Overview: Steroid hormone receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Dahlman-Wright et al., 2006; Lu et al., 2006) are nuclear hormone receptors of the NR3 class, with endogenous agonists that include 5α-dihydrotestosterone (DHT), aldosterone, cortisol, corticosterone, progesterone, testosterone and estradiol. These receptors exist as dimers coupled with chaperone molecules (such as HSP90 and immunophilin HSP65), which are shed on binding the steroid hormone. Although rapid signalling phenomena are observed (see Levin, 2008; Prossnitz and Maggiolini, 2009), the principal signalling cascade appears to involve binding of the activated receptors to nuclear hormone response elements of the genome, with a 15-nucleotide consensus sequence AGAACAnnnTGTTCT (i.e. an inverted palindrome) as homo- or heterodimers. They also affect transcription by protein–protein interactions with other transcription factors, such as activator protein 1 and nuclear factor κB. Splice variants of each of these receptors can form functional or non-functional monomers that can dimerize to form functional or non-functional receptors. For example, alternative splicing of PR mRNA produces A and B monomers that combine to produce functional AA, AB and BB receptors with distinct characteristics (Vegeto et al., 1993).
A 7TM receptor responsive to oestrogen (GPER, also known as GPR30, ENSG00000164850, see Prossnitz et al., 2008) has been described. Human orthologues of 7TM ‘membrane progestin receptors’ (ENSG00000182749, ENSG00000170915 and ENSG00000137819), initially discovered in fish (Zhu et al., 2003a,b;), appear to localize to intracellular membranes and appear to respond to ‘non-genomic’ progesterone analogues independently of G proteins (Smith et al., 2008).
| Nomenclature | Glucocorticoid | Mineralocorticoid | Progesterone | Androgen |
|---|---|---|---|---|
| Preferred abbreviation | GR | MR | PR | AR |
| Systematic nomenclature | NR3C1 | NR3C2 | NR3C3 | NR3C4 |
| Other names | Type II glucocorticoid receptor | Type I glucocorticoid receptor, aldosterone receptor | – | dihydrotestosterone receptor |
| Ensembl ID | ENSG00000113580 | ENSG00000151623 | ENSG00000082175 | ENSG00000169083 |
| Rank order of potency | Cortisol, corticosterone >> aldosterone, deoxycortisone (Rupprecht et al., 1993) | Corticosterone, cortisol, aldosterone, progesterone (Rupprecht et al., 1993) | Progesterone | DHT>testosterone |
| Selective agonists | RU28362, RU26988 | Aldosterone | ORG2058, progesterone | DHT, mibolerone, R1881 |
| Selective antagonists | Mifepristone, ZK112993, onapristone | RU28318, ZK112993, onapristone | Mifepristone, ZK112993, onapristone | Hydroxyflutamide, nilutamide |
| Probes | [3H]-Dexamethasone | [3H]-Aldosterone | [3H]-ORG2058 | [3H]-DHT, [3H]-mibolerone, [3H]-R1881 |
[3H]-Dexamethasone also binds to MR in vitro. PR antagonists have been suggested to subdivide into Type I (e.g. onapristone) and Type II (e.g. ZK112993) groups. These groups appear to promote binding of PR to DNA with different efficacies and evoke distinct conformational changes in the receptor, leading to a transcription-neutral complex (Gass et al., 1998; Leonhardt et al., 1998). Mutations in AR underlie testicular feminization and androgen insensibility syndromes, spinal and bulbar muscular atrophy (Kennedy's disease).
| Nomenclature | Oestrogen α | Oestrogen β |
|---|---|---|
| Preferred abbreviation | ERα | ERβ |
| Systematic nomenclature | NR3A1 | NR3A2 |
| Other names | Estradiol | Estradiol |
| Ensembl ID | ENSG00000091831 | ENSG00000140009 |
| Selective agonists | PPT (Kraichely et al., 2000; Stauffer et al., 2000) | DPN (Meyers et al., 2001) |
| Selective antagonists | MPP (Sun et al., 2002) | PHTPP (Compton et al., 2004), R,R-THC (Meyers et al., 1999; Sun et al., 1999) |
r,r-THC exhibits partial agonist activity at ERα (Meyers et al., 1999; Sun et al., 1999). Oestrogen receptors may be blocked non-selectively by tamoxifen and raloxifene and labelled by [3H]-estradiol and [3H]-tamoxifen. Many agents thought initially to be antagonists at oestrogen receptors appear to have tissue-specific efficacy (e.g. tamoxifen is an antagonist at oestrogen receptors in the breast, but is an agonist at oestrogen receptors in the uterus), hence the descriptor SERM (selective oestrogen receptor modulator) or SnuRM (selective nuclear receptor modulator). Y134 has been suggested to be an ERα-selective oestrogen receptor modulator (Ning et al., 2007).
