1,25-dihydroxyvitamin receptor

Dihydroxyvitamin (283) is the endogenous ligand for the vitamin receptor (VDR). It modulates genomic function in a tissue and developmentaHy specific manner and affects ceU proliferation, differentiation, and mineral homeostasis (74). Vitamin mobilizes calcium from the bone to maintain plasma Ca " levels. Vitamin and VDR are present in the CNS where they may play a role in regulating Ca " homeostasis. Vitamin D has potent immunomodulatory activity in vivo. 

LiEL Y, SHANY s, SMIRNOFF p and SCHWARTZ B (1999) Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinol 140, 280-85. 

Other vitamin D analogs available in the United States include paricalcitol (19-nor-l,25-dihydroxyvitamin D2, Zemplar by Abbott Laboratories, North Chicago, IL) and doxercalciferol (1 -a-hydroxyvitamin D2, Hectoral by Bone Care International, Middleton, WI). Alfacalcidiol (1-a-hydroxyvitamin D3) is only available outside the United States. Paricalcitol has less effect on vitamin D receptors in the intestines, decreasing the effects on... 

Vitamin D receptor (VDR) 1,25 dihydroxyvitamin-D3 Vitamin D response in patients affected with rickets (96) Susceptibility to osteoporosis (97) and autosomal dominant rickets disease (96)... 

Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses PTH synthesis and secretion and upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. The dose depends on the stage of CKD and type of dialysis (Table 76-4). 

Milde, P., Merke, J., Ritz, E., Haussler, M., and Rauterberg, E. (1989) Immuno-histochemical detection of 1,25-dihydroxyvitamin D3 receptors and estrogen receptors by monoclonal antibodies comparison of four immunoperoxidase methods. J. Histochem. Cytochem. 37,1609-1617. 

The hormonally active la,25-dihydroxyvitamin D is distributed through the bloodstream to all parts of the body. It is taken up rapidly by nuclei of cells of the intestinal lining where it binds to a 55-kDa receptor protein. In response, the cells synthesize calbindins (Chapter 6), Ca2+-binding proteins which facilitate the uptake of calcium ions by the body.1 v (see also Fig. 6-7). 

Other target organs for the action of 1,25-dihydroxyvitamin D include the kidneys, bone, muscle,vwand skin. The hormone promotes reabsorption of both Ca2+ and inorganic phosphate by kidney tubules. In bone it binds to a specific receptor where it promotes the mobilization of calcium ions. This effect may result in part from stimulation of calcium-activated ATPase of the outer membrane of bone cells. Dissolution of bone also requires the presence of parathyroid hormone (PTH), the 83-residue hormone secreted by the parathyroid gland. In women past the age of menopause and in elderly men the production of 1,25-dihydroxyvitamin D decreases.w This may be a cause of the serious bone loss (osteoporosis) frequently observed. Treatment with 1,25-dihydroxyvitamin D3 or a synthetic analog seems to be helpful to such individuals. /Xy See also Chapter 30, Section A,5. 

Canaff, L and Hendy, GN, 2002, Human calcium-sensing receptor gene. Vitamin D response elements in promoters PI and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D, J Biol Chem 277 30337-30350... 

Recently, Palmer et al., working with human colon cancer cell lines, reported dramatic up-regulation of kallikreins 6 and 10 by la, 25-dihydroxyvitamin D3 [158]. This finding raises the possibility that some kallikreins could be regulated by a multitude of nuclear receptors. 

Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. EndocrRev 1999 20(2) ... 

Meyer MB, Watanuki M, Kim S, et al. The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol Endocrinol 2006 20(6) 1447-1461. 

Figure 30-4. Hormone action of 1,25-dihydroxyvitamin D. VDR, vitamin D receptor RXR, retinoic acid receptor VDRE, vitamin D response element.

