Vitamin D Receptor as a Drug Discovery Target

Pinette, Karen V.; Yee, Ying K.; Amegadzie, Bernard Y.; Nagpal, Sunil

doi:10.2174/1389557033488204

Cited by 77 publications

(56 citation statements)

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“…The carboxy terminus of VDR contains a multifunctional domain harboring the LBD, the RXR heterodimerization motif, and a ligand-dependent transactivation function (AF-2). When ligand binds to VDR, a conformational change ensues, resulting in the enhancement of RXR/VDR heterodimer formation (Cheskis and Freedman, 1994;Prufer et al, 2000;Pinette et al, 2003;Sutton and MacDonald, 2003). There is only one VDR isoform encoded by a single gene in both humans and other organisms.…”

Section: A Vitamin D Receptor Structurementioning

confidence: 99%

“…VDR functions as a heterodimer with another NR, the RXR. RXR, a nuclear receptor for 9-cis-retinoic acid, is an obligate partner of VDR in mediating 1,25-(OH) 2 D 3 action (Yu et al, 1991;Kliewer et al, 1992;Pinette et al, 2003;Sutton and MacDonald, 2003). In the absence of ligand, the majority of VDR is present in the cytoplasm (Barsony et al, 1990).…”

Section: B Vitamin D Receptor Functionmentioning

confidence: 99%

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Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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Section: A Vitamin D Receptor Structurementioning

confidence: 99%

Section: B Vitamin D Receptor Functionmentioning

confidence: 99%

Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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“…The hormonally active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 (VD3), is associated with calcium and phosphorus homeostasis, and maintains bone content through effects on the intestine, bone, kidney, and parathyroid gland (13). In addition to these traditional calcemic activities, VD3 is involved in cell proliferation, differentiation, and immunomodulation (11).…”

mentioning

confidence: 99%

“…In addition to these traditional calcemic activities, VD3 is involved in cell proliferation, differentiation, and immunomodulation (11). Many of the biological actions of VD3 are mediated by the nuclear vitamin D receptor (VDR), a ligand-dependent transcription factor belonging to the superfamily of steroid/thyroid hormone receptors (13). Moreover, VD3 modulates the intracellular Ca 2+ concentration ([Ca 2+ ] i ) in some cell types (14,16,19,20 …”

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confidence: 99%

Effect of 1,25-dihydroxyvitamin D3 on spontaneous calcium responses in rat dental epithelial SF2 cells revealed by long-term imaging

et al. 2016

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Genetically encoded calcium indicators (GECIs) are suitable for long-term imaging studies. In this study, we employed a highly sensitive GECI, G-GECO, and achieved efficient gene delivery with an adenoviral vector. The adenoviral vector allowed us to express G-GECO in more than 80% of cells. More than 80% of G-GECO-expressing cells showed an ATP-induced increase in fluorescence intensity due to Ca 2+ release from intracellular stores and subsequent Ca 2+ entry. The fluorescence intensity of these cells was increased more than 2-fold by stimulation with 10 μM ATP. We applied long-term imaging (for ~10 h) to monitor Ca 2+ responses in SF2, a rat dental epithelial cell line, in culture conditions. SF2 cells showed intermittent rises in the intracellular Ca 2+ concentration in the presence of 100 nM 1,25-dihydroxyvitamin D 3 . Many of these Ca 2+ responses began at a specific location in the cytoplasm and spread throughout the entire cytoplasm. The combination of efficient gene delivery with an adenoviral vector and long-term imaging with a highly sensitive GECI enabled detection of intermittent Ca 2+ responses that occur only 3-10 times/h/ 100 cells. This method could be useful to study the effects of Ca 2+ responses for regulating longterm processes, such as gene expression, cell migration, and cell division, in many cell types.The hormonally active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 (VD3), is associated with calcium and phosphorus homeostasis, and maintains bone content through effects on the intestine, bone, kidney, and parathyroid gland (13). In addition to these traditional calcemic activities, VD3 is involved in cell proliferation, differentiation, and immunomodulation (11). Many of the biological actions of VD3 are mediated by the nuclear vitamin D receptor (VDR), a ligand-dependent transcription factor belonging to the superfamily of steroid/thyroid hormone receptors (13). Moreover, VD3 modulates the intracellular Ca 2+ concentration ([Ca 2+

