Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
Mol Cell Endocrinol. 2011 Jan 30;332(1-2):163-9. doi: 10.1016/j.mce.2010.10.008. Epub 2010 Oct 21.
Involvement of the pituitary BMP system in the modulation of prolactin (PRL) secretion regulated by somatostatin analogs, including octreotide (OCT) and pasireotide (SOM230), and a dopamine agonist, bromocriptine (BRC), was examined in GH3 cells. GH3 cells are rat pituitary somato-lactotrope tumor cells that express somatostatin receptors (SSTRs) and BMP system molecules including BMP-4 and -6. Treatment with BMP-4 and -6 increased PRL and cAMP secretion by GH3 cells. The BMP-4 effects were neutralized by adding a BMP-binding protein Noggin. These findings suggest the activity of endogenous BMPs in augmenting PRL secretion by GH3 cells. BRC and SOM230 reduced PRL secretion, but OCT failed to reduce the PRL level. In GH3 cells activated by forskolin, BRC suppressed forskolin-induced PRL secretion with reduction in cAMP levels. OCT did not affect forskolin-induced PRL level, while SOM230 reduced PRL secretion and PRL mRNA expression induced by forskolin. BMP-4 treatment enhanced the reducing effect of SOM230 on forskolin-induced PRL level while BMP-4 did not affect the effects of OCT or BRC. Noggin treatment had no significant effect on the BRC actions reducing PRL levels by GH3 cells. However, in the presence of Noggin, OCT elicited an inhibitory effect on forskolin-induced PRL secretion and PRL mRNA expression, whereas the SOM230 effect on PRL reduction was in turn impaired. It was further found that BMP-4 and -6 suppressed SSTR-2 but increased SSTR-5 mRNA expression of GH3 cells. These findings indicate that Noggin rescues SSTR-2 but downregulates SSTR-5 by neutralizing endogenous BMP actions, leading to an increase in OCT sensitivity and a decrease in SOM230 sensitivity of GH3 cells. In addition, BMP signaling was facilitated in GH3 cells treated with forskolin. Collectively, these findings suggest that BMPs elicit differential actions in the regulation of PRL release dependent on cellular cAMP-PKA activity. BMPs may play a key role in the modulation of SSTR sensitivity of somato-lactotrope cells in an autocrine/paracrine manner.
我们研究了垂体 BMP 系统在生长抑素类似物（包括奥曲肽（OCT）和帕瑞肽（SOM230））和多巴胺激动剂溴隐亭（BRC）调节催乳素（PRL）分泌中的作用，GH3 细胞是大鼠垂体生长激素-催乳素细胞瘤，表达生长抑素受体（SSTRs）和 BMP 系统分子，包括 BMP-4 和 -6。BMP-4 和 -6 的处理增加了 GH3 细胞的 PRL 和 cAMP 分泌。BMP-4 的作用被添加 BMP 结合蛋白 Noggin 中和。这些发现表明内源性 BMP 可增强 GH3 细胞的 PRL 分泌。BRC 和 SOM230 降低 PRL 分泌，但 OCT 未能降低 PRL 水平。在被 forskolin 激活的 GH3 细胞中，BRC 抑制 forskolin诱导的 PRL 分泌，同时降低 cAMP 水平。OCT 不影响 forskolin 诱导的 PRL 水平，而 SOM230 降低 forskolin诱导的 PRL 分泌和 PRL mRNA 表达。BMP-4 处理增强了 SOM230 对 forskolin 诱导的 PRL 水平的降低作用，而 BMP-4 对 OCT 或 BRC 的作用没有影响。Noggin 处理对 BRC 通过 GH3 细胞降低 PRL 水平的作用没有显著影响。然而，在 Noggin 存在的情况下，OCT 对 forskolin 诱导的 PRL 分泌和 PRL mRNA 表达产生抑制作用，而 SOM230 对 PRL 减少的作用则受到损害。进一步发现，BMP-4 和 -6 抑制 GH3 细胞的 SSTR-2，但增加 SSTR-5 mRNA 表达。这些发现表明，Noggin 通过中和内源性 BMP 作用挽救 SSTR-2，但下调 SSTR-5，导致 GH3 细胞对 OCT 的敏感性增加和对 SOM230 的敏感性降低。此外，在用 forskolin 处理的 GH3 细胞中促进了 BMP 信号传导。总之，这些发现表明，BMP 以依赖细胞 cAMP-PKA 活性的方式在调节 PRL 释放中产生不同的作用。BMP 可能以自分泌/旁分泌方式在调节生长激素-催乳素细胞的 SSTR 敏感性方面发挥关键作用。
