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Mineralocorticoid receptor

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NR3C2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNR3C2, MCR, MLR, MR, NR3C2VIT, nuclear receptor subfamily 3 group C member 2
External IDsOMIM: 600983; MGI: 99459; HomoloGene: 121495; GeneCards: NR3C2; OMA:NR3C2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4306

110784

Ensembl

ENSG00000151623

ENSMUSG00000031618

UniProt

P08235

Q8VII8

RefSeq (mRNA)

NM_000901
NM_001166104
NM_001354819

NM_001083906

RefSeq (protein)

NP_000892
NP_001159576
NP_001341748

n/a

Location (UCSC)Chr 4: 148.08 – 148.44 MbChr 8: 77.63 – 77.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

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.[6]

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.[7]

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.[8] 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.[8]

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.[9] 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:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000151623 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031618 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Fan YS, Eddy RL, Byers MG, Haley LL, Henry WM, Nowak NJ, Shows TB (1989). "The human mineralocorticoid receptor gene (MLR) is located on chromosome 4 at q31.2". Cytogenetics and Cell Genetics. 52 (1–2): 83–4. doi:10.1159/000132846. PMID 2558856.
  6. ^ Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, et al. (October 1988). "Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor". Lancet. 2 (8618): 986–9. doi:10.1016/S0140-6736(88)90742-8. PMID 2902493. S2CID 206004965.
  7. ^ Fuller PJ, Young MJ (December 2005). "Mechanisms of mineralocorticoid action". Hypertension. 46 (6): 1227–35. CiteSeerX 10.1.1.319.6620. doi:10.1161/01.HYP.0000193502.77417.17. PMID 16286565. S2CID 14749847.
  8. ^ a b Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, et al. (July 2000). "Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy". Science. 289 (5476): 119–23. Bibcode:2000Sci...289..119G. doi:10.1126/science.289.5476.119. PMID 10884226.
  9. ^ Baker ME, Katsu Y (July 2020). "Progesterone: An enigmatic ligand for the mineralocorticoid receptor". Biochemical Pharmacology. 177: 113976. doi:10.1016/j.bcp.2020.113976. PMID 32305433. S2CID 216028937.
  10. ^ a b Savory JG, Préfontaine GG, Lamprecht C, Liao M, Walther RF, Lefebvre YA, Haché RJ (February 2001). "Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces". Molecular and Cellular Biology. 21 (3): 781–93. doi:10.1128/MCB.21.3.781-793.2001. PMC 86670. PMID 11154266.
  11. ^ Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombès M (September 2001). "A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action". Molecular Endocrinology. 15 (9): 1586–98. doi:10.1210/mend.15.9.0689. PMID 11518808.
  12. ^ Thénot S, Henriquet C, Rochefort H, Cavaillès V (May 1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry. 272 (18): 12062–8. doi:10.1074/jbc.272.18.12062. PMID 9115274.

Further reading

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