Accepted Preprint (first posted online 3 May 2017)

    Evolution of the mineralocorticoid receptor: sequence, structure and function

    1. Yoshinao Katsu
    1. M Baker, Department of Medicine 0693, University of California, San Diego, United States
    2. Y Katsu, Department of Biological Sciences, Hokkaido University, Sapporo, 060-0810, Japan
    1. Correspondence: Michael Baker, Email: mbaker{at}


    The mineralocorticoid receptor (MR) is descended from a corticoid receptor (CR), which has descendants in lamprey and hagfish, cyclostomes (jawless fish), a taxon that evolved at the base of the vertebrate line. A distinct MR and GR first appear in cartilaginous fishes (Chondrichthyes), such as sharks, skates, rays and chimaeras. Skate MR has a strong response to corticosteroids that are mineralocorticoids and glucocorticoids in humans. The half-maximal responses (EC50s) for skate MR for the mineralocorticoids aldosterone and 11-deoxycorticosterone are 0.07 nM and 0.03 nM, respectively. EC50s for the glucocorticoids cortisol and corticosterone are 1 nM and 0.09 nM, respectively. The physiological mineralocorticoid in ray-finned fish, which do not synthesize aldosterone, is not fully understood because several 3-ketosteroids, including cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone are transcriptional activators of fish MR. Further divergence of the MR and GR in terrestrial vertebrates, which synthesize aldosterone, led to emergence of aldosterone as a selective ligand for the MR . Here, we combine sequence analysis of the CR and vertebrate MRs and GRs, analysis of crystal structures of human MR and GR and data on transcriptional activation by 3-ketosteroids of wild-type and mutant MRs and GRs to investigate the evolution of selectivity for 3-ketosteroids by the MR in terrestrial vertebrates and ray-finned fish, as well as the basis for binding of some glucocorticoids by human MR and other vertebrate MRs.

    • Received 19 December 2016
    • Received in final form 13 April 2017
    • Accepted 3 May 2017
    • Accepted Preprint first posted online on 3 May 2017

    This Article

    1. J Endocrinol JOE-16-0661
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      1. JOE-16-0661v1
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