Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
Department of Biological Sciences, Hokkaido University, Sapporo, Japan.
Sci Signal. 2018 Jul 3;11(537):eaao1520. doi: 10.1126/scisignal.aao1520.
Although multiple steroid ligands of the glucocorticoid, mineralocorticoid, and progestin families bind to and regulate the activity of mineralocorticoid receptors (MRs), the responses to these ligands differ across species. To understand how the different domains of MRs contribute to the ligand-induced activation or inhibition of MR activity, we studied the response to eight steroids (aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone, and spironolactone) of human, chicken, alligator, frog, and zebrafish full-length MRs and truncated MRs, which lacked the N-terminal domain (NTD) and DNA binding domain (DBD). Compared to full-length MRs, some truncated MRs were not activated by the steroids, and others required higher steroid concentrations for activation. Progesterone, 19-norprogesterone, and spironolactone did not activate full-length or truncated human, alligator, or frog MRs. However, at 10 nM, these steroids activated full-length chicken and zebrafish MRs, whereas at 100 nM, these steroids had little activity for truncated chicken MRs, but they retained activity for truncated zebrafish MRs. This suggests that regulation of the activation of the chicken MR by progestin resides in the NTD-DBD and that of the zebrafish MR resides in the hinge-LBD. Zebrafish and chicken MRs contain a serine corresponding to Ser in human MR, which is required for the antagonist activity of progesterone for human MR, suggesting a previously uncharacterized mechanism of regulation of progestin activation of chicken and zebrafish MRs. These findings suggest that progesterone may be a physiological activator of chicken and zebrafish MRs.
尽管糖皮质激素、盐皮质激素和孕激素家族的多种甾体配体结合并调节盐皮质激素受体 (MR) 的活性，但这些配体在不同物种中的反应不同。为了了解 MR 的不同结构域如何导致配体诱导的 MR 活性的激活或抑制，我们研究了对八种甾体（醛固酮、11-脱氧皮质酮、11-脱氧皮质醇、皮质醇、皮质酮、孕酮、19-去甲孕酮和螺内酯）的反应全人、鸡、鳄鱼、青蛙和斑马鱼全长 MR 和缺乏 N 端结构域（NTD）和 DNA 结合结构域（DBD）的截断 MR。与全长 MR 相比，一些截断的 MR 不受甾体激活，而其他 MR 需要更高的甾体浓度才能激活。孕酮、19-去甲孕酮和螺内酯不能激活全长或截断的人、鳄鱼或青蛙 MR。然而，在 10 nM 时，这些甾体激活全长鸡和斑马鱼 MR，而在 100 nM 时，这些甾体对 100 nM 时，这些甾体对截断的鸡 MR 几乎没有活性，但对截断的斑马鱼 MR 仍有活性。这表明孕激素对鸡 MR 激活的调节位于 NTD-DBD，而对斑马鱼 MR 的调节位于铰链-LBD。斑马鱼和鸡 MR 含有与人 MR 中的丝氨酸相对应的丝氨酸，这是孕激素对人 MR 拮抗活性所必需的，表明孕激素激活鸡和斑马鱼 MR 的调节存在以前未表征的机制。这些发现表明孕酮可能是鸡和斑马鱼 MR 的生理激活剂。
