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- Steroid hormone receptors
- 3C. 3-Ketosteroid receptors
3C. 3-Ketosteroid receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [1,7,20]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol.
Receptors
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Androgen receptor / NR3C4
C
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Glucocorticoid receptor / NR3C1
C
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Mineralocorticoid receptor / NR3C2
C
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Progesterone receptor / NR3C3
C
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Further reading
* Key recommended reading is highlighted with an asterisk
Arango-Lievano M, Lambert WM, Jeanneteau F. (2015) Molecular Biology of Glucocorticoid Signaling. Adv Exp Med Biol, 872: 33-57. [PMID:26215989]
* Baker ME, Katsu Y. (2017) 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function. J Endocrinol, 234 (1): T1-T16. [PMID:28468932]
Bauersachs J, Jaisser F, Toto R. (2015) Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertension, 65 (2): 257-63. [PMID:25368026]
* Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD. (2017) Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer, 17 (1): 54-64. [PMID:27885264]
Clifton VL, Cuffe J, Moritz KM, Cole TJ, Fuller PJ, Lu NZ, Kumar S, Chong S, Saif Z. (2017) Review: The role of multiple placental glucocorticoid receptor isoforms in adapting to the maternal environment and regulating fetal growth. Placenta, 54: 24-29. [PMID:28017357]
* Cohen DM, Steger DJ. (2017) Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor. Trends Endocrinol Metab, 28 (7): 531-540. [PMID:28495406]
Davey RA, Grossmann M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev, 37 (1): 3-15. [PMID:27057074]
* de Kloet ER, Joëls M. (2017) Brain mineralocorticoid receptor function in control of salt balance and stress-adaptation. Physiol Behav, 178: 13-20. [PMID:28089704]
de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MH, Hasselmann H, Kliegel D, Joëls M. (2016) Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor. J Neuroendocrinol, 28 (8). [PMID:26970338]
* Garg D, Ng SSM, Baig KM, Driggers P, Segars J. (2017) Progesterone-Mediated Non-Classical Signaling. Trends Endocrinol Metab, 28 (9): 656-668. [PMID:28651856]
Gerbal-Chaloin S, Iankova I, Maurel P, Daujat-Chavanieu M. (2013) Nuclear receptors in the cross-talk of drug metabolism and inflammation. Drug Metab Rev, 45 (1): 122-44. [PMID:23330545]
Grimm SL, Hartig SM, Edwards DP. (2016) Progesterone Receptor Signaling Mechanisms. J Mol Biol, 428 (19): 3831-49. [PMID:27380738]
Gustafsson JA. (2016) Historical overview of nuclear receptors. J Steroid Biochem Mol Biol, 157: 3-6. [PMID:25797032]
Kapoor A, Hotte SJ. (2016) Androgen receptor axis-targeted agents. Can Urol Assoc J, 10 (7-8Suppl3): S146-S148. [PMID:27895812]
Kumar R. (2016) Steroid hormone receptors and prostate cancer: role of structural dynamics in therapeutic targeting. Asian J Androl, 18 (5): 682-6. [PMID:27364545]
Li W, Li X, Zhang B, Gao C, Chen Y, Jiang Y. (2016) Current Progresses and Trends in the Development of Progesterone Receptor Modulators. Curr Med Chem, 23 (23): 2507-54. [PMID:27121188]
* Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA. (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev, 58 (4): 782-97. [PMID:17132855]
* Lucas-Herald AK, Alves-Lopes R, Montezano AC, Ahmed SF, Touyz RM. (2017) Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci, 131 (13): 1405-1418. [PMID:28645930]
Meijsing SH. (2015) Mechanisms of Glucocorticoid-Regulated Gene Transcription. Adv Exp Med Biol, 872: 59-81. [PMID:26215990]
Moss ME, Jaffe IZ. (2015) Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis. Front Endocrinol (Lausanne), 6: 153. [PMID:26441842]
Oakley RH, Cidlowski JA. (2011) Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem, 286 (5): 3177-84. [PMID:21149445]
Petta I, Dejager L, Ballegeer M, Lievens S, Tavernier J, De Bosscher K, Libert C. (2016) The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases. Microbiol Mol Biol Rev, 80 (2): 495-522. [PMID:27169854]
Thomas C, Gustafsson JÅ. (2015) Progesterone receptor-estrogen receptor crosstalk: a novel insight. Trends Endocrinol Metab, 26 (9): 453-4. [PMID:26277479]
* Wadosky KM, Koochekpour S. (2017) Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget, 8 (11): 18550-18576. [PMID:28077788]
* Weikum ER, Knuesel MT, Ortlund EA, Yamamoto KR. (2017) Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol, 18 (3): 159-174. [PMID:28053348]
References
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2. Auerbach SS, DrugMatrix® and ToxFX® Coordinator National Toxicology Program. National Toxicology Program: Dept of Health and Human Services. Accessed on 02/05/2014. Modified on 02/05/2014. DrugMatrix, https://ntp.niehs.nih.gov/drugmatrix/index.html
