Nuclear Vitamin D Receptors

Zanello, L. P. and Norman, A. W. Rapid modulation of osteoblast ion channel responses by loc25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. Proc. Natl Acad. Sci. USA 101 1589-1594,2004. 

Rochel, N., Tocchini-Valentini, G., Egea, P.F., fuNTUNEN, K., Garnier, J.-M., ViHKO, P., Moras, D. Functional and stmctural characterization of the insertion region in the ligand binding domain of the vitamin D nuclear receptor. Eur. J. Biochem. 2001, 268, 971-979. 

In osteoblasts, keratinocytes, and colonocytes, andpossibly other cells, calcitriol acts via cell surface receptors linked to phospholipase C, resulting in release of diacylglycerol and inositol trisphosphate (Section 14.4.1), followed by opening of intracellular calcium channels and activation of protein kinase C and mitogen-activated protein (MAP) kinases. The effect of this is inhibition of cell proliferation and induction of differentiation. A variety of analogs of calcitriol that do not bind to the nuclear receptor do bind to, and activate, the cell surface receptor, including l,25-dihydroxy-7-dehydrocholesterol and 1,25-dihydroxylumisterol. The rapid nongenomic responses to vitamin D can be demonstrated in knockout mice that lack the vitamin D nuclear receptor (Farach-Carson and Ridall, 1998 Nemere and Farach-Carson, 1998). 

Gascon-Barre, M., Demers, C., Mirshahi, A., Neron, S., Zalzal, S., and Nanci, A. (2003) The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 37, 1034-1042. 

Vitamin D Retinoid 1,25-Dihydroxycholecalciferol Retinoic acid From cholesterol From vitamin A Nuclear receptors transcriptional regulation... 

Retinoic acid modulates gene expression and tissue differentiation, acting by way of nuclear receptors. Historically, there was confusion between the effects of deficiency of vitamins A and D by the 1950s, it was believed that the confusion had been resolved. Elucidation of the nuclear actions of the two vitamins has shown that, in many systems, the two act in concert, forming retinoid-vitamin D heterodimeric receptors hypervitaminosis A can antagonize the actions of vitamin D. 

Figure 10.12 Response elements for heterodimers of the nuclear receptor for ds-retinoic acid (RXR) with the receptors for vitamin D (VDR), thyroid hormone (TR) and trans-retinoic acid (RAR). The half-sites of these response elements have identical nucleotide sequences and are organized as direct repeats. They differ in the number of base pairs in the spacer region between the half-sites. This difference forms the basis for the ability of the heterodimers to discriminate between the different response elements.

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Vitamin D is not strictly a vitamin since it can be synthesized in the skin, and under most conditions that is its major source. Only when sunlight is inadequate is a dietary source required. The main function of vitamin D is in the regulation of calcium absorption and homeostasis most of its actions are mediated by way of nuclear receptors that regulate gene expression. Deficiency—leading to rickets in children and osteomalacia in adults—continues to be a problem in northern latitudes, where sunlight exposure is poor. 

Krasowski, M.D., Yasuda, K., Hagey, L.R. and Schuetz, E.G. (2005) Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors). Nuclear Receptor, 3, 1—20. 

The superfamily of nuclear receptors includes about 150 proteins in the human genome. These are the targets of all principal classes of steroids as well as those of retinoids, vitamin D, and thyroid hormones. 

Mammals have several classes of hormones, distinguishable by their chemical structures and their modes of action (Table 23-1). Peptide, amine, and eicosanoid hormones act from outside the target cell via surface receptors. Steroid, vitamin D, retinoid, and thyroid hormones enter the cell and act through nuclear receptors. Nitric oxide also enters the cell, but activates a cytosolic enzyme, guanylyl cyclase (see Fig. 12-10). 

Vitamin D is obtained in the diet or by photolysis of 7-dehydrocholesterol in skin exposed to sunlight. Calcitriol works in concert with parathyroid hormone in Ca2+ homeostasis, regulating [Ca2+] in the blood and the balance between Ca2+ deposition and Ca2+ mobilization from bone. Acting through nuclear receptors, calcitriol activates the synthesis of an intestinal Ca2+-binding protein essential for uptake of dietary Ca2+. Inadequate dietary vitamin D or defects in the biosynthesis of calcitriol result in serious diseases such as rickets, in which bones are weak and malformed (see Fig. 10-20b). 

Steroid, vitamin D, retinoid, and thyroid hormones enter target cells and alter gene expression by interacting with specific nuclear receptors. 

Carlberg C. Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res. 2003 164 29-42. 

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