Tissues contain two types of receptors for 1,25-dihydroxyvitamin D a classic steroid hormone nuclear receptor and a putative membrane receptor. 1,25-Dihydroxyvitamin D interacts with the nuclear receptor to form a receptor-ligand complex (Fig. 30-4). This complex then interacts with other nuclear proteins, such as the retinoic acid receptor (RXR) to form a functional transcription complex. The main effect of this transcription complex is to alter the amount of mRNAs coding for selected proteins such as cal-bindin, the calcium transport protein in the intestine, and the vitamin D receptor. In concert with PTH, 1,25-dihydroxyvitamin D acts to mobilize calcium from bone.As a consequence, serum calcium and phosphate homeostasis is maintained by a combination of 1,25-dihydroxyvitamin D stimulation of intestinal absorption and bone turnover. 

H19. Hsieh, T., and Wu, J. M., Induction of apoptosis and altered nuclear/cytoplasmic distribution of the androgen receptor and prostate-specific antigen by 1 alpha, 25 dihydroxyvitamin D3 in androgen responsive LNCaP cells. Biochem. Biophys. Res. Commun. 235, 539-544 (1997). 

I, 25-dihydroxyvitamin D j (1,25-dihydroxycholecalciferol). Activation of the receptor leads to expression of particular proteins, notably an intestinal Ca2+ binding protein, and regulation of intestinal Ca2+ uptake and Ca2+ sequestration in kidney and bone. Vitamin D2 (ergocalciferol) is industrially obtained from irradiation of yeast-derived ergosterol and is hydroxylated to form an active vitamin D receptor agonist. Vitamin D deficiency causes rickets. 

Griffin JE and Zerwekh JE (1983) Impaired stimulation of 25-hydroxyvitamin D-24-hydroxylase in fihrohlasts from a patient with vitamin D-dependent rickets, type II. A form of receptor-positive resistance to 1,25-dihydroxyvitamin Journal of Clinical Investigation 72,1190-9. 

Norman AW, Bishop JE, Collins ED, Seo EG, SatcheU DP, Dormanen MG, Zanello SB, Farach-Garson MC, Bouillon R, and Okamura WH (1996) Differing shapes of lalpha, 25-dihydroxyvitamin D3 function as ligands for the D-binding protein, nuclear receptor and membrane receptor a status report. Journal of Steroid Biochemistry and Molecular Biology 56,13-22. 

Yamamoto K, Inaba Y, Yoshimoto N, Choi M, DeLuca HE, Yamada S. 22-alkyl-20-epi-lalpha,25-dihydroxyvitamin D3 compounds of superagonistic activity syntheses, biological activities and interaction with the receptor. J. Med. Chem. 2007 50 932-939. 

Liu, Y-Y-, Collins, E. D., Norman, A. W., and Peleg, S. (1997). Differential interaction of Iffi S-dihydroxyvitamin Dj analogues and their 20-epi homologues with the vitamin D receptor. ). PieJ. Chem. 271, 3336-3345. 

Darwish, H., and DeLuca, H. F. (1996). Analysis of binding of the 1,25-dihydroxyvitamin Ds receptor to positive and negative vitamin D response elements. Arch. Biochem. Biophys. 334,223-234. 

Jurutka, P. W., Hsieh, J.-C., Remus, L. S., Whitfield, G. K., Thompson, R D., Haussler, C., Blanco, J. C., Ozato, K., and Haussler, M. R. (1997). Mutations in the 1,25-dihydroxyvitamin D3 receptor identifying C-terminal amino acids requited for transcriptional activation that are functionally dissociated from hormone binding, heterodimeric DNA binding, and interaction with basal transcription factor IIB, in vitro. J. Biol. Chem. 272, 14592-14599. 

Zou, A., Elgort, M. G., and Allegretto, E. A. (1997). Retinoid X receptor (RXR) ligands activate the human 25-hydroxyvitamin D3 24 hydroxylase promoter via RXR heterodimer binding to two vitamin D-responsive elements and elicit additive effects with 1,25-dihydroxyvitamin D3. /. Biol Chem. 272,19027-19034. 

Figure 49-19 Flow diagram outlining determination of 1,25-dihydroxyvitamin D using a single-column extraction and purification method and a nonequilibrium radioreceptor assay With vitamin D receptor from calf thymus.

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