What is the intracellular signaling mechanism triggered by mineralocorticoid once it binds to the mineralocorticoid receptor (MR)?

From the Guidelines

The mineralocorticoid receptor (MR) signaling mechanism is triggered when aldosterone binds to the MR, causing a conformational change that leads to the dissociation of chaperone proteins and translocation to the nucleus, where it acts as a transcription factor to regulate target genes involved in sodium reabsorption and potassium secretion. The process begins with the binding of aldosterone to the MR in the cytoplasm, which is then followed by a series of events that ultimately lead to the regulation of gene expression. Although the provided study 1 discusses the use of mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone in the treatment of heart failure, it does not directly describe the intracellular signaling mechanism triggered by mineralocorticoid binding to the MR. Key points about the MR signaling mechanism include:

• The binding of aldosterone to the MR causes a conformational change that leads to the dissociation of chaperone proteins like heat shock proteins
• The activated receptor-hormone complex then translocates to the nucleus where it functions as a transcription factor
• The MR binds to specific hormone response elements on DNA, recruiting co-activators and the transcriptional machinery, leading to increased transcription of target genes
• Key target genes include the epithelial sodium channel (ENaC), Na+/K+-ATPase, and serum and glucocorticoid-regulated kinase 1 (SGK1), which play important roles in sodium reabsorption and potassium secretion. However, the study 1 highlights the importance of MRAs in the treatment of heart failure, suggesting that the benefits of these drugs may extend to all patients with systolic heart failure.

From the Research

Intracellular Signaling Mechanism of Mineralocorticoid Receptor (MR)

The intracellular signaling mechanism triggered by mineralocorticoid once it binds to the mineralocorticoid receptor (MR) involves several key steps and interactions.

• The binding of mineralocorticoid to MR confers a ligand-specific conformation upon the receptor 2.
• This conformation determines subsequent interactions with different domains of the receptor, chromatin, coregulators, and other transcription factors 2.
• The MR activates transcription of target genes upon aldosterone binding 3.
• The MR also utilizes a number of intracellular signalling cascades, often by transactivating unrelated receptors, to change cell function more rapidly 4.
• The cellular response to aldosterone is mediated by the mineralocorticoid receptor (MR), which has wide tissue distribution with multiple roles in cardiovascular function, immune cell signaling, neuronal fate, and adipocyte differentiation 2.
• Ligand-activated receptors modulate the transcription rates of responsive genes by interacting with responsive elements in the promoters of these genes or by influencing the activities of other transcription factors, via protein-protein interactions 5.

Key Interactions and Signaling Pathways

• The critical region for ligand-binding specificity is located on the surface of the molecule, not in the ligand-binding pocket 6.
• The interactions between the N-terminal and ligand-binding domains of the MR are important for its function 6.
• The MR signal-transduction can be viewed as a series of interactions, which contribute to ligand- and tissue-specificity 2.
• Tissue-selective and mineralocorticoid-specific effects are conferred through the enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status, and properties of the MR itself 4.