The concept of multiple vitamin D signaling pathways.

Nuclear signaling by 1 alpha, 25-dihydroxyvitamin D3 (VD) is mediated by its nuclear receptor (VDR). It is widely accepted that VDR forms heterodimers with retinoid X receptors (RXRs) that bind in 5'-RXR-VDR-3' polarity to response elements formed by direct repeats of hexameric core binding motifs spaced by three nucleotides. This model, however, might be too simple to explain the multiplicity of nuclear signaling by VD. Recently, it was reported that VDR forms homodimers and heterodimers with the nuclear receptors for all-trans retinoic acid and thyroid hormone. All four different VDR complexes bind not only to direct repeats, but also to inverted palindromes; moreover, in heterodimeric complexes VDR can also take the 5' position. Taken together, this discriminates at least seven different types of VDR complexes binding each to two types of response elements. For half of these 14 cases, representative natural VD response elements have already been identified, which demonstrates that nature takes advantage of this concept of diversity. It is our hypothesis that the different physiological functions of VD can be related to different VD signaling pathways. Therefore, the identification of VD analogs that specifically trigger these pathways is the goal of our present and future investigations.