Additional ‘orphan’ oestrogen receptor-related proteins have been described (ERRα ENSG00000173153; ERRβ ENSG00000119715; ERRγ ENSG00000057103); DY131 is an agonist with selectivity for ERRβ and ERRγ compared with ERRα, ERα and ERβ (Yu and Forman, 2005).
Glossary
Abbreviations:
- DHT
5α-dihydrotestosterone
- DPN
2,3-bis(4-hydroxyphenyl)propionitrile
- DY131
N′-([1E]-[4-(diethylamino)phenyl]methylene)-4-hydroxybenzohydrazide
- MPP
1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-[2-piperidinylethoxy]phenol)-1H-pyrazole
- ORG2058
16-α-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione
- PPT
4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol
- PHTPP
4-(2-phenyl-5,7-bis[trifluoromethyl]pyrazolo[1,5-a]pyrimidin-3-yl)phenol
- R1881
17β-hydroxy-17α-methyl-estra-4,9,11-triene-3-one, also known as methyltrienolone
- r,r-THC
r,r-tetrahydrochrysene
- RU26988
11β,17β-dihydroxy-21-methyl-17α-pregna-1,4,6-trien-20-yl-3-on
- RU28318
3-oxo-7-propyl-17-hydroxy-androstan-4-en-17-yl
- RU28362
11β,17β-dihydroxy-6-methyl-17-(1-propionyl)androsta-1,4,6-triene-3-one
- Y134
(6-hydroxy-2-[4-hydroxyphenyl]-benzo[b]thiophen-3-yl)-(4-[4-isopropylpiperazin-1-yl]-phenyl)methanone
- ZK112993
11β-(4-acetylphenyl)-17β-hydroxyl-17α-(1-propinyl)-4,8-estradiene-3-one
Further Reading
Blaustein JD (2008). Progesterone and progestin receptors in the brain: the neglected ones. Endocrinology149: 2737–2738.
Brinton RD (2009). Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci30: 212–222.
Chen Y, Sawyers CL, Scher HI (2008). Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol8: 440–448.
Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS et al. (2006). International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev58: 773-781.
Gao W, Dalton JT (2007). Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). Drug Discov Today12: 241–248.
Gross KL, Cidlowski JA (2008). Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol Metab19: 331–339.
Hadoke PW, Iqbal J, Walker BR (2009). Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Br J Pharmacol156: 689–712.
Handelsman DJ (2008). Indirect androgen doping by oestrogen blockade in sports. Br J Pharmacol154: 598–605.
Heemers HV, Tindall DJ (2007). Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev28: 778–808.
Joels M, Karst H, DeRijk R, de Kloet ER (2008). The coming out of the brain mineralocorticoid receptor. Trends Neurosci31: 1–7.
Kellner M, Wiedemann K (2008). Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy. Eur J Pharmacol583: 372–378.
Kerkhofs S, Denayer S, Haelens A, Claessens F (2009). Androgen receptor knockout and knock-in mouse models. J Mol Endocrinol42: 11–17.
Lange CA, Gioeli D, Hammes SR, Marker PC (2007). Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annu Rev Physiol69: 171–199.
Levin ER (2008). Rapid signaling by steroid receptors. Am J Physiol Regul Integr Comp Physiol295: R1425–R1430.
Lowenberg M, Verhaar AP, van den Brink GR, Hommes DW (2007). Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression. Trends Mol Med13: 158–163.
Lu NZ, Cidlowski JA (2006). Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol16: 301–307.
Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V et al. (2006). International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev58: 782–797.
McMaster A, Ray DW (2008). Drug insight: selective agonists and antagonists of the glucocorticoid receptor. Nat Clin Pract Endocrinol Metab4: 91–101.
Matsumoto T, Shiina H, Kawano H, Sato T, Kato S (2008). Androgen receptor functions in male and female physiology. J Steroid Biochem Mol Biol109: 236–241.
Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y et al. (2009). Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem52: 3597–3617.
Moriarty K, Kim KH, Bender JR (2006). Minireview: estrogen receptor-mediated rapid signaling. Endocrinology147: 5557–5563.
Patten RD, Karas RH (2006). Estrogen replacement and cardiomyocyte protection. Trends Cardiovasc Med16: 69–75.
Picard D (2006). Chaperoning steroid hormone action. Trends Endocrinol Metab17: 229–235.
Pippal JB, Fuller PJ (2008). Structure-function relationships in the mineralocorticoid receptor. J Mol Endocrinol41: 405–413.
Prossnitz ER, Maggiolini M (2009). Non-genomic signaling by steroids. Mol Cell Endocrinol308: 1–2.
Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ (2008). Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol70: 165–190.
Schumacher M, Sitruk-Ware R, De Nicola AF (2008). Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol8: 740–746.
Taplin ME (2007). Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol4: 236–244.
Weiser MJ, Foradori CD, Handa RJ (2008). Estrogen receptor β in the brain: from form to function. Brain Res Rev57: 309–320.
Woolley CS (2007). Acute effects of estrogen on neuronal physiology. Annu Rev Pharmacol Toxicol47: 657–680.
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