The Mineralocorticoid Receptor: A Journey Exploring Its Diversity and Specificity of Action

Abstract

The mineralocorticoid receptor (MR) integrates hormonal signaling and activates the expression of aldosterone target genes, which control various physiological processes. In recent years, evidence has been provided for an important role of MR not only in the regulation of sodium and water homeostasis but also in cardiovascular function, neuronal fate, and adipocyte differentiation. MR belongs to the steroid receptor family that displays common mechanism of action. As a result, some apparent similarities with the glucocorticoid receptor (GR) have shaded MR's own specificities. The description of its gene structure, messenger isoforms, protein variants, functional domains, and posttranslational modifications (phosphorylation, ubiquitinylation, sumoylation, acetylation) as well as a panel of interactions with coregulators, progressively depicted an original portrait of MR and shed light on its specific mechanism of action. In this review, after an overview of MR characteristics, the multiple levels of MR selectivity over other steroid receptors, in particular GR, will be described as well as the consequences for aldosterone-regulated gene expression.

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

“…4,25 Aldo has been shown to induce vascular inflammation and fibrosis. However, the induction of OPN has been a well-known function of Aldo in various organs.…”

“…MR is distributed in not only distal renal tubules but also nonepithelial tissues, such as the cardiovascular system, including vascular smooth muscle cells (VSMCs). 4,5 There is a large body of evidence that Aldo induces inflammatory changes in the vasculature leading to deterioration in vascular function. 6,7 Aldo and sodium load have been reported to cause inflammation and fibrosis in the cardiovascular system.…”

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

“…However, the multivariate analysis did not add any extra information. The cortisol signaling cascade is complex and involves numerous chaperones, accessory proteins, co-regulators and interacting transcription factors that permit differentiation between the MR-and GR-mediated actions (De Bosscher et al, 2003;Pascual-Le Tallec and Lombes, 2005). For instance, recently it was found that increase in recurrence of depressive episodes is associated with a variant in a gene (FKBP5) that regulates GR activity (Binder et al, 2004).…”

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

“…The MR contains an A/B domain at the N-terminus (NTD), a DNA-binding domain (DBD) (C domain) near the center, a short hinge domain (D domain) and a steroid-binding domain (LBD) (E domain) at the C-terminus (Arriza et al 1988, Pascual-Le Tallec & Lombes 2005, Yang & Young 2009, Huang et al 2010, Huyet et al 2012. The A/B domain contains an activation function 1 [AF1], and the E domain contains an AF2 domain , Pascual-Le Tallec & Lombes 2005, Huyet et al 2012, Faresse 2014. Each domain in MR is important for transcriptional responses (Faresse 2014, Fuller et al 2012.…”