Nomenclature: Mineralocorticoid receptor

Systematic Nomenclature: NR3C2

Family: 3C. 3-Ketosteroid receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

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 27
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
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
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:  7
Natural/Endogenous Ligands
aldosterone
corticosterone
cortisol
progesterone
Rank order of potency (Human)
corticosterone, cortisol, aldosterone, progesterone  [30]
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]aldosterone Rn Agonist 9.52 – 9.4 pKd 16,34
pKd 9.52 – 9.4 (Kd 3x10-10 – 4x10-10 M) [16,34]
prednisolone Hs Agonist 7.43 pKi
pKi 7.43 (Ki 3.7x10-8 M)
progesterone Hs Agonist 11.0 pIC50 30
pIC50 11.0 [30]
deoxycorticosterone Hs Agonist 11.0 pIC50 30
pIC50 11.0 [30]
fludrocortisone Hs Agonist 9.92 pIC50 30
pIC50 9.92 [30]
aldosterone Hs Agonist 9.8 – 10.0 pIC50 17,30
pIC50 9.8 – 10.0 [17,30]
cortisol Hs Agonist 9.8 – 9.95 pIC50 17,30
pIC50 9.8 – 9.95 [17,30]
dexamethasone Hs Agonist 9.0 pIC50 17,30
pIC50 9.0 [17,30]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
spironolactone Hs Antagonist 8.63 pKi 4
pKi 8.63 (Ki 2.32x10-9 M) [4]
eplerenone Hs Antagonist 6.91 pKi 4
pKi 6.91 (Ki 1.24x10-7 M) [4]
nimodipine Hs Antagonist 6.8 pIC50 13
pIC50 6.8 (IC50 1.6x10-7 M) inhibition of aldosterone-induced luciferase activity in a reporter system driven by the mineralocorticoid receptor ligand binding domain [13]
RU28318 Hs Antagonist - -
drospirenone Hs Antagonist - - 28
[28]
onapristone Hs Antagonist - -
ZK112993 Hs Antagonist - -
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
11beta-HSD2 Physical, Functional Cellular localization 14
Glucocorticoid receptor Physical, Functional DNA binding 21-23
HSP90 Physical, Functional Cellular localization 29
HMGD Physical, Functional DNA binding 9,38
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. 24
PPARGC1A Co-activator No Yes No Strong MR coactivator and highly expressed in brown adipocytes. 15
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. 26
NCOR1 Co-repressor No No Yes Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC). 39
NCOR2 Co-repressor No No Yes Recruited to antagonist bound steroid receptors followed by recruitment of histone deacetylase proteins (HDAC). 39
PIAS1 Co-repressor Yes Yes No PIAS1, a SUMO-E3 ligase, inhibits transactivation by MR and AR but not that by GR. 36
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. 1,33
Sgk1 Rat Activated the focal induction of serum and glucocorticoid-regulated kinase 1 (SGK1) is in the distal nephron and colon 6,11,32
Fxyd4 Rat Activated Fxyd4 or the chanel-inducing factor (Chif) is a member of the FXYD membrane protein family associated with Na+K+ATPase. 10
Main Target Genes Comments
K-Ras2 gene is activated by MR in Xenopus [37]. 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 [18-19,19].
Tissue Distribution
Liver, brain, heart, kidney, colon, aorta, hippocampus, hypothalamus, adrenal fasciculata.
Species:  Human
Technique:  Northern, Q-PCR, in situ, Western, immunohistology
References:  12,20
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:  5
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:  5,33
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:  5
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

Show »

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: 
References:  31,35
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: 
References:  31,35
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
Type:  Alternative promoters and splicing
Species:  Human
Description:  mineralocorticoid receptor isoform 1 (MR-A) is the full length transcript
Protein accession: 
References:  25
Type:  Alternative promoters and splicing
Species:  Human
Description:  mineralocorticoid receptor isoform 2 (MR-B) is an N-terminus truncated transcript of hMR
Protein accession: 
References:  25
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 [8,40-41].

REFERENCES

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36. Tallec LP, Kirsh O, Lecomte MC, Viengchareun S, Zennaro MC, Dejean A, Lombès 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 (12): 2529-42. [PMID:14500761]

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To cite this database page, please use the following:

3C. 3-Ketosteroid receptors: Mineralocorticoid receptor. Last modified on 13/12/2013. Accessed on 03/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=626.

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