Mineralocorticoid Receptor (MR)
What is the Mineralocorticoid Receptor (MR)?
The mineralocorticoid receptor (MR) is a nuclear receptor that plays a crucial role in regulating electrolyte and fluid balance by responding to the endogenous ligand aldosterone. Dysregulation of MR signaling is associated with various cardiovascular and renal disorders, making it an attractive drug discovery target. Selective MR antagonists, such as spironolactone and eplerenone, have been successfully used to manage heart failure and hypertension, highlighting the therapeutic potential of targeting the MR for various conditions related to salt and water balance and cardiovascular health.
MR’s Role in Disease
The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily and acts as a ligand-activated transcription factor. It plays a crucial role in the regulation of electrolyte and fluid balance, particularly by modulating the reabsorption of sodium and water in the kidneys. The primary endogenous ligand for the MR is aldosterone, a steroid hormone secreted by the adrenal glands in response to changes in blood pressure and sodium levels. When aldosterone binds to the MR, the receptor undergoes a conformational change and translocates to the nucleus, where it regulates the expression of target genes involved in sodium and potassium transport in the kidneys. In addition to aldosterone, certain glucocorticoids, such as cortisol, can also bind to the MR with lower affinity. This cross-reactivity between MR and glucocorticoids is tightly regulated by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts cortisol to its inactive metabolite, cortisone, preventing inappropriate activation of MR by glucocorticoids.
MR’s Role in Drug Discovery
Interest in the MR as a drug discovery target has grown due to its critical role in the pathogenesis of cardiovascular and kidney diseases. Dysregulation of MR signaling has been implicated in hypertension, heart failure, and renal dysfunction. As a result, selective MR antagonists have been developed as therapeutics to counteract MR activation and reduce sodium and water retention, which can alleviate hypertension and improve cardiac function. One such selective MR antagonist is spironolactone, which has been used for decades to manage conditions like primary hyperaldosteronism and congestive heart failure. Eplerenone is another MR antagonist specifically developed for heart failure and hypertension. Ongoing research seeks to identify novel MR modulators with improved selectivity and efficacy to target specific pathophysiological processes and minimize side effects. Designing new small molecule antagonists for MR poses a significant challenge for the medicinal chemist. The nature of the MR binding pocket, which is overall lipophilic, provides a challenge to combine balanced physicochemical properties with good potency to place newly designed compounds in a chemical space with more drug-like properties.
INDIGO’s MR Reporter Assays
INDIGO Biosciences offers cell-based luciferase reporter assay kits for the Mineralocorticoid Receptor. Our assays provide an all-inclusive luciferase reporter system that includes, in addition to MR Reporter Cells, optimized media for use during cell culture and in diluting the user’s test samples, a reference agonist, Luciferase Detection Reagent, and a cell culture-ready assay plate. INDIGO can also perform the MR assay in its own lab as a service for researchers.
INDIGO’s cell-based reporter assays allow scientists to screen and discover drugs that can be used to treat MR-related diseases. They provide an efficient way to examine a compound for its ability to regulate nuclear receptor activity in agonist, inverse-agonist, or antagonist mode using firefly luciferase reporter gene technology. Since the receptor binding controls the expression of the luciferase reporter gene, luciferase activity in the cells can be correlated directly with the activity of the receptor. Contact us today to learn more about our Mineralocorticoid Receptor assay kits and screening capabilities!