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

TL;DR

This study investigates how corticosteroids and progesterone activate the mineralocorticoid receptor in elephant sharks, revealing evolutionary insights and potential physiological roles of progesterone in early vertebrates.

Contribution

It demonstrates that progesterone can activate elephant shark MR and suggests progesterone was an ancestral ligand, providing new understanding of MR evolution in vertebrates.

Findings

Aldosterone is not present in cartilaginous fishes.

Progesterone activates elephant shark MR, indicating an ancestral role.

Progesterone does not activate human MR, showing evolutionary divergence.

Abstract

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Based on 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 fishes. Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes. Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.