Calcitriol receptor

Calcipotriene (Dovonex), a synthetic vitamin D3 derivative, is indicated for the treatment of moderate plaque psoriasis. Its mechanism of action is unknown, although it competes for calcitriol receptors on keratinocytes and normalizes differentiation. It also has a variety of immunomodulatory effects in the skin. Although the drug can cause local irritation, the most serious toxicities are hypercalciuria and hypercalcemia, which are usually reversible. 

Fluorination of calcitriol has been performed on the A-ring and on the side chain. Introduction of fluorine atoms on the A-ring of vitamin D3 metabolites has been realised on the positions 2 and 4 [152]. Surprisingly, while introduction of fluorine at C-2 strongly decreases the affinity for the calcitriol receptor... 

Both calcidiol and calcitriol are substrates for24-hydroxylation, catalyzed by a cytochrome P4so-dependent enzyme in kidneys, intestinal mucosa, cartilage, and other tissues that contain calcitriol receptors. This enzyme is induced by calcitriol the activities of calcidiol 1-hydroxylase and 24-hydroxylase in the kidney are subject to regulation in opposite directions, so that decreased requirement for, and synthesis of, calcitriol results in increased formation of 24-hydroxycalcidiol. Kidney epithelial cells in culture show increased formation of 24-hydroxycalcidiol, and decreased formation of calcitriol, after the addition of calcitriol or high concentrations of calcium to the culture medium. 

Type II vitamin D-resistant rickets (Section 3.4.2) is associated with target tissue resistance to calcitriol. Most cases are from either a lack of calcitriol receptors or impaired binding of calcitriol to the receptor. Thus, higher than normal concentrations of calcitriol are required to saturate the receptor. Some affected families show normal binding of calcitriol to the receptor, with an apparent defect in the DNA binding domain (Griffin and Zerwekh, 1983). 

Hair follicles also have calcitriol receptors and type 11 vitamin D-resistant rickets (Section 3.4.2), which is caused hy lack of calcitriol receptor function, is associated with total alopecia, suggesting that calcitriol has a role in their development. 

Calcitriol receptors have been identified in a variety of tissues in some of these, the effect of calcitriol is to induce the synthesis of calbindin-D in others, it is regulation of cell proliferation and differentiation. 

Type 11 vitamin D-resistant rickets is characterized by a lack of responsiveness of target tissues to calcitriol and is caused by a genetic defect in the calcitriol receptor. Affected children develop more or less normally until about 9 months of age, then develop severe rickets with alopecia and a wide variety of disorders, including immune system dysfunction. Three variants are known ... 

Increased uptake of calcium by arterial smooth muscle, leading to increased muscle tone, and hence increased circulatory resistance and blood pressure. This could reflect increased sensitivity of vascular smooth muscle to calcitriol (vitamin D) action in vitamin Bg deficiency the membrane calcium-binding protein is regulated by vitamin D, and vascular tissue has calcitriol receptors. 

Intracellular calcitriol receptors are widespread in the body. They are found, for example, in the small intestine, the kidneys, the bones, and the parathyroid gland. Calcitriol binds to these receptors and induces at the DNA level the transcription of hormone-sensitive genes. It influences cell differentiation and proliferation, stimulates an increased uptake of calcium ions from the intestine through enhanced formation of calcium-binding proteins, and also controls the release of calcium from the bones. [91] Since the counter-ion of the calcium is mostly phosphate, calcitriol raises consequently the phosphate level in blood as well. While the release of calcium from the bones appears counterproductive, this effect is however over-compensated by the increased intestinal calcium resorption, resulting in an elevated serum concentration. 

Kumar R, Schaefer J, Grande JP, Roche PC. (1994)Immunolocalization of calcitriol receptor, 24-hydroxylase cytochrome P 50, and cal-bindin D28k in human kidney. Am J Physiol Ren Physiol. 266 477-485. 

Calcitriol acts like a steroid hormone, binding to a nuclear receptor protein (section 10.4). The calcitriol-receptor complex then binds to the enhancer site of the gene coding for a calcium-binding protein, increasing its transcription and so increasing the amount of calcium-binding protein in the cell. 

In all of these actions, the role of calcitriol seems to be the induction or maintenance of synthesis of calcium-binding proteins, and the effects are secondary to increased calcium uptake into the target cells. Several of these actions are also modulated by vitamin A as discussed in section 11.2.3.2, vitamin A (RXR) receptors form heterodimers with calcitriol receptors, so that both vitamins are required together for some actions. 

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