The physiology of vitamin D receptor activation.

Vitamin D is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. In addition to its endocrine effects, vitamin D has important autocrine/paracrine roles. The last step in the activation of vitamin D, the hydroxylation on carbon 1, takes place mainly in the kidney. However, extrarenal sites showing 1alpha-hydroxylase activity have been also found. The hormonally active form of vitamin D (1,25(OH)-D(3) or calcitriol) mediates its biological effects by binding to the vitamin D receptor, which then translocates to the nuclei of the cell and binds to specific DNA sites to modify the expression of target genes. After activation of the receptor, the protein changes its tridimensional conformation, this change being the key process in order to exert its nuclear actions. Several steps take place in order to increase or decrease the transcription rate of a target gene. First, homodimerization of the vitamin D receptor or heterodimerization with the retinoic X receptor allows the complex to go into the nucleus and bind to the DNA. Then several proteins are recruited to the complex that either increase or decrease chromatin condensation acting then as corepresors or coactivators, respectively, and decreasing or increasing the target gene transcription. The coactivators bind several extra proteins that build a bridge to the basal transcription machinery. Therefore, little changes in the receptor's tridimensional change elicted by the activator can lead to differences in protein recruitment and, thus, in gene transactivation. Furthermore, differences in the cellular environment can yield different responses to the same activator. This characteristic of the nuclear receptors makes them a good candidate as a valuable therapeutic target.