Estrogen Suppresses Interaction of Melanocortin 2 Receptor and Its Accessory Protein in the Primate Fetal Adrenal Cortex
Estrogen Suppresses Interaction of Melanocortin 2 Receptor and Its Accessory Protein in the Primate Fetal Adrenal Cortex
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DOI：
10.1210/en.2016-1562
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发表时间：
2016-12-01
期刊：
影响因子：
4.8
通讯作者：
Albrecht, Eugene D.
中科院分区：
文献类型：
--
作者：
Babischkin, Jeffery S.;Aberdeen, Graham W.;Albrecht, Eugene D.
我们已经表明，胎儿肾上腺胎儿区（FZ）的体积和血清硫酸脱氢表雄酮（DHAS）的水平增加，而最终和过渡区（DZ/TZ）的体积是不变的，在狒狒中，雌激素水平受到抑制的芳香化酶抑制剂来曲唑的管理。黑皮质素2受体（MC 2 R）与其辅助蛋白（MRAP）的相互作用对于将MC 2 R运输到肾上腺细胞表面以结合ACTH是必需的。本研究确定胎儿肾上腺皮质发育的雌激素依赖性调节是否由ACTH和/或MC 2 R和MRAP的表达/相互作用介导。在狒狒中评估胎儿垂体前阿黑皮素mRNA和血浆ACTH水平以及胎儿肾上腺MC 2 R-MRAP相互作用，其中在妊娠后半期通过来曲唑/来曲唑加雌二醇给药抑制/恢复雌激素。虽然胎儿垂体阿黑皮素原和血浆ACTH水平以及胎儿肾上腺MC 2 R和MRAP蛋白水平没有改变，但来曲唑处理的狒狒DZ/TZ中MC 2 R-MRAP相互作用比未处理的动物大2倍（P <0.05），并通过来曲唑加雌二醇处理恢复.我们认为，随着妊娠的推进，雌二醇水平的增加会抑制MC 2 R与MRAP的相互作用，从而减少MC 2 R向DZ/TZ细胞膜的移动。预计这将减少DZ中的祖细胞增殖和向FZ的迁移，从而抑制FZ生长和DHAS产生，以在妊娠后期将胎儿肾上腺DHAS和胎盘雌二醇水平维持在生理范围内。
We have shown that fetal adrenal fetal zone (FZ) volume and serum dehydroepiandrosterone sulfate (DHAS) levels were increased, whereas definitive and transitional zone (DZ/TZ) volume was unaltered, in baboons in which estrogen levels were suppressed by the administration of the aromatase inhibitor letrozole. The interaction of the melanocortin 2 receptor (MC2R) with its accessory protein (MRAP) is essential for trafficking MC2R to the adrenal cell surface for binding to ACTH. The present study determined whether the estrogen- dependent regulation of fetal adrenocortical development is mediated by ACTH and/or expression/interaction of MC2R and MRAP. Fetal pituitary proopiomelanocortin mRNA and plasma ACTH levels and fetal adrenal MC2R- MRAP interaction were assessed in baboons in which estrogen was suppressed/restored by letrozole/letrozole plus estradiol administration during the second half of gestation. Although fetal pituitary proopiomelanocortin and plasma ACTH levels and fetal adrenal MC2R and MRAP protein levels were unaltered, MC2R- MRAP interaction was 2- fold greater (P < .05) in the DZ/TZ in letrozole- treated baboons than in untreated animals and restored by letrozole plus estradiol treatment. We propose that the increasing levels of estradiol with advancing pregnancy suppress interaction of MC2R with MRAP, thereby diminishing MC2R movement to the cell membrane in the DZ/TZ. This would be expected to reduce progenitor cell proliferation in the DZ and migration to the FZ, thereby restraining FZ growth and DHAS production to maintain fetal adrenal DHAS and placental estradiol levels in a physiological range late in gestation.