丘脑激素——生长激素释放激素（GHRH）和生长抑素相互作用的调节，它们通过与垂体前叶生长激素细胞上的特定细胞表面受体结合来发挥作用。此外，体内GH的释放还可能受第三种受体——生长激素促分泌素受体的控制，这是一种G蛋白偶联受体，称为1a型生长激素促分泌素受体（GHSR1a），它是利用非肽类生长激素促分泌素（MK - 0677）在人类垂体和下丘脑中鉴定出来的。胃饥饿素是GHS - R1a的内源性配体，是一种从人胃中分离出的28个氨基酸的肽，其丝氨酸3位通过共价连接的直链辛酰基修饰，这对其内分泌活性至关重要。这种主要由胃表达和分泌的激素对GH分泌和食物摄入具有双重作用，表明这些作用之间存在相互依赖性。禁食和进食分别增加和减少胃饥饿素分泌这一发现表明，这种激素可能是连接体细胞生长、身体组成与能量代谢的桥梁，并且似乎在甲状腺功能减退和甲状腺功能亢进等病理生理状态下的能量稳态和体重改变中发挥作用。尽管如此，对于胃饥饿素发挥其调节作用所通过的细胞内信号传导知之甚少。细胞内钙动员的激活是已知最早由胃饥饿素引发的细胞信号之一。在表达GHS - R1a的HEK - 293细胞中，胃饥饿素诱导双相性胞质钙升高，其特征为反应的尖峰期，反映细胞内储存的Ins(1,4,5)P3依赖性钙动员，以及反应的持续期，这是由于钙通过电容性钙通道（储存操纵性钙通道）开放触发的跨质膜内流所致。重复给药后，胃饥饿素对胃饥饿素介导的细胞内钙升高表现出明显的抑制作用。这种同源脱敏代表了一种重要的生理机制，可调节受体反应性，并作为细胞内信号系统的信息过滤器。胃饥饿素的发现为负责调节GH分泌以及食欲和能量稳态的复杂机制增添了一个新的组成部分。
