The mineralocorticoid receptor forms higher order oligomers upon DNA binding.

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate-size quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.

The mineralocorticoid receptor forms higher order oligomers upon DNA binding.

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.

The Glucocorticoid Receptor is Required for Efficient Aldosterone-Induced Transcription by the Mineralocorticoid Receptor.

The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR co-expression on MR genome-wide chromatin binding and transcriptional responses to aldosterone and glucocorticoids, both physiological ligands of this receptor. Our data show that GR co-expression alters MR genome-wide binding to consensus DNA sequences in a locus- and ligand-specific way. MR binding to consensus DNA sequences is affected by GR. Transcriptional responses of MR in the absence of GR are weak and show poor correlation with chromatin binding. In contrast, co-expression of GR potentiates MR-mediated transcription, particularly in response to aldosterone. Finally, single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that co-expression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids.

Structural and molecular determinants of mineralocorticoid receptor signalling.

During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.