Beyond the heterodimer model for mineralocorticoid and glucocorticoid receptor interactions in nuclei and at DNA

Abstract

Glucocorticoid (GR) and mineralocorticoid receptors (MR) are believed to classically bind DNA as homodimers or MR-GR heterodimers to influence gene regulation in response to pulsatile basal or stress-evoked glucocorticoid secretion. Pulsed corticosterone presentation reveals MR and GR co-occupy DNA only at the peaks of glucocorticoid oscillations, allowing interaction. GR DNA occupancy was pulsatile, while MR DNA occupancy was prolonged through the inter-pulse interval. In mouse mammary 3617 cells MR-GR interacted in the nucleus and at a chromatin-associated DNA binding site. Interactions occurred irrespective of ligand type and receptors formed complexes of higher order than heterodimers. We also detected MR-GR interactions ex-vivo in rat hippocampus. An expanded range of MR-GR interactions predicts structural allostery allowing a variety of transcriptional outcomes and is applicable to the multiple tissue types that co-express both receptors in the same cells whether activated by the same or different hormones.

Glucocorticoid-dependent transcription in skin requires epidermal expression of the glucocorticoid receptor and is modulated by the mineralocorticoid receptor

“…Despite the high structural and functional homology between GR and MR, and in particular the identity in their DNA binding domain (greater than 90%), the global or epidermal-specific phenotypes of the knock-out mouse models for these transcription factors clearly indicate that they do not play overlapping functions 3 . It is thus expected that they regulate different gene subsets, as recently shown by in vitro and in vivo data 8 , 31 – 34 . It is also expected that the relative functions of GR and MR, either alone or combined depend on the cell-type.…”

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

“…Likewise, GR has been found to form a heterodimer with the mineralocorticoid receptor (MR) ( 34 ) in a number of different tissues and cells, including the hippocampus and mammary cells. Here, the GR-MR complex binds to GREs and regulates gene expression ( 131 , 132 ). Although a GR-MR complex has not, to our knowledge, been shown to be functional in the liver, it has been suggested that GR-MR could regulate hepatic expression of G6Pase ( 133 ) ( Figure 3B ).…”

Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks

“…The GR and MR are closely related members of the nuclear receptor superfamily. In addition to a high degree of sequence conservation, GR and MR share overlapping hormone specificity, similarities of binding domain affinity and transcriptional activity at common hormone response elements (Pooley et al, 2020). However, GR and MR also display specific properties in terms of distribution, molecular action and ligand specificity (Mifsud and Reul, 2018;Pearce, 1994) as well as activation patterns in response to ultradian and stressinduced stimulation (Conway-Campbell et al, 2007;Mifsud and Reul, 2016).…”

“…The interdependent actions of GR and MR also possibly result from their interaction in the nucleoplasm and at chromatin-associated DNA binding sites occurring during the peak of glucocorticoid oscillation and during the normal physiological stress response (Pooley et al, 2020). The precise mechanisms by which GR and MR interact at certain GREs are, however, still unclear.…”

“…In fact, GR and MR have been classically believed to influence gene regulation, in response to pulsatile basal or stress-evoked glucocorticoid secretion, by binding DNA as homodimers or GR-MR heterodimers (Liu et al, 1995;Trapp et al, 1994) or through GR receptor self-interactions (Pearce, 1994). However, recent work shows that the interaction of GR and MR as true 1:1 heterodimers through D-loop dimerization interface is unlikely and rather suggests allosteric flexibility through oligomerization (Pooley et al, 2020;Rivers et al, 2019).…”