Research ArticleSteroid Receptors

Evolution of human, chicken, alligator, frog, and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity

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Sci. Signal.  03 Jul 2018:
Vol. 11, Issue 537, eaao1520
DOI: 10.1126/scisignal.aao1520

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Evolving steroid responses

Mineralocorticoid receptors (MRs) are members of the nuclear receptor family of transcription factors, and they are activated by steroid hormones including mineralocorticoids, such as aldosterone, and glucocorticoids, such as cortisol. Katsu et al. studied the effects of eight different steroids on the transcriptional activity of full-length and truncated MRs from five different species. Truncated MRs generally showed weaker activation than full-length receptors, and, among terrestrial vertebrate receptors, only chicken MR was activated by progesterone, a property shared by the zebrafish receptor. Together, these findings suggest that interactions between different domains within the MR were important in determining steroid specificity.

Abstract

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 Ser810 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.

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