Mineralocorticoid receptor

• OMIM: 600 983
• UniProt: P08235

The mineralocorticoid receptor ( aldosterone receptor, MR, NR3C2 ) is a nuclear receptor that is activated by the binding of the steroid hormones cortisol and aldosterone, and then acts as a transcription factor. He is involved in kidney and colon in the regulation of water-electrolyte balance. In addition, he has numerous functions in various other tissues. NR3C2 mutations in gene can have a change in the activity of the transcription factor to the sequence; Loss -of-function mutations are then the cause of pseudohypoaldosteronism type 1 and gain - of-function mutations lead to congenital hypertension.

• 4.1 antagonists
• 4.2 agonists

Structure

The cloning of the mineralocorticoid receptor gene was first described in 1987. The MR gene is located on chromosome 4, region q31.1 and comprises approximately 450 kb. Within the superfamily of nuclear receptors of the mineralocorticoid receptor belongs to the subfamily 3 ( estrogen -like ), Group C.

The mineralocorticoid receptor is composed of three functional domains: the N- terminal domain (NTD ) interacts to a ligand - independent with co-factors and on the other hand depends on a ligand with the ligand-binding domain (LBD ). The ligand- binding domain exhibits a high structural similarity within the steroid receptor family.

Mechanism of Action

The mechanism of action of the mineralocorticoid receptor is that of a transcription factor. In the absence of ligand, the receptor is present as a complex with heat shock proteins in the cytoplasm. After binding of a ligand MR forms dimers and translocated into the nucleus. There it binds to a specific DNA sequence ( AGAACANNNTGTTCT ) in the promoter region of target genes and regulates the transcription. Aldosterone and cortisol bind with comparable affinity to MR, whereby cortisol in plasma is present in approximately 1000-fold higher concentration. The (relative) selectivity of MR for aldosterone is achieved by a variety of mechanisms: the co- expressed enzyme 11 -beta- Hydroxsteroiddehydrogenase ( 11 βHSD2 ) converts cortisol to cortisone in the inactive form, thereby preventing the MR activation. In addition, influences the transcriptional activity of the receptor by the interaction of receptor subunits with each other as well as numerous co-activators and repressors. A process described target gene of the mineralocorticoid receptor is serum glucocorticoid regulated kinase 1 ( Sgk1 ), a protein kinase that is considered as the starting point for various cellular signaling cascades.

Aldosterone mediates its effect also MR independently so-called non - genomic signaling pathways that are not blocked by inhibitors of transcription and antagonists on mineralocorticoid.

Function

The mineralocorticoid receptor is expressed in numerous tissues, including the kidney and in the colon, in the heart and central nervous system, where it exerts different functions in each case. In particular, the function in epithelial cells is distinguished from that in non- epithelial cells.

Epithelium

The mineralocorticoid receptor is involved in epithelial cells in the kidney and colon in the regulation of water-electrolyte balance. The activation of the receptor leads to increased expression of ion channels and transporters such as the amiloride-sensitive sodium channel ( ENaC) and basolateral sodium potassium ATPase. Thus, the transport of sodium across the epithelium is facilitated, which attracts an increased water reabsorption by itself. At the same time, potassium is excreted increased.

Non - epithelial

Cardiovascular system

Increased activation of the mineralocorticoid receptor leads on one hand to high blood pressure, but also has a direct effect on the heart from where elevated aldosterone levels can cause a pathological enlargement of the heart and of connective tissue. The molecular mechanisms leading to these effects are not yet fully understood. There is evidence that the mineralocorticoid receptor in macrophages at the above-mentioned connective tissue is pathogenetically involved.

Central Nervous System

Mineralocorticoid lie in the central nervous system, including the hypothalamus, a high density before. There is evidence that central MR are involved in the control of the sympathetic nervous system and the blood pressure.

Pharmacology

Antagonists

Spironolactone is a competitive antagonist at the mineralocorticoid receptor and belongs to the group of potassium-sparing diuretics. The substance has long been in clinical use and found inter alia in the treatment of ascites using. A modern substance eplerenone relative to other steroid receptors has a more favorable side effect profile, due to its higher specificity for the MR. Early 21st century showed two large clinical trials, RALES and EPHESUS, a life-prolonging effect of aldosterone antagonists in chronic heart disease and thus contributed to an increasing importance of the substances. 2011 could these results be confirmed for patients with mild heart failure.

Agonists

Clinical use of synthetic mineralocorticoid fludrocortisone finds, which is used in primary adrenal insufficiency under adrenogenitaler syndromes.