TABLE 2

MR

Receptor nomenclature NR3C2
Receptor code 4.10.1:MC:3:C2
Other names MR, MCR, MLR, aldosterone receptor
Molecular information Hs: 984aa, P08235, chr. 4q31.11
Rn: 981aa, P22199, chr. 19q112
Mm: 978aa, Q8VII8, chr. 8 C13
DNA binding
   Structure Homodimer, heterodimer
   HRE core sequence ACAAGANNNTGTTCT (GRE, half-site, palindrome)
Partners HSP90 (physical, functional): cellular localization4; HMGB (physical, functional): DNA binding5,6; 11β-HSD2 (functional): tissue specificity7
Agonists Desoxycorticosterone (1 × 10–11 M), progesterone (1 × 10–11 M),* fludrocortisone (1.2 × 10–10 M), cortisol (1.1–1.5 × 10–10 M), dexamethasone (1 × 10–9 M)* [IC50]8,9; aldosterone (1–1.5 × 10–10)* [Kd]8,9
Antagonists Drospirenone (<1 × 10–10 M), spironolactone (1.4 × 10–8 M), eplerenone (1 × 10–7 M) [IC50]8,1012
Coactivator NCOA1, PGC-1α, ELL1315
Corepressor NCOR1, NCOR2, PIAS116,17
Biologically important isoforms MR-A {Hs, Mm, Rn}: main isoform18; MR-B {Hs, Mm, Rn}: truncated N terminus18; various splice variants also exist resulting in either altered DNA or ligand binding {Hs, Rn}1921
Tissue distribution Liver, brain, heart, kidney, colon, aorta, hippocampus, hypothalamus, adrenal fasciculate, epidermal keratinocytes, neurons of the CNS, cardiac myocytes, endothelial and smooth muscle cells of the vasculature {Hs,Mm,Rn} [Northern blot, Q-PCR, in situ hybridization, Western blot, immunohistology]2233
Functional assay Renal clearance {Mm}34; colonic transepithelial Na+ reabsorption {Mm}34,35
Main target genes Activated: Enac {Hs}36,37 SGK1{Rn},3840 GILZ{Rn}41
Mutant phenotype Homozygous MR-deficient mice have a normal prenatal development; during the 1st week of life, these animals develop symptoms of pseudohypoaldosteronism, lose weight, and eventually die at around day 10 due to kidney failure {Mm} [knockout]34; a conditional knockout model expressing solely in the heart an antisense mRNA directed against the murine MR; within 2–3 months, mice develop severe heart failure in the absence of hypertension or chronic hyperaldosteronism {Mm} [antisense oligonucleotide]3
Human disease Hypertension: Ser810 → Ile SNP causes gain of function42; pseudohypoaldosteronism type 1: various polymorphisms cause loss of activity; autosomal-dominant; haploinsufficiency seems to be the predominant mechanism43,44
  • aa, amino acids; chr., chromosome; HRE, hormone response element; ELL, eleven-nineteen lysine-rich leukemia; HMGB, chromosomal high-mobility group B; 11β-HSD2, 11β-hydroxysteroid dehydrogenase 2; Q-PCR, quantitative polymerase chain reaction; SNP, single-nucleotide polymorphism; GRE, glucocorticoid response element

  • * Radioligand

  • 1. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, and Evans RM (1987) Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science (Wash DC) 237: 268-275

  • 2. Patel PD, Sherman TG, Goldman DJ, and Watson SJ (1989) Molecular cloning of a mineralocorticoid (type I) receptor complementary DNA from rat hippocampus. Mol Endocrinol 3: 1877-1885

  • 3. Beggah AT, Escoubet B, Puttini S, Cailmail S, Delage V, Ouvrard-Pascaud A, Bocchi B, Peuchmaur M, Delcayre C, Farman N, et al. (2002) Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes. Proc Natl Acad Sci USA 99: 7160-7165

  • 4. Pratt WB, Galigniana MD, Morishima Y, and Murphy PJ (2004) Role of molecular chaperones in steroid receptor action. Essays Biochem 40: 41-58

