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We report the analysis of activation by corticosteroids and progesterone offull-length mineralocorticoid receptor (MR) from elephant shark, acartilaginous fish belonging to the oldest group of jawed vertebrates. Based ontheir measured activities, aldosterone, cortisol, 11-deoxycorticosterone,corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone arepotential physiological mineralocorticoids. However, aldosterone, thephysiological mineralocorticoid in humans and other terrestrial vertebrates, isnot found in cartilaginous or ray-finned fishes. Because progesterone is aprecursor for corticosteroids that activate elephant shark MR, we propose thatprogesterone was an ancestral ligand for elephant shark MR. Althoughprogesterone activates ray-finned fish MRs, progesterone does not activatehuman, amphibian or alligator MRs, suggesting that during the transition toterrestrial vertebrates, progesterone lost the ability to activate the MR.Comparison of RNA-sequence analysis of elephant shark MR with that of human MRsuggests that MR expression in the human brain, heart, ovary, testis and othernon-epithelial tissues evolved in cartilaginous fishes. Together, these datasuggest that progesterone-activated MR may have unappreciated functions inelephant shark ovary and testis.

Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone