TABLE 8

VDR

Receptor Nomenclature NR1I1
Receptor code
Other names
Molecular information Hs: 427aa, P11473, chr. 12q13.111
Rn: 423aa, P13053, chr. 7q362
Mm: 422aa, P48281, chr. 15 F13
DNA binding
   Structure Heterodimer, RXR partner
   HRE core sequence DR-3
Partners
Agonists KH1060 (6.5 × 10–11 M), EB1089 (2.7 × 10–10 M), 1α ,25-(OH)2D3 (6.2 × 10–10 M),* 25-OHD3 (1.2 × 10–9 M), (23S,25R)-1α ,25-(OH)2D3-26,23-lactone (3.1 × 10–8 M) [Kd]4–7; 2MD (1 × 10–10 M) [ED50]8; MC903 (131), TV-02 (66), F6-1α ,25(OH)2D3 (45), Gemini [1R,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D3] (38), OCT (10) [RCI]5,9–13; Ro-26-9228 (6.2 × 10–9 M) [IC50]14; LG190178 (1.5 × 10–7 M), 3-keto-LCA (2.9 × 10–7 M), LCA (8 × 10–6 M) [Ki]15,16; ED-71, 1α -OHD2, 19-nor-1α ,25(OH)2D217,18
Antagonists TEI-9647 (10), ZK159222 (7) [RCI]19,20
Coactivator
Corepressor
Biologically important isoforms
Tissue distribution
Functional assay
Main target genes
Mutant phenotype Knockout mice exhibit typical rachitic features such as hypocalcemia, hyperparathyroidism, impaired bone formation, uterine hypoplasia, growth retardation, and alopecia after weaning; they also have an impaired insulin secretory capacity {Mm} [knockout21–23]
Human disease Vitamin D-dependent rickets type II24,25

  • aa, amino acids; chr., chromosome; HRE, hormone response element; OCT, 22-oxa-1α ,25-dihydroxyvitamin-D3; LCA, lithocholic acid; RCI, relative competitive index

  • ↵* Radioligand

  • ↵1. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, and O'Malley BW (1988) Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 85: 3294-3298

  • ↵2. Burmester JK, Maeda N, and DeLuca HF (1988) Isolation and expression of rat 1,25-dihydroxyvitamin D3 receptor cDNA. Proc Natl Acad Sci USA 85: 1005-1009

  • ↵3. Kamei Y, Kawada T, Fukuwatari T, Ono T, Kato S, and Sugimoto E (1995) Cloning and sequencing of the gene encoding the mouse vitamin D receptor. Gene 152: 281-282

  • ↵4. Wiberg K, Ljunghall S, Binderup L, and Ljunggren O (1995) Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro. Bone 17: 391-395

  • ↵5. Bishop JE, Collins ED, Okamura WH, and Norman AW (1994) Profile of ligand specificity of the vitamin D binding protein for 1α ,25-dihydroxyvitamin D3, and its analogs. J Bone Miner Res 9: 1277-1288

  • ↵6. Erben RG, Soegiarto DW, Weber K, Zeitz U, Lieberherr M, Gniadecki R, Möller G, Adamski J, and Balling R (2002) Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D. Mol Endocrinol 16: 1524-1537

  • ↵7. Shiina Y, Abe E, Miyaura C, Tanaka H, Yamada S, Ohmori M, Nakayama K, Takayama H, Matsunaga I, Nishii Y, et al. (1983) Biological activity of 24,24-difluoro-1α ,25-dihydroxyvitamin D3 and 1α ,25-dihydroxyvitamin D3-26,23-lactone in inducing differentiation of human myeloid leukemia cells. Arch Biochem Biophys 220: 90-94

  • ↵8. Sicinski RR, Prahl JM, Smith CM, and DeLuca HF (1998) New 1α ,25-dihydroxy-19-norvitamin D3 compounds of high biological activity: synthesis and biological evaluation of 2-hydroxymethyl, 2-methyl, and 2-methylene analogues. J Med Chem 41: 4662-4674

