Biology:Mineralocorticoid receptor

Short description: Nuclear receptor that mediates the effects of the mineralocorticoid hormone Aldosterone

Generic protein structure example

The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.

MR is a receptor with equal affinity for mineralocorticoids and glucocorticoids. It belongs to the nuclear receptor family where the ligand diffuses into cells, interacts with the receptor and results in a signal transduction affecting specific gene expression in the nucleus. The selective response of some tissues and organs to mineralocorticoids over glucocorticoids occurs because mineralocorticoid-responsive cells express Corticosteroid 11-beta-dehydrogenase isozyme 2, an enzyme which selectively inactivates glucocorticoids more readily than mineralocorticoids.

Function

MR is expressed in many tissues, such as the kidney, colon, heart, central nervous system (hippocampus), brown adipose tissue and sweat glands. In epithelial tissues, its activation leads to the expression of proteins regulating ionic and water transports (mainly the epithelial sodium channel or ENaC, Na+/K+ pump, serum and glucocorticoid induced kinase or SGK1) resulting in the reabsorption of sodium, and as a consequence an increase in extracellular volume, increase in blood pressure, and an excretion of potassium to maintain a normal salt concentration in the body.

The receptor is activated by mineralocorticoids such as aldosterone and its precursor deoxycorticosterone as well as glucocorticoids like cortisol. In intact animals, the mineralocorticoid receptor is "protected" from glucocorticoids by co-localization of an enzyme, corticosteroid 11-beta-dehydrogenase isozyme 2 (a.k.a. 11β-hydroxysteroid dehydrogenase 2; 11β-HSD2), that converts cortisol to inactive cortisone.

Activation of the mineralocorticoid receptor, upon the binding of its ligand aldosterone, results in its translocation to the cell nucleus, homodimerization and binding to hormone response elements present in the promoter of some genes. This results in the complex recruitment of the transcriptional machinery and the transcription into mRNA of the DNA sequence of the activated genes.

An activating mutation in the NR3C2 gene (S810L) results in constitutive activity of the mineralocorticoid receptor, leading to severe early-onset hypertension that is exacerbated by pregnancy. In a family known to harbor the S810L mutation, 3 individuals carrying the mutation died of chronic heart failure before age 50. Additional studies have shown that this activated version of MR can positively respond to ligands that are traditionally antagonists, such as endogenous hormones like progesterone, and the diuretic drugs spironolactone and eplerenone.

Ligands

Aldosterone, 11-deoxycorticosterone, and cortisol are endogenous agonists of the MR. Fludrocortisone is a synthetic agonist of the MR which is used clinically. Progesterone is a potent endogenous antagonist of the MR. Synthetic antagonists of the MR include the steroidal compounds spironolactone, canrenone, eplerenone, and drospirenone and the nonsteroidal compounds apararenone, esaxerenone, and finerenone.

Interactions

Mineralocorticoid receptor has been shown to interact with:

• Glucocorticoid receptor and
• TRIM24.

See also

• Aldosterone
• Glucocorticoid
• Mineralocorticoid

Further reading

• "Mechanistic aspects of mineralocorticoid receptor activation". Kidney International 57 (4): 1250–5. April 2000. doi:10.1046/j.1523-1755.2000.00958.x. PMID 10760050. 
• "Nuclear receptors. II. Intestinal corticosteroid receptors". American Journal of Physiology. Gastrointestinal and Liver Physiology 282 (5): G742-6. May 2002. doi:10.1152/ajpgi.00531.2001. PMID 11960770. 
• "[The psychotherapeutic society--utopia or nightmare?]". Läkartidningen 72 (12): 1160–1. March 1975. PMID 1134129. 
• "Overexpression and characterization of the human mineralocorticoid receptor". The Journal of Biological Chemistry 266 (27): 18072–81. September 1991. doi:10.1016/S0021-9258(18)55238-8. PMID 1655735. 
• "Regional chromosomal assignment of the human mineralocorticoid receptor gene to 4q31.1". Human Genetics 85 (1): 130–2. June 1990. doi:10.1007/BF00276340. PMID 2162806. 
• "The human mineralocorticoid receptor gene (MLR) is located on chromosome 4 at q31.2". Cytogenetics and Cell Genetics 52 (1–2): 83–4. 1989. doi:10.1159/000132846. PMID 2558856. 
• "Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor". Science 237 (4812): 268–75. July 1987. doi:10.1126/science.3037703. PMID 3037703. Bibcode: 1987Sci...237..268A. 
• "Identification of a splice variant of the rat and human mineralocorticoid receptor genes". The Journal of Steroid Biochemistry and Molecular Biology 55 (2): 159–62. November 1995. doi:10.1016/0960-0760(95)00162-S. PMID 7495694. 
• "Human mineralocorticoid receptor interacts with actin under mineralocorticoid ligand modulation". FEBS Letters 384 (2): 112–6. April 1996. doi:10.1016/0014-5793(96)00295-5. PMID 8612804. 
• "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry 272 (18): 12062–8. May 1997. doi:10.1074/jbc.272.18.12062. PMID 9115274. 
• "Tissue-specific expression of alpha and beta messenger ribonucleic acid isoforms of the human mineralocorticoid receptor in normal and pathological states". The Journal of Clinical Endocrinology and Metabolism 82 (5): 1345–52. May 1997. doi:10.1210/jcem.82.5.3933. PMID 9141514. 
• "The unliganded mineralocorticoid receptor is associated with heat shock proteins 70 and 90 and the immunophilin FKBP-52". Receptors & Signal Transduction 7 (2): 85–98. 1997. PMID 9392437. 
• "Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I". Nature Genetics 19 (3): 279–81. July 1998. doi:10.1038/966. PMID 9662404. 
• "Cysteines 849 and 942 of human mineralocorticoid receptor are crucial for steroid binding". Biochemistry 37 (35): 12153–9. September 1998. doi:10.1021/bi980593e. PMID 9724527. 
• "Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis". Nature Genetics 22 (3): 239–47. July 1999. doi:10.1038/10297. PMID 10391210. 
• "The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies". Genes & Development 14 (4): 422–34. February 2000. doi:10.1101/gad.14.4.422. PMID 10691735. 
• "Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy". Science 289 (5476): 119–23. July 2000. doi:10.1126/science.289.5476.119. PMID 10884226. Bibcode: 2000Sci...289..119G. 
• "Crucial role of the H11-H12 loop in stabilizing the active conformation of the human mineralocorticoid receptor". Molecular Endocrinology 14 (8): 1210–21. August 2000. doi:10.1210/mend.14.8.0502. PMID 10935545. 
• "Expression of mineralocorticoid and glucocorticoid receptor mRNA in the human hippocampus". Neuroscience Letters 290 (2): 121–4. August 2000. doi:10.1016/S0304-3940(00)01325-2. PMID 10936692. 

External links

• Mineralocorticoid+Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)