Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells
Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells
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DOI：
10.1016/j.mce.2011.06.016
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发表时间：
2011-09
影响因子：
4.1
通讯作者：
Naoko Tsukamoto;F. Otsuka;T. Miyoshi;K. Inagaki;Eri Nakamura;T. Terasaka;M. Takeda;T. Ogura;Y. Iwasaki;H. Makino
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文献类型：
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作者：
Naoko Tsukamoto;F. Otsuka;T. Miyoshi;K. Inagaki;Eri Nakamura;T. Terasaka;M. Takeda;T. Ogura;Y. Iwasaki;H. Makino
使用小鼠促肾上腺皮质激素 AtT20 细胞，重点关注 BMP-4 的生物活性，研究了 GHRP 刺激促肾上腺皮质激素细胞中 ACTH 释放的机制。 GHRP-2 增加 AtT20 细胞的 ACTH 和 cAMP 分泌；然而，其作用不如 CRH 有效。 BMP-4 抑制基础 ACTH 产生和 POMC 转录，内源性 BMP 受体信号传导的抑制导致 ACTH 产生增加。值得注意的是，BMP-4 比 GHRP-2 更有效地抑制 CRH 诱导的 ACTH 产生和 POMC 启动子活性。 BMP-4对CRH或GHRP-2诱导的cAMP合成没有显着影响。用 CRH（而非 GHRP-2）刺激可激活 ERK1/2、p38、SAPK/JNK 和 Akt 磷酸化，其中 CRH 诱导的 ERK 和 p38 磷酸化被 BMP-4 抑制。 GHRP-2诱导的ACTH分泌不受ERK、p38和Akt通路抑制剂的影响，有效抑制了CRH诱导的ACTH释放。阻断 cAMP-PKA 途径可逆转 CRH 以及 GHRP-2 诱导的 ACTH 分泌。此外，抑制 ERK 和 p38 显着减少 CRH 诱导的 cAMP 合成，但不减少 GHRP-2 诱导的 cAMP 合成。因此，除了 cAMP-PKA 途径外，CRH 还通过 ERK 和 p38 途径激活 ACTH 产生，cAMP-PKA 途径也在 MAPK 下游被激活。另一方面，GHRP-2 诱导的 ACTH 产生主要与 cAMP-PKA 途径相关。此外，CRH和GHRP-2上调BMP受体信号传导，而BMP-4、CRH和GHRP-2对GHSR的表达水平没有显着影响。此外，GHRP-2 抑制 Smad7 的表达，Smad7 是 BMP-Smad1/5/8 通路的抑制剂。总的来说，结果揭示了 GHRP-2 和 BMP 信号传导之间的功能相互作用，其中内源性 BMP 可能充当控制 ACTH 产生的自动调节系统。
Mechanisms by which GHRP stimulates ACTH release in corticotrope cells were investigated using mouse corticotrope AtT20 cells by focusing on the biological activity of BMP-4. GHRP-2 increased ACTH and cAMP secretion by AtT20 cells; however, its effects were less potent than the effects of CRH. BMP-4 suppressed basal ACTH production and POMC transcription, and the inhibition of endogenous BMP receptor signaling led to an increase in ACTH production. Of note, BMP-4 suppressed ACTH production and POMC-promoter activity induced by CRH more efficaciously than that induced by GHRP-2. BMP-4 had no significant effect on cAMP synthesis induced by CRH or GHRP-2. Stimulation with CRH, but not GHRP-2, activated ERK1/2, p38, SAPK/JNK and Akt phosphorylation, in which CRH-induced phosphorylation of ERK and p38 was suppressed by BMP-4. GHRP-2-induced ACTH secretion was not affected by inhibitors of ERK, p38 and Akt pathways, which effectively suppressed CRH-induced ACTH release. Blockage of the cAMP-PKA pathway reversed CRH- as well as GHRP-2-induced ACTH secretion. Furthermore, the inhibition of ERK and p38 significantly reduced cAMP synthesis induced by CRH but not by GHRP-2. Thus, CRH activates ACTH production through ERK and p38 pathways in addition to the cAMP-PKA pathway, which is also activated downstream of MAPK. On the other hand, GHRP-2-induced ACTH production was predominantly linked to the cAMP-PKA pathway. Moreover, CRH and GHRP-2 upregulated BMP receptor signaling, while BMP-4, CRH and GHRP-2 had no significant effect on the expression level of GHSR. In addition, GHRP-2 suppressed the expression of Smad7, which is an inhibitor of the BMP-Smad1/5/8 pathway. Collectively, the results revealed a functional interaction between GHRP-2 and BMP signaling, in which endogenous BMP may act as an autoregulatory system in controlling ACTH production.