The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. [5] Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer with the retinoid-X receptor. The VDR heterodimer then enters the nucleus and binds to Vitamin D responsive elements (VDRE) in genomic DNA. VDR binding results in expression or transrepression of many specific gene products. VDR is also involved in microRNA-directed post transcriptional mechanisms. [6] In humans, the vitamin D receptor is encoded by the VDR gene located on chromosome 12q13.11. [7]
VDR is expressed in most tissues of the body, and regulates transcription of genes involved in intestinal and renal transport of calcium and other minerals. [8] Glucocorticoids decrease VDR expression. [8] Many types of immune cells also express VDR. [9]
The VDR gene encodes the nuclear hormone receptor for vitamin D. The most potent natural agonist is calcitriol (1,25-dihydroxycholecalciferol) and the vitamin D2 homologue ercalcitriol, 1-alpha,25-dihydroergocalciferol) is also a strong activator. Other forms of vitamin D bind with lower affinity, as does the secondary bile acid lithocholic acid. The receptor belongs to the family of trans-acting transcriptional regulatory factors and shows similarity of sequence to the steroid and thyroid hormone receptors. [10]
Downstream targets of this nuclear hormone receptor include many genes involved in mineral metabolism. [8] The receptor regulates a variety of other metabolic pathways, such as those involved in the immune response and cancer. [9] VDR variants that bolster vitamin-D action and that are directly correlated with AIDS progression rates and VDR association with progression to AIDS follows an additive model. [11] FokI polymorphism is a risk factor for enveloped virus infection as revealed in a meta-analysis. [12] The importance of this gene has also been noted in the natural aging process were 3’UTR haplotypes of the gene showed an association with longevity. [13]
Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternative splicing results in multiple transcript variants encoding the same protein. [14] VDR gene variants seem to influence many biological endpoints, including those related to osteoporosis [15]
The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals. [16] Experimental studies have shown that the unliganded VDR interacts with regulatory regions in cWnt (wnt signaling pathway) and sonic hedgehog target genes and is required for the induction of these pathways during the postnatal hair cycle. [17] These studies have revealed novel actions of the unliganded VDR in regulating the post-morphogenic hair cycle.
Researchers have focused their efforts in elucidating the role of VDR polymorphisms in different diseases and normal phenotypes such as the HIV-1 infection susceptibility and progression or the natural aging process. The most remarkable findings include the report of VDR variants that bolster vitamin-D action and that are directly correlated with AIDS progression rates, that VDR association with progression to AIDS follows an additive model [11] and the role of FokI polymorphism as a risk factor for enveloped virus infection as revealed in a meta-analysis. [12]
Vitamin D receptor has been shown to interact with many other factors which will affect transcription activation:
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction.
Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium (Ca2+) mainly by increasing the uptake of calcium from the intestines.
TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.
25-Hydroxyvitamin D 1-alpha-hydroxylase also known as calcidiol 1-monooxygenase or cytochrome p450 27B1 (CYP27B1) or simply 1-alpha-hydroxylase is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene.
Calcitroic acid (1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D3) is a major metabolite of 1α,25-dihydroxyvitamin D3 (calcitriol). Around 1980, scientists first reported the isolation of calcitroic acid from the aqueous extract of radioactively treated animals' livers and intestines. Subsequent researches confirmed calcitroic acid to be a part of enterohepatic circulation. Often synthesized in the liver and kidneys, calcitroic acid is generated in the body after vitamin D is first converted into calcitriol, an intermediate in the fortification of bone through the formation and regulation of calcium in the body. These pathways managed by calcitriol are thought to be inactivated through its hydroxylation by the enzyme CYP24A1, also called calcitriol 24-hydroxylase. Specifically, It is thought to be the major route to inactivate vitamin D metabolites. The hydroxylation and oxidation reactions will yield either calcitroic acid via the C24 oxidation pathway or 1,25(OH2)D3-26,23-lactone via the C23 lactone pathway.
The nuclear receptor coactivator 2 also known as NCoA-2 is a protein that in humans is encoded by the NCOA2 gene. NCoA-2 is also frequently called glucocorticoid receptor-interacting protein 1 (GRIP1), steroid receptor coactivator-2 (SRC-2), or transcriptional mediators/intermediary factor 2 (TIF2).
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).
Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.
Thyroid hormone receptor beta (TR-beta) also known as nuclear receptor subfamily 1, group A, member 2 (NR1A2), is a nuclear receptor protein that in humans is encoded by the THRB gene.
Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the HNRNPC gene.
Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D3). It has also been identified as vitamin D3 24-hydroxylase.(EC 1.14.15.16)
Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.
Peroxisome proliferator-activated receptor gamma coactivator 1-beta is a protein that in humans is encoded by the PPARGC1B gene.
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.
CYP2R1 is cytochrome P450 2R1, an enzyme which is the principal vitamin D 25-hydroxylase. In humans it is encoded by the CYP2R1 gene located on chromosome 11p15.2. It is expressed in the endoplasmic reticulum in liver, where it performs the first step in the activation of vitamin D by catalyzing the formation of 25-hydroxyvitamin D.
24,25-Dihydroxycholecalciferol, also known as 24,25-dihydroxyvitamin D3 and (24R)-hydroxycalcidiol (abbreviated as 24(R),25-(OH)2D3), is a compound which is closely related to 1,25-dihydroxyvitamin D3, the active form of vitamin D3. Like vitamin D3 itself and calcifediol (25-hydroxyvitamin D3), it is inactive as a hormone both in vitro and in vivo. It was first identified in 1972 in the laboratory of Hector DeLuca and Michael F. Holick.
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and for many other biological effects. In humans, the most important compounds in this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).
Michael F. Holick is an American adult endocrinologist, specializing in vitamin D, such as the identification of both calcidiol, the major circulating form of vitamin D, and calcitriol, the active form of vitamin D. His work has been the basis for diagnostic tests and therapies for vitamin D-related diseases. He is a professor of medicine at the Boston University Medical Center and editor-in-chief of the journal Clinical Laboratory.
Vitamin D response element (VDRE) is a type of DNA sequence that is found in the promoter region of vitamin D regulated genes. This sequence binds the vitamin D receptor (VDR), when complexed with calcitriol (1,25(OH)2D), the active form of vitamin D, and so regulates the expression of many genes.
Vitamin D is a steroid hormone that plays a vital role in calcium and phosphate absorption. Recent studies show several associations between low levels of vitamin D, or hypovitaminosis D, and neuropsychiatric disorders, including Alzheimer's disease, autism, epilepsy, multiple sclerosis, Parkinson's disease, and schizophrenia.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.