Corticosteroid and progesterone transactivation of mineralocorticoid receptors from Amur sturgeon and tropical gar

Abstract

The response to a panel of steroids by the mineralocorticoid receptor (MR) from Amur sturgeon and tropical gar, two basal ray-finned fish, expressed in HEK293 cells was investigated. Half-maximal responses (EC50s) for transcriptional activation of sturgeon MR by 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol and aldosterone, and progesterone (Prog) were between 13 and 150 pM. For gar MR, EC50s were between 8 and 55 pM. Such low EC50s support physiological regulation by these steroids of the MR in sturgeon and gar. Companion studies with human and zebrafish MRs found higher EC50s compared with EC50s for sturgeon and gar MRs, with EC50s for zebrafish MR closer to gar and sturgeon MRs than was human MR. For zebrafish MR, EC50s were between 75 and 740 pM; for human MR, EC50s were between 65 pM and 2 nM. In addition to Prog, spironolactone (spiron) and 19nor-progesterone (19norP) were agonists for all three fish MRs, in contrast with their antagonist activity for human MR, which is hypothesized to involve serine-810 in human MR because all three steroids are agonists for a mutant human Ser810Leu-MR. Paradoxically, sturgeon, gar, and zebrafish MRs contain a serine corresponding to serine-810 in human MR. Our data suggest alternative mechanism(s) for Prog, spiron, and 19norP as MR agonists in these three ray-finned fishes and the need for caution in applying data for Prog signaling in zebrafish to human physiology.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

“…Similar findings were reported for rat MR (Krozowski & Funder 1983, Myles & Funder 1994) and guinea pig MR (Myles & Funder 1994). Progesterone (Prog) also has high affinity for human MR (Arriza et al 1987, Rupprecht et al 1993b, Sugimoto et al 2016, rat MR (Myles & Funder 1996) and guinea pig MR (Myles & Funder 1996). This indicated that the steroid-binding site on the human MR was not selective for physiological mineralocorticoids (Aldo, DOC) over glucocorticoids (F, B, S) and Prog.…”

“…Indeed, a follow-up paper (Arriza et al 1988) showed that the half-maximal response (EC50) of Aldo for human MR was over 100X lower than that of F. Subsequent reports extended the stronger response of the human MR to Aldo compared to other corticosteroids (Rupprecht et al 1993b, Lombes et al 1994, Hellal-Levy et al 1999, Mani et al 2016, Sugimoto et al 2016. The basis for the stronger response to Aldo is not understood.…”

“…11βHSD2 first appears in Chondrichthyes , Rossier et al 2015, in which 11βHSD2 may regulate access of B to the MR. Although Aldo is not found in ray-finned fish, Aldo is a strong transcriptional activator of fish MR (Greenwood et al 2003, Sturm et al 2005, Stolte et al 2008, Pippal et al 2011, Sugimoto et al 2016. Indeed, the physiological mineralocorticoid in ray-finned fish is not fully understood because several 3-ketosteroids, including F, DOC, B, S and Prog are transcriptional activators of the MR (Greenwood et al 2003, Sturm et al 2005, Stolte et al 2008, Pippal et al 2011, Sugimoto et al 2016, and one or more of these steroids could be a physiological mineralocorticoid.…”

“…In this regard, allosteric interactions between the A/B domain and the ligand-binding domain also are important in differences among corticosteroids in transcriptional activation of the GR (Pearce & Yamamoto 1993, Rupprecht et al 1993a, Oka et al 2015. Interestingly, Prog is an antagonist for human MR (Kagawa 1958, Wambach & Higgins 1978, Funder & Adam 1981, Rupprecht et al 1993b, Geller et al 2000, Sugimoto et al 2016.…”

“…Aldo first appears in lungfish (Joss et al 1994, Rossier et al 2015, which also secrete F and B. Lungfish are the closest extant forerunners of tetrapods (Woolston 2013). (Rupprecht et al 1993b, Geller 2000 and an agonist for fish MRs (Sturm et al 2005, Pippal et al 2011, Sugimoto et al 2016.…”