  • 5. Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, Nordeen SK, Allegretto EA, and Edwards DP (1998) High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol Cell Biol 18: 4471-4487

  • 6. Verrijdt G, Haelens A, Schoenmakers E, Rombauts W, and Claessens F (2002) Comparative analysis of the influence of the high-mobility group box 1 protein on DNA binding and transcriptional activation by the androgen, glucocorticoid, progesterone and mineralocorticoid receptors. Biochem J 361: 97-103

  • 7. Farman N and Rafestin-Oblin ME (2001) Multiple aspects of mineralocorticoid selectivity. Am J Physiol 280: F181-F192

  • 8. Rupprecht R, Reul JM, van Steensel B, Spengler D, Soder M, Berning B, Holsboer F, and Damm K (1993) Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur J Pharmacol 247: 145-154

  • 9. Hellal-Levy C, Couette B, Fagart J, Souque A, Gomez-Sanchez C, and Rafestin-Oblin M (1999) Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett 464: 9-13

  • 10. Pollow K, Juchem M, Elger W, Jacobi N, Hoffmann G, and Mobus V (1992) Dihydrospirorenone (ZK30595): a novel synthetic progestagen—characterization of binding to different receptor proteins. Contraception 46: 561-574

  • 11. de Gasparo M, Joss U, Ramjoue HP, Whitebread SE, Haenni H, Schenkel L, Kraehenbuehl C, Biollaz M, Grob J, Schmidlin J, et al. (1987) Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 240: 650-656

  • 12. Hu X, Li S, McMahon EG, Lala DS, and Rudolph AE (2005) Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone. Mini Rev Med Chem 5: 709-718

  • 13. Onate SA, Tsai SY, Tsai MJ, and O'Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science (Wash DC) 270: 1354-1357

  • 14. Fuse H, Kitagawa H, and Kato S (2000) Characterization of transactivational property and coactivator mediation of rat mineralocorticoid receptor activation function-1 (AF-1). Mol Endocrinol 14: 889-899

  • 15. Pascual-Le Tallec L, Simone F, Viengchareun S, Meduri G, Thirman MJ, and Lombes M (2005) The elongation factor ELL (eleven-nineteen lysine-rich leukemia) is a selective coregulator for steroid receptor functions. Mol Endocrinol 19: 1158-1169

  • 16. Wang Q, Anzick S, Richter WF, Meltzer P, and Simons SS Jr (2004) Modulation of transcriptional sensitivity of mineralocorticoid and estrogen receptors. J Steroid Biochem Mol Biol 91: 197-210

  • 17. Pascual-Le Tallec L, Kirsh O, Lecomte MC, Viengchareun S, Zennaro MC, Dejean A, and Lombes M (2003) Protein inhibitor of activated signal transducer and activator of transcription 1 interacts with the N-terminal domain of mineralocorticoid receptor and represses its transcriptional activity: implication of small ubiquitin-related modifier 1 modification. Mol Endocrinol 17: 2529-2542

  • 18. Pascual-Le Tallec L, Demange C, and Lombes M (2004) Human mineralocorticoid receptor A and B protein forms produced by alternative translation sites display different transcriptional activities. Eur J Endocrinol 150: 585-590

  • 19. Bloem LJ, Guo C, and Pratt JH (1995) Identification of a splice variant of the rat and human mineralocorticoid receptor genes. J Steroid Biochem Mol Biol 55: 159-162

  • 20. Zhou MY, Gomez-Sanchez CE, and Gomez-Sanchez EP (2000) An alternatively spliced rat mineralocorticoid receptor mRNA causing truncation of the steroid binding domain. Mol Cell Endocrinol 159: 125-131

  • 21. Zennaro MC, Souque A, Viengchareun S, Poisson E, and Lombes M (2001) A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol 15: 1586-1598

  • 22. Krozowski ZS and Funder JW (1983) Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity. Proc Natl Acad Sci USA 80: 6056-6060

  • 23. McEwen BS, De Kloet ER, and Rostene W (1986) Adrenal steroid receptors and actions in the nervous system. Physiol Rev 66: 1121-1188

