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Mineralocorticoid receptor

Systematic Nomenclature: NR3C2

Family: 3C. 3-Ketosteroid receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Agonists
Antagonists
DNA Binding
Co-binding Partners
Main Co-regulators
Main Target Genes
Tissue Distribution
Functional Assays
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
References
Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 984 4q31.1 NR3C2 nuclear receptor subfamily 3, group C, member 2 2
Mouse 980 8 35.0 cM Nr3c2 nuclear receptor subfamily 3, group C, member 2 3
Rat 981 19q11 Nr3c2 nuclear receptor subfamily 3, group C, member 2 26
Previous and Unofficial Names
MR
MCR
MGC133092
MLR
Mineralocorticoid
Type I glucocorticoid receptor
aldosterone receptor
Mineralocorticoid receptor (aldosterone receptor)
mineralocorticoid receptor
nuclear receptor subfamily 3, group C, member 2
Database Links
ChEMBL Target 48 (Hs), 11010 (Rn)
DrugBank Target 737 (Hs)
Ensembl ENSG00000151623 (Hs), ENSMUSG00000031618 (Mm), ENSRNOG00000034007 (Rn)
Entrez Gene 4306 (Hs), 110784 (Mm), 25672 (Rn)
GeneCards NR3C2 (Hs)
GenitoUrinary Development Molecular Anatomy Project Nr3c2 (Mm)
HomoloGene 121495 (Hs)
Human Protein Reference Database 02991 (Hs)
InterPro P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
KEGG Gene hsa:4306 (Hs), mmu:110784 (Mm), rno:25672 (Rn)
NURSA Receptor 3C2
OMIM 600983 (Hs)
Orphanet Gene ORPHA123920 (Hs)
PharmGKB Gene PA242 (Hs)
PhosphoSitePlus P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
RefSeq Nucleotide NM_000901 (Hs), NM_001083906 (Mm), NM_013131 (Rn)
RefSeq Protein NP_001159576 (Hs), NP_000892 (Hs), NP_001077375 (Mm), NP_037263 (Rn)
TreeFam ENSG00000151623 (Hs), ENSMUSG00000031618 (Mm), ENSRNOG00000034007 (Rn)
UniProt P08235 (Hs), Q8VII8 (Mm), P22199 (Rn)
Steroid hormone
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Ligand Binding Domain (Mineralocorticoid receptor)
PDB Id:  2AA5
Ligand:  progesterone   This ligand is endogenous
Resolution:  2.2Å
Species:  Human
References:  6
Search for other structures on the PDB
Search by keyword: Mineralocorticoid receptor Search by accession number: P08235, P22199, Q8VII8
Natural/Endogenous Ligand(s)
aldosterone
corticosterone
cortisol
progesterone
Rank order of potency (Human)
corticosterone,cortisol,aldosterone,progesterone  [29]
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
deoxycorticosterone Hs Agonist 11.0 pIC50 29
progesterone Hs Agonist 11.0 pIC50 29
fludrocortisone Hs Agonist 9.92 pIC50 29
aldosterone Hs Agonist 9.8 – 10.0 pIC50 15,29
cortisol Hs Agonist 9.8 – 9.95 pIC50 15,29
dexamethasone Hs Agonist 9.0 pIC50 15,29
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
drospirenone Hs Antagonist 1.0 – 5.0 pIC50 27
eplerenone Hs Antagonist 1.0 pIC50 11,16
spironolactone Hs Antagonist 1.0 pIC50 11
DNA Binding
Structure:  Homodimer, Heterodimer
HRE core sequence:  ACAAGANNNTGTTCT
Response element:  GRE, Half site, Palindrome
DNA Binding Comments
MR and GR can heterodimerize. HRE sequence has variations that contribute to gene-specific regulation.
Co-binding Partners
Name Interaction Effect Reference
Glucocorticoid receptor Physical, Functional DNA binding 20-22
HSP90 Physical, Functional Cellular localization 28
HMGD Physical, Functional DNA binding 8,36
11beta-HSD2 Physical, Functional Cellular localization 13
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOA1 Co-activator No Yes Yes First member of a large coactivator family (SRC1, 2, 3). DNA-bound steroid receptors interact with SRC-1 which initiate sequential recruitment of SWI/SNF chromatin remodeling complexes, histone-methyltransferase proteins CARM1/PRMT1 and histone acetylases such as CBP/p300-pCAF. 23
PPARGC1A Co-activator No Yes No Strong MR coactivator and highly expressed in brown adipocytes. 14
PPARGC1A Co-activator Yes Yes No Elongation factor that directly interacts with the N-terminal domain of MR and acts as a potent coactivator; strongly represses GR transactivation and has no effect on AR or PR activity. 25
