Stojilkovic S S, Catt K J
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Front Neuroendocrinol. 1996 Jul;17(3):327-69. doi: 10.1006/frne.1996.0009.
Endothelins (ETs) were initially thought to be primarily involved in the control of cardiovascular activity, but the presence of ETs and their receptors in a wide variety of other tissues has suggested a much broader range of functions. Specific receptors for ETs are found in nonvascular tissues including neuronal, neuroendocrine, and endocrine cells. In addition, immunoreactive ETs are present in the brain, pituitary, and peripheral endocrine tissues. However, the ET levels in hypothalamo-hypophysial portal and peripheral blood are low, suggesting that the ET system participates in neuroendocrine regulation through paracrine and/or autocrine mechanisms. Both ETA and ETB receptors are expressed in the hypothalamus, adrenal, parathyroid glands, pancreas, ovary, uterus, placenta, and prostate, while only ETA receptors are expressed in GT1 neurons, anterior pituitary cells, alpha T3-1 immortalized gonadotropes, parathyroid-derived cells, thyrocytes, testicular Leydig and Sertoli cells, normal and neoplastic ovarian granulosa cells, chondrocytes, and other cell types. Activation of ET receptors elicits the sequence of cellular events typical of Ca(2+)-mobilizing receptors, with prominent increases in phosphoinositide hydrolysis and elevations of [Ca2+]i that occur in oscillatory and nonoscillatory modes depending on the cell type. ET-induced activation of the phosphoinositide/Ca(2+)- mobilizing pathway in neuronal and endocrine cells is associated with rapid stimulation of secretory responses, including release of gonadotropin-releasing hormone, oxytocin, vasopressin, substance P, atrial natriuretic peptides, gonadotropins, thyrotropin, growth hormone, parathyroid hormone, aldosterone, and catecholamines. On the other hand, ET has inhibitory actions on prolactin, progesterone, and renin release. In addition to stimulating phospholipase C-dependent pathways, ETs also activate phospholipase D-and MAP-kinase-dependent pathways in some of their target cells, as well as expression of early response genes and increased mitogenic activity. In many neuroendocrine cells, ET induces rapid and marked desensitization of its signaling system, in association with extensive internalization of ET receptors and reduced signaling and secretory responses. These findings raise the possibility that ETs participate in the control of secretory responses in the hypothalamo-pituitary system and peripheral endocrine cells, as well as in long-term aspects of regulation in certain neuroendocrine cells.
内皮素（ETs）最初被认为主要参与心血管活动的调控，但ETs及其受体在多种其他组织中的存在表明其功能范围更为广泛。在包括神经元、神经内分泌和内分泌细胞在内的非血管组织中发现了ETs的特异性受体。此外，免疫反应性ETs存在于脑、垂体和外周内分泌组织中。然而，下丘脑 - 垂体门脉系统和外周血中的ET水平较低，这表明ET系统通过旁分泌和/或自分泌机制参与神经内分泌调节。ETA和ETB受体在下丘脑、肾上腺、甲状旁腺、胰腺、卵巢、子宫、胎盘和前列腺中均有表达，而仅ETA受体在GT1神经元、垂体前叶细胞、αT3 - 1永生化促性腺激素细胞、甲状旁腺衍生细胞、甲状腺细胞、睾丸间质细胞和支持细胞、正常和肿瘤性卵巢颗粒细胞、软骨细胞及其他细胞类型中表达。ET受体的激活引发了典型的钙动员受体的细胞事件序列，磷酸肌醇水解显著增加，[Ca2+]i升高，其以振荡和非振荡模式出现，具体取决于细胞类型。ET诱导的神经元和内分泌细胞中磷酸肌醇/钙动员途径的激活与分泌反应的快速刺激相关，包括促性腺激素释放激素、催产素、血管加压素、P物质、心房利钠肽、促性腺激素、促甲状腺激素、生长激素、甲状旁腺激素、醛固酮和儿茶酚胺的释放。另一方面，ET对催乳素、孕酮和肾素的释放具有抑制作用。除了刺激依赖磷脂酶C的途径外，ETs还在其一些靶细胞中激活依赖磷脂酶D和丝裂原活化蛋白激酶的途径，以及早期反应基因的表达并增加有丝分裂活性。在许多神经内分泌细胞中，ET诱导其信号系统快速且显著的脱敏，这与ET受体的广泛内化以及信号传导和分泌反应的降低相关。这些发现增加了ETs参与下丘脑 - 垂体系统和外周内分泌细胞分泌反应的控制以及某些神经内分泌细胞长期调节的可能性。