  • ↵9. Ikeda M, Takahashi K, Dan A, Koyama K, Kubota K, Tanaka T, and Hayashi M Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3. Bioorg Med Chem 8: 2157-2166

  • ↵10. Weyts FA, Dhawan P, Zhang X, Bishop JE, Uskokovic MR, Ji Y, Studzinski GP, Norman AW, and Christakos S (2004) Novel Gemini analogs of 1α ,25-dihydroxyvitamin D3 with enhanced transcriptional activity. Biochem Pharmacol 67: 1327-1336

  • ↵11. Abe J, Takita Y, Nakano T, Miyaura C, Suda T, and Nishii Y (1989) A synthetic analogue of vitamin D, 22-oxa-1α ,25-dihydroxyvitamin D3, is a potent modulator of in vivo immunoregulating activity without inducing hypercalcemia in mice. Endocrinology 124: 2645-2647

  • ↵12. Sato K, Nishii Y, Woodiel FN, and Raisz LG (1993) Effects of two new vitamin D3 derivatives, 22-oxa-1α ,25-dihydroxyvitamin-D3 (OCT) and 2β-(3-hydroxypropoxy)-1α ,25-dihydroxyvitamin-D3 (ED-71), on bone metabolism in organ culture. Bone 14: 47-51

  • ↵13. Okano T, Tsugawa N, Masuda S, Takeuchi A, Kobayashi T, and Nishii Y (1989) Protein-binding properties of 22-oxa-1α ,25-dihydroxyvitamin D, a synthetic analogue of 1α ,25-dihydroxyvitamin D. J Nutr Sci Vitaminol (Tokyo) 35: 529-533

  • ↵14. Peleg S, Uskokovic M, Ahene A, Vickery B, and Avnur Z (2002) Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats. Endocrinology 143: 1625-1636

  • ↵15. Boehm MF, Fitzgerald P, Zou A, Elgort MG, Bischoff ED, Mere L, Mais DE, Bissonnette RP, Heyman RA, Nadzan AM, et al. (2002) Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3. Chem Biol 6: 265-275

  • ↵16. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, and Mangelsdorf DJ (2002) Vitamin D receptor as an intestinal bile acid sensor. Science (Wash DC) 296: 1313-1316

  • ↵17. Miyamoto K, Murayama E, Ochi K, Watanabe H, and Kubodera N (1993) Synthetic studies of vitamin D analogues. XIV. Synthesis and calcium regulating activity of vitamin D3 analogues bearing a hydroxyalkoxy group at the 2β -position. Chem Pharm Bull (Tokyo) 41: 1111-1113

  • ↵18. Okano T, Tsugawa N, Masuda S, Takeuchi A, Kobayashi T, Takita Y, and Nishii Y (1989) Regulatory activities of 2 β -(3-hydroxypropoxy)-1α ,25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism. Biochem Biophys Res Commun 163: 1444-1449

  • ↵19. Miura D, Manabe K, Ozono K, Saito M, Gao Q, Norman AW, and Ishizuka S (1999) Antagonistic action of novel 1α ,25-dihydroxyvitamin D3-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1α ,25-dihydroxyvitamin D3. J Biol Chem 274: 16392-16399

  • ↵20. Fujishima T, Kojima Y, Azumaya I, Kittaka A, and Takayama H (2003) Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2α -methyl introduction on antagonistic activity. Bioorg Med Chem 11: 3621-3631

  • ↵21. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, et al. (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16: 391-396

  • ↵22. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, and Demay MB (1997) Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94: 9831-9835

  • ↵23. Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, and Erben RG (2003) Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 17: 509-511

  • ↵24. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, and O'Malley BW (1988) Point mutations in the human vitamin D receptor associated with hypocalcemic rickets. Science (Wash DC) 242: 1702-1705

  • ↵25. Malloy PJ, Pike JW, and Feldman D (1999) The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 20: 156-188