3. Bell MG, Gernert DL, Grese TA, Belvo MD, Borromeo PS, Kelley SA, Kennedy JH, Kolis SP, Lander PA, Richey R et al.. (2007) (S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor. J Med Chem, 50 (26): 6443-5. [PMID:18038968]
4. Bergink EW, van Meel F, Turpijn EW, van der Vies J. (1983) Binding of progestagens to receptor proteins in MCF-7 cells. J Steroid Biochem, 19 (5): 1563-70. [PMID:6645495]
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8. Edwards JP, Zhi L, Pooley CL, Tegley CM, West SJ, Wang MW, Gottardis MM, Pathirana C, Schrader WT, Jones TK. (1998) Preparation, resolution, and biological evaluation of 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinolines: potent, orally active, nonsteroidal progesterone receptor agonists. J Med Chem, 41 (15): 2779-85. [PMID:9667968]
9. Fuller PJ, Yao YZ, Jin R, He S, Martín-Fernández B, Young MJ, Smith BJ. (2019) Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist. Proc Natl Acad Sci U S A, 116 (37): 18578-18583. [PMID:31439819]
10. Gass EK, Leonhardt SA, Nordeen SK, Edwards DP. (1998) The antagonists RU486 and ZK98299 stimulate progesterone receptor binding to deoxyribonucleic acid in vitro and in vivo, but have distinct effects on receptor conformation. Endocrinology, 139 (4): 1905-19. [PMID:9528977]
11. Ge RS, Dong Q, Sottas CM, Latif SA, Morris DJ, Hardy MP. (2005) Stimulation of testosterone production in rat Leydig cells by aldosterone is mineralocorticoid receptor mediated. Mol Cell Endocrinol, 243 (1-2): 35-42. [PMID:16188378]
12. Giwercman A, Kledal T, Schwartz M, Giwercman YL, Leffers H, Zazzi H, Wedell A, Skakkebaek NE. (2000) Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene. J Clin Endocrinol Metab, 85 (6): 2253-9. [PMID:10852459]
13. Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK. (1996) Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether. J Med Chem, 39 (9): 1778-89. [PMID:8627601]
14. Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman Jr D, Farquhar R, Guo Z, Qiu Y et al.. (2005) Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem, 48 (8): 2972-84. [PMID:15828836]
15. Hellal-Levy C, Couette B, Fagart J, Souque A, Gomez-Sanchez C, Rafestin-Oblin M. (1999) Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett, 464 (1-2): 9-13. [PMID:10611474]
16. Higuchi RI, Arienti KL, López FJ, Mani NS, Mais DE, Caferro TR, Long YO, Jones TK, Edwards JP, Zhi L et al.. (2007) Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. J Med Chem, 50 (10): 2486-96. [PMID:17439112]
17. Kinoyama I, Taniguchi N, Toyoshima A, Nozawa E, Kamikubo T, Imamura M, Matsuhisa A, Samizu K, Kawanimani E, Niimi T et al.. (2006) (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist. J Med Chem, 49 (2): 716-26. [PMID:16420057]
18. Leonhardt SA, Altmann M, Edwards DP. (1998) Agonist and antagonists induce homodimerization and mixed ligand heterodimerization of human progesterone receptors in vivo by a mammalian two-hybrid assay. Mol Endocrinol, 12 (12): 1914-30. [PMID:9849965]
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20. Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA. (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev, 58 (4): 782-97. [PMID:17132855]
21. Manfredi MC, Bi Y, Nirschl AA, Sutton JC, Seethala R, Golla R, Beehler BC, Sleph PG, Grover GJ, Ostrowski J et al.. (2007) Synthesis and SAR of tetrahydropyrrolo[1,2-b][1,2,5]thiadiazol-2(3H)-one 1,1-dioxide analogues as highly potent selective androgen receptor modulators. Bioorg Med Chem Lett, 17 (16): 4487-90. [PMID:17574413]
22. Millan DS, Ballard SA, Chunn S, Dybowski JA, Fulton CK, Glossop PA, Guillabert E, Hewson CA, Jones RM, Lamb DJ et al.. (2011) Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma. Bioorg Med Chem Lett, 21 (19): 5826-30. [PMID:21880489]
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NC-IUPHAR subcommittee and family contributors
Subcommittee members:
John Cidlowski (Liaison for all NHR subcommittees)
Derek Cain
Dean P. Edwards
Peter Fuller, BMedSci MBBS PhD FRACP
Sandra L. Grimm
Sean Hartig
Carol A. Lange
Robert H. Oakley, Ph.D.
Jennifer K. Richer
Carol A. Sartorius
Marc Tetel
Morag J. Young, Ph.D. |
Other contributors:
Nancy Weigel, Ph.D. (Past contributor) |
How to cite this family page
Database page citation (select format):
Cain D, Cidlowski J, Edwards DP, Fuller P, Grimm SL, Hartig S, Lange CA, Oakley RH, Richer JK, Sartorius CA, Tetel M, Weigel N, Young MJ. 3C. 3-Ketosteroid receptors in GtoPdb v.2023.1. IUPHAR/BPS Guide to Pharmacology CITE. 2023; 2023(1). Available from: https://doi.org/10.2218/gtopdb/F98/2023.1.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Cidlowski JA, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Nuclear hormone receptors. Br J Pharmacol. 180 Suppl 2:S223-240.
[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 [10,18]. Mutations in AR underlie testicular feminization and androgen insensitivity syndromes, spinal and bulbar muscular atrophy (Kennedy's disease).