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 begins when aldosterone (the primary mineralocorticoid) binds to the MR in the cytoplasm, triggering a conformational change that leads to the dissociation of chaperone proteins and the translocation of the receptor-hormone complex to the nucleus, where it functions as a transcription factor to initiate gene transcription. This process is crucial in regulating sodium reabsorption, potassium excretion, and blood pressure. The MR signaling mechanism involves the binding of aldosterone to the MR, which then undergoes a conformational change, causing the dissociation of heat shock proteins and other chaperone proteins 1.

The activated receptor-hormone complex then translocates to the nucleus, where it binds to specific DNA sequences called hormone response elements, recruiting co-activators and other transcription machinery to initiate gene transcription 1. This leads to increased expression of proteins involved in sodium reabsorption, particularly the epithelial sodium channel (ENaC) and Na+/K+-ATPase in the distal tubule and collecting duct of the kidney. The increased sodium reabsorption is accompanied by water retention and potassium excretion, ultimately resulting in increased blood volume and blood pressure.

According to the most recent guidelines, aldosterone receptor antagonists are recommended in patients with NYHA class II–IV HF and who have LVEF of 35% or less, unless contraindicated, to reduce morbidity and mortality 1. This highlights the importance of the MR signaling mechanism in clinical practice, particularly in the management of heart failure. The genomic pathway typically takes hours to produce effects, though mineralocorticoids can also trigger rapid non-genomic effects through membrane-associated receptors that activate kinase cascades within minutes, affecting ion transport independently of gene transcription.

Key aspects of the MR signaling mechanism include:

• Binding of aldosterone to the MR in the cytoplasm
• Conformational change and dissociation of chaperone proteins
• Translocation of the receptor-hormone complex to the nucleus
• Binding to hormone response elements and initiation of gene transcription
• Increased expression of proteins involved in sodium reabsorption and potassium excretion
• Regulation of blood volume and blood pressure.

Overall, the MR signaling mechanism plays a critical role in regulating electrolyte balance, blood pressure, and fluid status, and its dysregulation can have significant clinical implications, particularly in the context of heart failure and hypertension 1.

From the FDA Drug Label

Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone binds to mineralocorticoid receptors in both epithelial (e. g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

The intracellular signaling mechanism triggered by mineralocorticoid once it binds to the mineralocorticoid receptor (MR) is not explicitly described in the provided drug label. The label mentions that aldosterone binds to mineralocorticoid receptors and increases blood pressure through induction of sodium reabsorption, but it does not provide details on the intracellular signaling mechanism. 2

From the Research

Intracellular Signaling Mechanism

The intracellular signaling mechanism triggered by mineralocorticoid once it binds to the mineralocorticoid receptor (MR) involves:

• Genomic mechanisms that increase sodium transport through activation and de novo synthesis of epithelial sodium channels in renal epithelia 3
• Rapid steroid actions that lead to increased concentrations of intracellular sodium, activating sodium-potassium-ATPase molecules mainly at the basolateral membrane 3
• Release of intracellular Ca(2+) in vascular smooth muscle cells, which is characterized by high specificity for mineralocorticoids versus glucocorticoids 3
• Involvement of phospholipase C and protein kinase C in the rapid effects of mineralocorticoids 3

Mineralocorticoid Receptor Signaling

The mineralocorticoid receptor (MR) signaling mechanism can be viewed as a series of interactions, including:

• Binding of ligand to the MR, which confers a ligand-specific conformation upon the receptor 4
• Interactions with different domains of the receptor, chromatin, coregulators, and other transcription factors 4
• Utilization of intracellular signaling cascades to change cell function more rapidly, often by transactivating unrelated receptors 5

Regulation of Cell Function

Mineralocorticoid regulation of cell function involves:

• Traditional genomic mechanisms of mineralocorticoid action, which have been increasingly elucidated over the past four decades 3
• Rapid signaling and gene transcription pathways, which are utilized by the MR to regulate epithelial handling of electrolytes and induce diverse effects on other tissues 5
• Tissue-selective and mineralocorticoid-specific effects, which are conferred through the enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status, and properties of the MR itself 5