Genomic signaling of vitamin D

It took several hundred million years of evolution, in order to develop the endocrine vitamin D signaling system, which is formed by a nuclear receptor, the transcription factor VDR (vitamin D receptor), its ligand, the vitamin D₃ metabolite 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) and several metabolizing enzymes and transport proteins. Even within the nuclear receptor superfamily the affinity of VDR for 1,25(OH)₂D₃ is outstandingly high (K_D = 0.1 nM). The activation of VDR by 1,25(OH)₂D₃ is the core mechanism of genomic signaling of vitamin D₃, which results in the modulation of the epigenome at thousands of promoter and enhancer regions as well as finally in the activation or repression of hundreds of target gene transcription. In addition, rapid non-genomic actions of vitamin D are described, which are mechanistically far less understood. The main function of vitamin D is to keep the human body in homeostasis. This implies the control of calcium levels, which is essential for bone mineralization, as well as for pushing of innate immunity to react sufficiently strong to microbe infection and preventing overreactions of adaptive immunity, i.e., not to cause autoimmune diseases. This review will discuss whether genomic signaling is sufficient for explaining all physiological functions of vitamin D₃.