Vitamin D receptor(s): in the nucleus but also at membranes?

The genomic actions of the vitamin D are mediated via its biologically most potent metabolite 1α,25‐dihydroxyvitamin D3 (1,25(OH)2D3) and the transcription factor vitamin D receptor (VDR). Activation of VDR by 1,25(OH)2D3 leads to change in the expression of more 1000 genes in various human tissues. Based on (epi)genome, transcriptome and crystal structure data the molecular details of this nuclear vitamin D signalling pathway are well understood. Vitamin D is known for its role on calcium homeostasis and bone formation, but it also modulates energy metabolism, innate and adaptive immunity as well as cellular growth, differentiation and apoptosis. The observation of rapid, non‐genomic effects of 1,25(OH)2D3 at cellular membranes and in the cytosol initiated the question, whether there are alternative vitamin D‐binding proteins in these cellular compartments. So far, the best candidate is the enzyme PDIA3 (protein disulphide isomerase family A member 3), which is found at various subcellular locations. Furthermore, also VDR seems to play a role in membrane‐based responses to vitamin D. In this viewpoint, we will dispute whether these rapid, non‐genomic pathways are a meaningful addition to the genome‐wide effects of vitamin D.final draftpeerReviewe