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“…1,25(OH) 2 D3 binds to the Vitamin D Receptor (VDR) which ultimately lead to its various biological functions (Figure 1). Apart from their classical action of regulating bone health and calcium homeostasis, there are accumulating evidence in the literature suggesting that vitamin D3 also have non-classical actions including strong inhibition of cell proliferation, promotion of cell differentiation, and suppression of inflammation responses [5][6][7][8]. However, the use of 1,25(OH) 2 D3 at its effective dose is often limited by its severe hypercalcemic side effect in which calcium concentrations in serum reaches dangerously high levels (>10.5 mg/dL) [9].…”

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confidence: 99%

Selective Vitamin D Receptor Modulators (SVIMS) as Potential Adjuvant Therapeutic Agents

2013

Mod Chem Appl

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Vitamin D3 (cholecalciferol, D3) is one of the most important forms of vitamin D in human health [1][2][3][4]. There are two sources for human beings to obtain vitamin D3. The first source is the conversion of 7-dehydrocholesterol (7-DHC) in the skin to pre-vitamin D3 by UVB irradiation from the sunlight, followed by thermal isomerization to produce vitamin D3 (Figure 1) [5]. This is a tightly regulated process by the human body, and it is impossible to result in vitamin D3 overdose. The second source is through diet supplements. Human body cannot regulate this source of intake well, and vitamin D3 overdose and subsequent toxicity could occur. Interestingly, vitamin D3 itself is not the biologically active form. It must be first hydroxylated at the C25 position in the liver to produce 25-hydroxyvitamin D3 (25(OH)D3), followed by a second hydroxylation at the C1 position in the kidney or by monocyte-macrophages in the immune system to produce the biologically active form 1,25-dihydroxyvitamin D3 (1,25(OH) 2 D3) ( Figure 1). 1,25(OH) 2 D3 binds to the Vitamin D Receptor (VDR) which ultimately lead to its various biological functions (Figure 1).Apart from their classical action of regulating bone health and calcium homeostasis, there are accumulating evidence in the literature suggesting that vitamin D3 also have non-classical actions including strong inhibition of cell proliferation, promotion of cell differentiation, and suppression of inflammation responses [5][6][7][8]. However, the use of 1,25(OH) 2 D3 at its effective dose is often limited by its severe hypercalcemic side effect in which calcium concentrations in serum reaches dangerously high levels (>10.5 mg/dL) [9]. The high concentration of circulating calcium could deposit in software tissues such as heart, liver, and kidney, and could ultimately result in tissue calcifications [9].There have been tremendous efforts in both industry and academia to develop new vitamin D3 analogs that can retain the beneficial effects but have minimal or absence of the undesired hypercalcemic side effects, for a variety of potential indications such as cancer and inflammation [8,[10][11][12][13][14][15][16]. Many potent vitamin D receptor ligands have been discovered or synthesized, and several made to clinical trials (examples are shown in Figure 2).While Zemplar is an approved drug used to treat secondary hyperparathyroidism (over activity of the parathyroid gland) in people with chronic kidney failure, at present, however, there are no FDA approved vitamin D3 analogs that can be used safely to effectively treat cancer or inflammation disorders (Figure 2).

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Vitamin D Receptor as a Drug Discovery Target

Cited by 77 publications

References 0 publications

Nuclear Receptors and Their Selective Pharmacologic Modulators

Nuclear Receptors and Their Selective Pharmacologic Modulators

<b>Effect of 1,25-dihydroxyvitamin D</b><b><sub>3</sub></b><b> on spontaneous calcium responses in rat dental epithelial SF2 cells revealed by long-term </b><b>imaging </b>

Selective Vitamin D Receptor Modulators (SVIMS) as Potential Adjuvant Therapeutic Agents

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