Retinoic acid, retinoid X and retinoic acid-related orphan
Jump toCytoplasmic cellular retinoid binding proteins I (ENSG00000114115), II (ENSG00000114113), III (ENSG00000139194) and IV (ENSG00000162444) are thought to control the levels of intracellular retinoids available for interaction with their receptors [14]. [3H]ATRA and [3H]9-cis-retinoic acid have been used to label RARs and RXRs respectively.
1B. Retinoic acid receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Retinoic acid receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [6]) are nuclear hormone receptors of the NR1B family activated by the vitamin A-derived agonists all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, and the RAR-selective synthetic agonists TTNPB and adapalene.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
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Ro 41-5253 has been suggested to be a PPARγ agonist [20]. LE135 is an antagonist with selectivity for RARα and RARβ compared with RARγ [14].
2B. Retinoid X receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Retinoid X receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [7]) are NR2B family members activated by 9-cis-retinoic acid and the RXR-selective agonists bexarotene and LG100268, sometimes referred to as rexinoids. These receptors form RXR–RAR heterodimers and RXR–RXR homodimers [4,16].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors
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1F. RAR-related orphan receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Retinoic acid-related orphan receptors (ROR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [2]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as cholesterol [10-11].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors
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all-trans-retinoic acid shows selectivity for RORβ within the ROR family [21]. RORα has been suggested to be a nuclear receptor responding to melatonin [23].
Benoit, G; Cooney, A; Giguere, V; Ingraham, H; Lazar, M; Muscat, G; Perlmann, T; Renaud, JP; Schwabe, J; Sladek, F; Tsai, MJ; Laudet, V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev., 58 (4): 798-836. [PMID:17132856]
Bour, G; Lalevée, S; Rochette-Egly, C. (2007) Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors. Trends Cell Biol., 17 (6): 302-9. [PMID:17467991]
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Germain, P; Chambon, P; Eichele, G; Evans, RM; Lazar, MA; Leid, M; De Lera, AR; Lotan, R; Mangelsdorf, DJ; Gronemeyer, H. (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev., 58 (4): 760-72. [PMID:17132853]
Lefebvre, P; Benomar, Y; Staels, B. (2010) Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol. Metab., 21 (11): 676-83. [PMID:20674387]
Maden, M. (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci., 8 (10): 755-65. [PMID:17882253]
Mark, M; Ghyselinck, NB; Chambon, P. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu. Rev. Pharmacol. Toxicol., 46: 451-80. [PMID:16402912]
Pérez, E; Bourguet, W; Gronemeyer, H; de Lera, AR. (2011) Modulation of RXR function through ligand design. Biochim Biophys Acta, [Epub ahead of print]. [PMID:21515403]
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7. Germain, P; Chambon, P; Eichele, G; Evans, RM; Lazar, MA; Leid, M; De Lera, AR; Lotan, R; Mangelsdorf, DJ; Gronemeyer, H. (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev., 58 (4): 760-72. [PMID:17132853]
8. Germain, P; Iyer, J; Zechel, C; Gronemeyer, H. (2002) Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature, 415 (6868): 187-92. [PMID:11805839]
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11. Kallen, JA; Schlaeppi, JM; Bitsch, F; Geisse, S; Geiser, M; Delhon, I; Fournier, B. (2002) X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure, 10 (12): 1697-707. [PMID:12467577]
12. Keidel, S; LeMotte, P; Apfel, C. (1994) Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping. Mol. Cell. Biol., 14 (1): 287-98. [PMID:8264595]
13. Le, Q; Dawson, MI; Soprano, DR; Soprano, KJ. (2000) Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids. Oncogene, 19 (11): 1457-65. [PMID:10723137]
14. Li, E. (1999) Structure and function of cytoplasmic retinoid binding proteins. Mol. Cell. Biochem., 192 (1-2): 105-8. [PMID:10331664]
15. Lund, BW; Piu, F; Gauthier, NK; Eeg, A; Currier, E; Sherbukhin, V; Brann, MR; Hacksell, U; Olsson, R. (2005) Discovery of a potent, orally available, and isoform-selective retinoic acid beta2 receptor agonist. J. Med. Chem., 48 (24): 7517-9. [PMID:16302793]
16. Mangelsdorf, DJ; Evans, RM. (1995) The RXR heterodimers and orphan receptors. Cell, 83 (6): 841-50. [PMID:8521508]
17. Martin, B; Bernardon, JM; Cavey, MT; Bernard, B; Carlavan, I; Charpentier, B; Pilgrim, WR; Shroot, B; Reichert, U. (1992) Selective synthetic ligands for human nuclear retinoic acid receptors. Skin Pharmacol., 5 (1): 57-65. [PMID:1315557]
18. Nahoum, V; Pérez, E; Germain, P; Rodríguez-Barrios, F; Manzo, F; Kammerer, S; Lemaire, G; Hirsch, O; Royer, CA; Gronemeyer, H; et al.. (2007) Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function. Proc. Natl. Acad. Sci. U.S.A., 104 (44): 17323-8. [PMID:17947383]
19. Paravicini, G; Steinmayr, M; André, E; Becker-André, M. (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem. Biophys. Res. Commun., 227 (1): 82-7. [PMID:8858107]
20. Schupp, M; Curtin, JC; Kim, RJ; Billin, AN; Lazar, MA. (2007) A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Mol. Pharmacol., 71 (5): 1251-7. [PMID:17290005]
21. Stehlin-Gaon, C; Willmann, D; Zeyer, D; Sanglier, S; Van Dorsselaer, A; Renaud, JP; Moras, D; Schüle, R. (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol., 10 (10): 820-5. [PMID:12958591]
22. Thacher, SM; Vasudevan, J; Chandraratna, RA. (2000) Therapeutic applications for ligands of retinoid receptors. Curr. Pharm. Des., 6 (1): 25-58. [PMID:10637371]
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