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

Abstract

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 chimeras. 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.

Postnatal triglyceride accumulation is regulated by mineralocorticoid receptor activation under basal and stress conditions

“…In combination with mammalian work (Joëls & de Kloet, ), this suggested that the primary role for this receptor may have been in stress sensing and appraisal prior to its mineralocorticoid role in the tetrapod lineage (Baker et al . ; Baker & Katsu, ). Here we demonstrate that in addition to stress sensing and behaviour, MR may also be involved in energy substrate partitioning during early‐life adipogenesis.…”

“…). The role of MR in lower vertebrates is unclear, as teleosts lack aldosterone, and GCs appear to be the primary endogenous ligand for MR (Baker & Katsu, ). This makes zebrafish an ideal model to study GC signalling as cortisol is thought to be the primary ligand for both receptors.…”

“…The zebrafish GR is also homologous to the human GR (Alsop & Vijayan, 2009), and the GR signalling pathways in teleosts appear to be conserved (Mommsen et al 1999). The role of MR in lower vertebrates is unclear, as teleosts lack aldosterone, and GCs appear to be the primary endogenous ligand for MR (Baker & Katsu, 2017). This makes zebrafish an ideal model to study GC signalling as cortisol is thought to be the primary ligand for both receptors.…”

Towards an Optimized Use of Ocular Corticosteroids: EURETINA Award Lecture 2017

“…Indeed, since circulating levels of cortisol are much higher than aldosterone levels, activation of MR by its specific ligand, aldosterone, can occur only in cells that express the HSD-2 enzyme, which converts cortisol into cortisone that has reduced affinity for MR, authorizing the binding of aldosterone to its specific receptor. The kidney is the classical aldosterone-sensitive organ, where aldosterone controlling the sodium and potassium excretion balance regulates blood pressure and body hydration [17,18]. In addition to the kidney, there are several other cells and organs expressing MR, in which MR activation is pathogenic, justifying the use of MR blockade [19].…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The scientific impact of cloning the mineralocorticoid receptor: 30 years on

“…We now know that the MR evolved millions of years ago, in cartilaginous and bony fish, before the first appearance of aldosterone in lungfish, as their name implies a transitional creature with both gills and lungs. This needs to be remembered before the otherwise too-easy assignation is made of aldosterone as the 'cognate' ligand for MR. Michael Baker is the undisputed leader in this area, combining his own studies with those of others to provide powerful insights into the probabilities underpinning MR evolution (Baker & Katsu 2017). Sequence is one thing, structure something else and function something else again.…”