Figure 2.

Metabolism of 1α,25(OH)₂D₃. Vitamin D₃ is either obtained from dietary sources or UV synthesis, before two hydroxylations occur to produce the active metabolite 1α,25(OH)₂D₃. TLR ligation can also increase levels of CYP27B1, resulting in enhanced 1α-hydroxylation of 25(OH)D₃. The 1α,25(OH)₂D₃ then binds to nuclear or membrane vitamin D receptors (VDRs). Nuclear VDR ligation results in heterodimerization with retinoid X receptor (RXR) and binding to vitamin D responsive elements (VDRE) in promoter regions of responsive genes. Components of the RNA polymerase II complex are then recruited for induction of gene transcription, or transcription is repressed. Membrane caveolae-associated VDR ligation results in the activation of second messenger systems, with one effect being the initiation of Ras/MAPK signal transduction. Nuclear MAPK modulates gene expression and engages in cross-talk with the VDR-RXR-VDRE complex. (Adapted from Slatopolsky et al. [104], and Parton and Simons [105]).