Research ArticleSteroid Hormones

Transcriptional activation of elephant shark mineralocorticoid receptor by corticosteroids, progesterone, and spironolactone

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Science Signaling  04 Jun 2019:
Vol. 12, Issue 584, eaar2668
DOI: 10.1126/scisignal.aar2668

Expanding mineralocorticoid functions

Mineralocorticoid receptors (MRs) belong to the nuclear receptor family of transcription factors. Aldosterone is a physiological ligand for the human MR, which is best known for regulating electrolyte homeostasis. Noting that the MR first arose in cartilaginous fish, which do not have aldosterone, Katsu et al. examined the binding and activity profiles of a range of corticosteroids and steroid hormones for the MR of the elephant shark, a cartilaginous fish found in the oldest group of jawed vertebrates. These studies suggest that elephant shark MR is activated by progesterone, which acts as an antagonist of the human MR. Given the abundance of the MR in elephant shark ovaries and testis, these findings suggest that the MR may play an unappreciated role in reproductive physiology.


The mineralocorticoid receptor (MR) is a nuclear receptor and part of a large and diverse family of transcription factors that also includes receptors for glucocorticoids, progesterone, androgens, and estrogens. The corticosteroid aldosterone is the physiological activator of the MR in humans and other terrestrial vertebrates; however, its activator is not known in cartilaginous fish, the oldest group of extant jawed vertebrates. Here, we analyzed the ability of corticosteroids and progesterone to activate the full-length MR from the elephant shark (Callorhinchus milii). On the basis of their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone, and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fish. Although progesterone activates MRs in ray-finned fish, progesterone does not activate MRs in humans, amphibians, or alligator, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis, and other nonepithelial tissues, suggesting that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that 19-norprogesterone– and progesterone-activated MR may have unappreciated functions in reproductive physiology.

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