Molecular interactions of glucocorticoid and mineralocorticoid receptors define novel transcription and biological functions.

Glucocorticoids are primary stress hormones necessary for life that function to maintain homeostasis. These hormones and their synthetic derivatives are widely used in the clinic to combat disease but are limited by development of resistance and by severe side effects. Understanding how glucocorticoids signal is crucial for developing safer and more effective glucocorticoids. Mechanistically glucocorticoid ligands induce glucocorticoid receptor (GR) homodimerization and regulation of gene expression. Here, we show that GR and mineralocorticoid receptor (MR) form molecular complexes with distinct transcriptional responses that alter the biological roles of GR. MR inhibited GR interaction with genomic DNA and diminished glucocorticoid-regulated gene expression as well as suppressed cell apoptosis induced by GR signaling. Provocatively, multiple therapeutic glucocorticoids differentially induced the GR-MR interaction revealing unknown drug effects that are exploitable for fine-tuning glucocorticoid drug treatments. Molecular modeling of the GR-MR complex predicted an interaction interface residing in the LBD of both GR and MR. Mutation of a key amino acid in the interface of GR compromised GR-MR interaction without affecting GR activity in a gene reporter assay. Overall, our findings uncovered unique crosstalk mechanisms between distinct nuclear receptors providing a novel mechanism of diversity in the action of glucocorticoids that may contribute to context-dependent GR signaling in human health and disease.