  • 24. Pearce P and Funder JW (1987) High affinity aldosterone binding sites (type I receptors) in rat heart. Clin Exp Pharmacol Physiol 14: 859-866

  • 25. Scott BA, Lawrence B, Nguyen HH, and Meyer WJ 3rd (1987) Aldosterone and dexamethasone binding in human arterial smooth muscle cells. J Hypertens 5: 739-744

  • 26. Arriza JL, Simerly RB, Swanson LW, and Evans RM (1988) The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1: 887-900

  • 27. Barnett CA and Pritchett EL (1988) Detection of corticosteroid type I binding sites in heart. Mol Cell Endocrinol 56: 191-198

  • 28. Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, and Bonvalet JP (1992) Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res 71: 503-510

  • 29. Van Eekelen JA and De Kloet ER (1992) Co-localization of brain corticosteroid receptors in the rat hippocampus. Prog Histochem Cytochem 26: 250-258

  • 30. Kenouch S, Lombes M, Delahaye F, Eugene E, Bonvalet JP, and Farman N (1994) Human skin as target for aldosterone: coexpression of mineralocorticoid receptors and 11β -hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 79: 1334-1341

  • 31. Lombes M, Alfaidy N, Eugene E, Lessana A, Farman N, and Bonvalet JP (1995) Prerequisite for cardiac aldosterone action: mineralocorticoid receptor and 11β -hydroxysteroid dehydrogenase in the human heart. Circulation 92: 175-182

  • 32. Zennaro MC, Farman N, Bonvalet JP, and Lombes M (1997) Tissue-specific expression of α and β messenger ribonucleic acid isoforms of the human mineralocorticoid receptor in normal and pathological states. J Clin Endocrinol Metab 82: 1345-1352

  • 33. de Kloet ER, Van Acker SA, Sibug RM, Oitzl MS, Meijer OC, Rahmouni K, and de Jong W (2000) Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int 57: 1329-1336

  • 34. Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Kriz W, Warth R, Greger R, and Schutz G (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci USA 95: 9424-9429

  • 35. Skrabal F, Aubock J, Edwards CR, and Braunsteiner H (1978) Subtraction potential difference: in-vivo assay for mineralocorticoid activity. Lancet 1: 298-302

  • 36. Epple HJ, Amasheh S, Mankertz J, Goltz M, Schulzke JD, and Fromm M (2000) Early aldosterone effect in distal colon by transcriptional regulation of ENaC subunits. Am J Physiol 278: G718-G724

  • 37. Amasheh S, Epple HJ, Mankertz J, Detjen K, Goltz M, Schulzke JD, and Fromm M (2000) Differential regulation of ENaC by aldosterone in rat early and late distal colon. Ann NY Acad Sci 915: 92-94

  • 38. Brennan FE and Fuller PJ (2000) Rapid upregulation of serum and glucocorticoid-regulated kinase (sgk) gene expression by corticosteroids in vivo. Mol Cell Endocrinol 166: 129-136

  • 39. Shigaev A, Asher C, Latter H, Garty H, and Reuveny E (2000) Regulation of sgk by aldosterone and its effects on the epithelial Na+ channel. Am J Physiol 278: F613-F619

  • 40. Bhargava A, Fullerton MJ, Myles K, Purdy TM, Funder JW, Pearce D, and Cole TJ (2001) The serum- and glucocorticoid-induced kinase is a physiological mediator of aldosterone action. Endocrinology 142: 1587-1594

  • 41. Soundararajan R, Zhang TT, Wang J, Vandewalle A, and Pearce D (2005) A novel role for glucocorticoid-induced leucine zipper protein in epithelial sodium channel-mediated sodium transport. J Biol Chem 280: 39970-39981

  • 42. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, and Lifton RP (2000) Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289: 119-123

  • 43. Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, Lifton RP (1998) Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet 19: 279-281

  • 44. Geller DS, Zhang J, Zennaro MC, Vallo-Boado A, Rodriguez-Soriano J, Furu L, Haws R, Metzger D, Botelho B, Karaviti L, et al. (2006) Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults. J Am Soc Nephrol 17: 1429-1436