Vitamin d receptor

The (nuclear) vitamin D receptor, VDR for short, belongs to the superfamily of nuclear transcription factors(nuclear receptors) and here to subfamily 1 (thyroid hormone receptor-like). This subfamily contains receptors that can form heterodimers with RXR (retinoid receptor) and that activate or inhibit the transcription of certain target genes (depending on the gene) and thus influence the metabolism (Kato S 2000).

In humans, the gene coding for the vitamin D receptor is located on chromosome 12 gene locus q13.11. It has 11 exons which, together with the introns in between, have a length of about 75 kb. The non-coding region at the 5' end houses the 3 exons 1A, 1B, and 1C.

The specific (natural) ligands of the vitamin D receptor are the individual vitamin D derivatives. However, the 1,25(OH)2D3(calcitriol) is the vitamin D derivative with by far the highest ligand binding affinity. Thus, 1,25(OH)2D3 (calcitriol) binds 100 up to 1000 times stronger to the VDR than 25(OH)D3 or 24,25(OH)2D3.

The activated vitamin D receptor binds as a heterodimer with the retinoid X receptor alpha (RXR alpha) to responsive segments in the DNA and induces the synthesis of numerous proteins such as: TRPV6 (transient receptor potential V6; calcium channel), calbindin D9K (responsible for calcium transport in enterocytes) and PMCA1b (plasma membrane Ca2+-ATPase, a calcium ATPase).

The following receptor families belong to subfamily 1 of nuclear receptors:

• Group A: Thyroid hormone receptor (thyroid hormones)
• Group B: retinoic acid receptor (vitamin A and related compounds)
• Group C: Peroxisome proliferator-activated receptors (fatty acids, prostaglandins)
• Group D: Rev-ErbA (heme)
• Group F: RAR-related orphan receptors (cholesterol, ATRA)
• Group H: Liver X receptor-like (oxysterol)
• Group I: Vitamin D receptor-like

The vitamin D receptor has the systematic name NR1I1 (NR=nuclear receptor, 1 subfamily1, I for group I, 1 for member 1; see below nuclear receptors).

Regulation of the intracellular concentration of VDR:

Homologous regulation of VDR: The intracellular concentration of VDR in a target cell for calcitriol is mainly upregulated by 1,25(OH)2D3 (homologous regulation).

Heterologous (non-genomic) regulation of VDR: Other hormones and growth factors that do not bind to VDR are also able to upregulate the intracellular concentration of the vitamin d receptor (heterologous regulation). This mechanism has significant species-, tissue- and cell-specific variations.

Receptor structure:

VDR consists of 427 amino acids and is divided into two major functional units: an N-terminal zinc finger DNA binding domain (DBD) and the C-terminal ligand binding domain (LBD). The DBD consists of two zinc finger DNA binding motifs responsible for high-affinity binding to specific DNA sequences in promoter regions of vitamin D-responsive elements (VDREs) (Aranda A et al. 1998; Issa L et al. 1998). The proximal (N-terminal) zinc finger binding motif gives the receptor specificity for DNA binding to VDREs, whereas the second zinc finger binding motif and the adjacent region, the so-called T-box, represent an interface for the dimerisation of VDR and retinoid X receptor (RXR) (Prufer K et al. 2000).

The ligand binding domain (LBD) consists of 12 α helixes and is located in the COOH-terminal section of the VDR molecule. The LBD is responsible for the high-affinity binding of calcitriol and mediates homo- and heterodimerization. At the C-terminal end is the activation domain AF-2, which enables the recruitment of VDR-interacting proteins, including components of the transcriptional start complex, RNA polymerase II, and nuclear transcriptional co-activators (Haussler MR et al.2008).

Cofactor binding is essential for the transcriptional activity of VDRs. The positive VDREs promote the binding of coactivator complexes such as the steroid receptor coactivator (SRC-1) or the nuclear coactivator (NcoA-62) to VDR-RXR heterodimers (Baudino TA et al. 1998; Pike JW et al. 2017).

Biological effects of the VDR receptor:

VDR-receptors have been shown to be present in numerous cells of the human organism. Their functions are cell-specific and complexly coregulated and include cell mechanisms such as proliferation, apoptosis, migration, invasion, and cell differentiation. Of particular biological relevance are the biological effects of the receptor for calcium and phosphate homeostasis. The discovery of vitamin D receptors in tissues not involved in calcium and phosphate homeostasis eventually led to the discovery of numerous other functions. VDR is expressed in the cell nuclei of gonads, thymus, pituitary, pancreas, stomach, teeth, placenta, heart muscle and skin, in cells of the immune system such as monocytes, macrophages, dendritic cells, natural killer cells and activated T- and B-lymphocytes. The receptor density in immune cells explains the immunomodulatory effects on innate and acquired immunity (Veldman C M et al 2000; Geldmeyer-Hilt K et al 2011).