NCOR1 Co-repressor No No Yes Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC). 37
NCOR2 Co-repressor No No Yes Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC). 37
PIAS1 Co-repressor Yes Yes No PIAS1, a SUMO-E3 ligase, inhibits transactivation by MR and AR but not that by GR. 34
Main Target Genes
Name Species Effect Technique Comments References
SCNN1A Human Activated ENaC (SCCN1A) is transcriptionally regulated by aldosterone as an early event in distal colon but not in the kidney. However, aldosterone does increase ENaC number and activity on kidney epithelial cell surface. 1,32
Sgk1 Rat Activated the focal induction of serum and glucocorticoid-regulated kinase 1 (SGK1) is in the distal nephron and colon 5,10,31
Fxyd4 Rat Activated Fxyd4 or the chanel-inducing factor (Chif) is a member of the FXYD membrane protein family associated with Na+K+ATPase. 9
Main Target Genes Comments
K-Ras2 gene is activated by MR in Xenopus [35]. A small G protein and a proto-oncogene was found to be rapidly induced by aldosterone, enhances Na+ current. Other genes activated include the following: Na+, K+ ATPase α1 and β1 [17-18,18].
Tissue Distribution
liver, brain, heart, kidney, colon, aorta, hippocampus, hypothalamus, adrenal fasciculata.
Species:  Human
Technique:  Northern, Q-PCR, In situ, Western, Immunohistology
References:  12,19
Tissue Distribution Comments
Classic aldosterone-sensitive tissues include epithelia with high electrical resistance, such as the distal parts of the nephron, the surface epithelium of the distal colon, and salivary and sweat gland ducts. More recently, other MR-expressing cells have been identified, either epithelial, as in epidermal keratinocytes, or nonepithelial, as in the neurons of the central nervous system, the cardiac myocytes, and the endothelial and smooth muscle cells of the vasculature (large vessels). Similar patterns of expression are also seen in rodents.
Functional Assays
Renal clearance
Species:  Mouse
Tissue:  urine
Response measured:  ion levels
References:  4
Colonic transepithelial Na+ reabsorption
Species:  Mouse
Tissue:  colon, in vivo
Response measured:  colonic transepithelial potential difference is measured in vivo by a double-barreled flexible polyethylene tube that could be perfused by Ringer-type solution ± amiloride (3 µmol/liter). This tube was inserted into the rectum at a length of 7 mm. The electrical potential of this tube is measured by a high input resistance differential amplifier and was referenced to an Ag/AgCl electrode that was inserted under the skin
References:  4,32
Physiological Consequences of Altering Gene Expression
Homozygous MR-deficient mice:- show normal prenatal development, during week one they developed symptoms of pseudohypoaldosteronism, lost weight and died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells
References:  4
A conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism.
Species:  Mouse
Tissue:  heart
Technique:  Antisense oligonucleotide
References:  3
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0002761 abnormal hippocampal mossy fiber morphology PMID: 16368758 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0001765 abnormal ion homeostasis PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002829 abnormal juxtaglomerular apparatus PMID: 9689096 
Nr3c2tm1Krst|Tg(Camk2a-cre)2Gsc Nr3c2tm1Krst/Nr3c2tm1Krst,Tg(Camk2a-cre)2Gsc/?
involves: FVB/N		 MGI:2181425  MGI:99459  MP:0004753 abnormal miniature excitatory postsynaptic currents PMID: 16361444 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005325 abnormal renal glomerulus morphology PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0010109 abnormal renal sodium reabsorption PMID: 9689096 
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0003461 abnormal response to novel object PMID: 16368758 
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0001463 abnormal spatial learning PMID: 16368758 
Nr3c2tm2Gsc|Tg(Camk2a-cre)2Gsc Nr3c2tm2Gsc/Nr3c2tm2Gsc,Tg(Camk2a-cre)2Gsc/0
