1. Signaling Pathways
  2. Vitamin D Related/Nuclear Receptor

Vitamin D Related/Nuclear Receptor

Vitamin D Related/Nuclear Receptor Vitamin D Related/Nuclear Receptor

Vitamin D Related/Nuclear Receptor

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Overview of Vitamin D Related/Nuclear Receptor

Vitamin D was first identified as a cure for nutritional rickets, a disease of bone growth caused by an inadequate uptake of dietary calcium. Vitamin D refers collectively to vitamin D3 and vitamin D2. Biologically active vitamin D is generated via largely hepatic 25-hydroxylation catalyzed by CYP2R1, CYP27A1, and possibly other enzymes to produce 25-hydroxvitamin D (25D), which has a long half-life and is the major circulating vitamin D metabolite. 25D is modified by 1α-hydroxylation catalyzed by CYP27B1, which produces hormonal 1,25-dihydroxyvitamin D (1,25D).

The biological actions of 1,25(OH)2D3 are mediated by the VDR. VDR belongs to the steroid receptor family which includes receptors for retinoic acid, thyroid hormone, sex hormones, and adrenal steroids. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. 1,25(OH)2D3 action regulates renal calcium reabsorption and phosphate loss, and thus control bone metabolism mainly indirectly by regulating mineral homeostasis.

Vitamin D deficiency increases rates of cancer, as well as autoimmune and infectious diseases. More than 3,000 vitamin D analogs are developed worldwide and several analogs demonstrated more potent antiproliferative and prodifferentating effects on cancer cell lines compared with 1,25(OH)2D3, which may lead to the development of new therapies to prevent and treat diseases.

 

Nuclear receptors refer to a family of receptors that are localized in the nucleus. They not only sense external ligands as stimuli to modulate cellular functions and consequently organ or whole-body fitness, but also serve as transcriptional regulators with direct DNA binding activity to control gene expression.

Most NRs are regulated endogenously by small lipophilic ligands such as steroids, retinoids, and phospholipids, but this protein family also contains “orphan” members for which no ligand has yet been identified. Two major subclasses of nuclear receptors with identified endogenous agonists can be identified: steroid and non-steroid hormone receptors.

Steroid hormone receptors include the estrogen receptor, androgen receptor, progesterone receptor, mineralocorticoid receptor, and glucocorticoid receptor. Steroid hormone receptors function typically as dimeric entities and are thought to be resident outside the nucleus in the unliganded state in a complex with chaperone proteins, which are liberated upon agonist binding. Migration to the nucleus and interaction with other regulators of gene transcription, including RNA polymerase, acetyltransferases and deacetylases, allows gene transcription to be regulated.

Non-steroid hormone receptors include the thyroid hormone receptors (TRα and β), retinoic acid receptors (RARα, β, and γ), vitamin D receptor (VDR), and peroxisome proliferator-activated receptors (PPARα, β, and γ). Non-steroid hormone receptors typically exhibit a greater distribution in the nucleus in the unliganded state and interact with other nuclear receptors to form heterodimers, as well as with other regulators of gene transcription, leading to changes in gene transcription upon agonist binding.

 

References:

[1] White JH. Infect Immun. 2008 Sep;76(9):3837-43.

[2] Christakos S, et al. Physiol Rev. 2016 Jan;96(1):365-408.

[3] Alexander SPH, et al. Br J Pharmacol. 2019;176 Suppl 1(Suppl 1):S229-S246.

[4] Yang Z, et al. Trends Cancer. 2021;7(6):541-556.