Thus, VDR activation induces the formation of antimicrobial proteins such as cathelicidin (LL-37) or β-defensin (DEFB4) in monocytes and macrophages. The induction of beta-defensin is NF-κB and IL-1beta dependent (Doss M et al. 2010). Calcitriol inhibits the expression of pro-inflammatory cytokines like TNF-α, IL-6 and IL-12 in monocytes (Zhang Y et al. (2012). In addition to the inhibitory effects, activation of VDRs results in increased IL-10 production, CCR10 expression and CD38 expression in B- and T-lymphocytes (Shirakawa AK et al. 2008; von Essen MR et al. 2010)

Beta cells in the pancreas also express the vitamin D receptor. Several studies demonstrated a significant association between low serum 25(OH) vitamin D3 status and the occurrence of T1 diabetes mellitus (Svoren BM et al. 2009).

Furthermore, VDR is expressed in different tumor cell lines. This observation, in conjunction with the known antiproliferative effect of 1,25(OH)2D3, has led to the inclusion of vitamin D or vitamin D analogues in the development of new approaches in tumour therapy. In the meantime, vitamin D analogues have proven to be effective proliferation inhibitors in various in vitro systems.

In the epidermis, receptors for 1,25(OH)2D3 have been detected in the stratum basale, stratum spinosum and granulosum as well as in the root sheath of the hair follicle and in skin fibroblasts. Here, too, the effect primarily consists in an inhibition of proliferation or stimulation of cell differentiation.

Mutations and polymorphisms:

• Numerous genetic polymorphisms and mutations of the VDR gene with great differences between ethnic groups have been proven. These differences are associated with different bone density, different propensity to hyperparathyroidism, resistance to vitamin D therapy, susceptibility to infections and propensity to certain autoimmune and tumor diseases. Furthermore, VDR polymorphisms are associated with an increased incidence of nephrolithisis. (Gonzales et al. 2019).
• A mutation in the vitamin D receptor leads to vitamin D-dependent rickets type 2.
• Vitamin D receptor mutations are associated with the clinical activity of bronchial asthma. (Santos HLBS et al. 2018).

1. Aranda A et al (1998) Nuclear hormone receptors and gene expression. Physiol Rev 2001. 81: 1269-1304.
2. Baudino T A et al (1998) Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription. J Biol Chem 273: 16434-16441.
3. González-Castro TB et al (2019) Association of vitamin D receptor polymorphisms and nephrolithiasis: A meta-analysis. Genes 711:143936.
4. Black PN et al (2005) Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 128: 3792-3798.
5. Doss M et al (2010) Human defensins and LL37 in mucosal immunity. J Leukoc Biol 87: 79-92.
6. Fukuoka M et al (1998) RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol). Br J Dermatol 138: 63-70.
7. Geldmeyer-Hilt K et all. (2011) 1,25-dihydroxyvitamin D3 impairs NF-kappaB activation in human naïve B cells. Biochem Biophys Res Commun 407: 699-702.
8. Haussler MR et al(2008) Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev 66: 98-112.
9. Hollams EM et al (2011) Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study.
10. Issa L et al (1998) J. A., Molecular mechanism of vitamin D receptor action. Inflamm Res 1998. 47: 451-475.
11. Kato S (2000) The function of vitamin D receptor in vitamin D action. J Biochem 127: 717-722.
12. Mayak P et al (2011) Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 127: 1294-1296.
13. Pike JW et al (2017) The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest 127:1146-1154.
14. Prufer K et al (2000) Dimerization with retinoid X receptors promotes nuclear localization and subnuclear targeting of vitamin D receptors. J Biol Chem 2000. 275: 41114-41123.
15. Rigby WF et al (1984) Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 74: 1451-1455.
16. Rosen C J et al (2012) The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 33: 456-492.
17. Santos HLBS et al (2018) Vitamin d receptor gene mutations and vitamin D serum levels in asthmatic children. Rev Paul Pediatr 36: 269-274.
18. Searing DA et al (2010) Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol125: 995-1000.
19. Shirakawa AK et al (2008) 1,25-dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B cells. J Immunol180: 2786-2795.
20. Sutherland E R et al (2010) Vitamin D levels, lung function, and steroid response in adult asthma. At J Respir Crit Care Med181: 699-704.
21. Svoren BM et al (2009) Significant Vitamin D Deficiency in Youth with Type 1 Diabetes Mellitus. Journal of Pediatrics 154: 132-134.
22. Veldman C M et al (2000) Expression of 1,25dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 374: 334-338.
23. von Essen MR et al (2010) Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol11: 344-349.
24. Zhang Y et al (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1 J Immunol 188: 2127-2135.