involves: 129P2/OlaHsd * C57BL/6 * FVB/N		 MGI:2181425  MGI:99459  MP:0008428 abnormal spatial working memory PMID: 16368758 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005634 decreased circulating sodium level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0001429 dehydration PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0010128 hypovolemia PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002666 increased circulating aldosterone level PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002666 increased circulating aldosterone level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005627 increased circulating potassium level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0003352 increased circulating renin level PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0003352 increased circulating renin level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002608 increased hematocrit PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005582 increased renin activity PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0005582 increased renin activity PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006316 increased urine sodium level PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006316 increased urine sodium level PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006275 natriuresis PMID: 9689096 
Nr3c2+|Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2+
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0006275 natriuresis PMID: 9689096 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0002082 postnatal lethality PMID: 9689096 
Nr3c2tm2.1Gsc Nr3c2tm2.1Gsc/Nr3c2tm2.1Gsc
involves: C57BL/6		 MGI:99459  MP:0002082 postnatal lethality PMID: 16368758 
Nr3c2tm1Gsc Nr3c2tm1Gsc/Nr3c2tm1Gsc
involves: 129P2/OlaHsd * C57BL/6		 MGI:99459  MP:0001263 weight loss PMID: 9689096 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Hypertension
OMIM:  605115
Orphanet:  88660
Comments:  Alteration at the receptor level: S819L mutant gains function.
References:  30,33
Click column headers to sort
Type Species Molecular location Description Reference
nonsynonymous point mutation- gain of function Human S819L
Disease:  Pseudohypoaldosteronism type 1 (PHA1)
OMIM:  177735
Orphanet:  171871
Comments:  Alteration at the receptor level: G633R, Q776R, L924P and L979P mutants lose activity.
References:  30,33
Click column headers to sort
Type Species Molecular location Description Reference
nonsynonymous point mutation:- loss of function Human G633R, Q776R, L924P and L979P
Biologically Significant Variants
mineralocorticoid receptor isoform 1 (MR-A) is the full length transcript
Protein accession:  NP_000892 
Type:  Alternative promoters and splicing
Species:  Human
References:  24
mineralocorticoid receptor isoform 2 (MR-B) is an N-terminus truncated transcript of hMR
Protein accession:  NP_001159576 
Type:  Alternative promoters and splicing
Species:  Human
References:  24
Biologically Significant Variant Comments
human mineralocorticoid receptor isoform 1 (MR-A) has higher transactivation activity than MR-B. Other splicing variants include: A 12-bp insertion at the 3' of exon 3 results in a four-residue addition in between the two zinc fingers of the DBD and no difference in activity compared to the wild-type receptor; a 10-bp deletion in rat MR results truncated LBD at residue 807, unresponsive to aldosterone, and no interference with wild-tpe receptor function; exon-skipping in human generates mutants lacking exon 5 or both exons 5 and 6 which binds to DNA and modulate wild-type receptor activity in a ligand-independent manner. [7,38-39]

REFERENCES

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To cite this database page, please use the following:

3C. 3-Ketosteroid receptors: Mineralocorticoid receptor. Last modified on 16/11/2012. Accessed on 22/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=626.


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