Mineralocorticoid receptor explained

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.^[1]

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.^[2]

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.^[3]

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.^[4] 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.^[5] 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^[6] and
• TRIM24.^{[6] [7] [8]}

See also

• Aldosterone
• Glucocorticoid
• Mineralocorticoid

Further reading

• Hellal-Levy C, Fagart J, Souque A, Rafestin-Oblin ME . Mechanistic aspects of mineralocorticoid receptor activation . Kidney International . 57 . 4 . 1250–5 . April 2000 . 10760050 . 10.1046/j.1523-1755.2000.00958.x . free .
• Sheppard KE . Nuclear receptors. II. Intestinal corticosteroid receptors . American Journal of Physiology. Gastrointestinal and Liver Physiology . 282 . 5 . G742-6 . May 2002 . 11960770 . 10.1152/ajpgi.00531.2001 .
• Kjellander CG . [The psychotherapeutic society--utopia or nightmare?] . Läkartidningen . 72 . 12 . 1160–1 . March 1975 . 1134129 .
• Alnemri ES, Maksymowych AB, Robertson NM, Litwack G . Overexpression and characterization of the human mineralocorticoid receptor . The Journal of Biological Chemistry . 266 . 27 . 18072–81 . September 1991 . 10.1016/S0021-9258(18)55238-8 . 1655735 . free .
• Morrison N, Harrap SB, Arriza JL, Boyd E, Connor JM . Regional chromosomal assignment of the human mineralocorticoid receptor gene to 4q31.1 . Human Genetics . 85 . 1 . 130–2 . June 1990 . 2162806 . 10.1007/BF00276340 . 9264993 .
• Fan YS, Eddy RL, Byers MG, Haley LL, Henry WM, Nowak NJ, Shows TB . The human mineralocorticoid receptor gene (MLR) is located on chromosome 4 at q31.2 . Cytogenetics and Cell Genetics . 52 . 1–2 . 83–4 . 1989 . 2558856 . 10.1159/000132846 .
• Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM . Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor . Science . 237 . 4812 . 268–75 . July 1987 . 3037703 . 10.1126/science.3037703 . 1987Sci...237..268A .
• Bloem LJ, Guo C, Pratt JH . 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 . 7495694 . 10.1016/0960-0760(95)00162-S . 10179119 .
• Jalaguier S, Mornet D, Mesnier D, Léger JJ, Auzou G . Human mineralocorticoid receptor interacts with actin under mineralocorticoid ligand modulation . FEBS Letters . 384 . 2 . 112–6 . April 1996 . 8612804 . 10.1016/0014-5793(96)00295-5 . 34685894 . free . 1996FEBSL.384..112J .
• Thénot S, Henriquet C, Rochefort H, Cavaillès V . Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1 . The Journal of Biological Chemistry . 272 . 18 . 12062–8 . May 1997 . 9115274 . 10.1074/jbc.272.18.12062 . free .
• Zennaro MC, Farman N, Bonvalet JP, Lombès M . 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 . 9141514 . 10.1210/jcem.82.5.3933 . free .
• Bruner KL, Derfoul A, Robertson NM, Guerriero G, Fernandes-Alnemri T, Alnemri ES, Litwack G . 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 . 9392437 .
• Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, Lifton RP . Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I . Nature Genetics . 19 . 3 . 279–81 . July 1998 . 9662404 . 10.1038/966 . 33028408 .
• Lupo B, Mesnier D, Auzou G . Cysteines 849 and 942 of human mineralocorticoid receptor are crucial for steroid binding . Biochemistry . 37 . 35 . 12153–9 . September 1998 . 9724527 . 10.1021/bi980593e .
• Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A, Cooper R, Lipshutz R, Chakravarti A . 6 . Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis . Nature Genetics . 22 . 3 . 239–47 . July 1999 . 10391210 . 10.1038/10297 . 4636523 .
• Freeman BC, Felts SJ, Toft DO, Yamamoto KR . 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 . 10.1101/gad.14.4.422 . 10691735 . 316379 .
• Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP . 6 . Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy . Science . 289 . 5476 . 119–23 . July 2000 . 10884226 . 10.1126/science.289.5476.119 . 2000Sci...289..119G .
• Hellal-Levy C, Fagart J, Souque A, Wurtz JM, Moras D, Rafestin-Oblin ME . 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 . 10935545 . 10.1210/mend.14.8.0502 . free .
• Watzka M, Beyenburg S, Blümcke I, Elger CE, Bidlingmaier F, Stoffel-Wagner B . Expression of mineralocorticoid and glucocorticoid receptor mRNA in the human hippocampus . Neuroscience Letters . 290 . 2 . 121–4 . August 2000 . 10936692 . 10.1016/S0304-3940(00)01325-2 . 45158226 .

Notes and References

1. Fan YS, Eddy RL, Byers MG, Haley LL, Henry WM, Nowak NJ, Shows TB . The human mineralocorticoid receptor gene (MLR) is located on chromosome 4 at q31.2 . Cytogenetics and Cell Genetics . 52 . 1–2 . 83–4 . 1989 . 2558856 . 10.1159/000132846 .
2. Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet ER, Monder C . 6 . Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor . Lancet . 2 . 8618 . 986–9 . October 1988 . 2902493 . 10.1016/S0140-6736(88)90742-8 . 1874/24458 . 206004965 . free .
3. Fuller PJ, Young MJ . Mechanisms of mineralocorticoid action . Hypertension . 46 . 6 . 1227–35 . December 2005 . 16286565 . 10.1161/01.HYP.0000193502.77417.17 . 14749847 . 10.1.1.319.6620 .
4. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP . 6 . Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy . Science . 289 . 5476 . 119–23 . July 2000 . 10884226 . 10.1126/science.289.5476.119 . 2000Sci...289..119G .
5. Baker ME, Katsu Y . Progesterone: An enigmatic ligand for the mineralocorticoid receptor . Biochemical Pharmacology . 177 . 113976 . July 2020 . 32305433 . 10.1016/j.bcp.2020.113976 . 216028937 . 2001.07822 .
6. Savory JG, Préfontaine GG, Lamprecht C, Liao M, Walther RF, Lefebvre YA, Haché RJ . Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces . Molecular and Cellular Biology . 21 . 3 . 781–93 . February 2001 . 11154266 . 86670 . 10.1128/MCB.21.3.781-793.2001 .
7. Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombès M . A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action . Molecular Endocrinology . 15 . 9 . 1586–98 . September 2001 . 11518808 . 10.1210/mend.15.9.0689 . free .
8. Thénot S, Henriquet C, Rochefort H, Cavaillès V . Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1 . The Journal of Biological Chemistry . 272 . 18 . 12062–8 . May 1997 . 9115274 . 10.1074/jbc.272.18.12062 . free .