Vitamin D receptor(s): In the nucleus but also at membranes?
Experimental Dematology 11 July 2020 https://doi.org/10.1111/exd.14147
Michal A. Zmijewski, Carsten Carlberg
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.
FIGURE 2 Vitamin D pathways. In the classic vitamin D pathway (black arrows) 1,25(OH)2D3
- penetrates the cell membrane as a free molecule (1) or,
- bound to DBP, it is transported via endocytosis mediated by the LRP2-CUBN complex (2).
The VDR-RXR complex binds the ligand already in the cytosol or in the nucleus (1) resulting in the modulation of target gene expression (Figure 1). Many cell types, including keratinocytes, express CYP27B1 in mitochondria and are able to produce 1,25(OH)2D3 from 25(OH)D3 (3) and HSP70 is believed to be intracellular a carrier for both.
In alternative vitamin D pathways (blue arrows) 1,25(OH)2D3 interacts also with membrane-bound proteins (4 and 5).
Membrane-associated VDR interacts with CAV1 and SRC in caveolae (4) and may down-regulate WNT, SSH and NOTCH signalling. PDIA3 is the best-studied protein associated with rapid, non-genomic response of vitamin D. PDIA3 mediates 1,25(OH)2D3-dependent membrane signalling cascades (5) including the activation of PLAA, PLA2, PLC and opening of Ca+ 2 and Pi (NaPi II a,c) channels. This results in the rapid accumulation of secondary messengers (6) including DAG, IP3, cAMP and Ca+2 followed by PKC or CAMK2G activation and the alteration of several downstream targets including MAPK pathways. PDIA3 was postulate to associate with both sides of the plasma membrane, circulates in the cytoplasm, is targeted to the endoplasmic reticulum or even translocates to the nucleus. PDIA3 was found to be stimulated by 1,25(OH)2D3 alone or together with the transcription factors NF-kB and STAT3 (7). 1,25(OH)2D3 may also directly (not shown) or indirectly via PDIA3 (5) activate Ca+2 and Pi channels and stimulate intestinal or renal Ca+2 and Pi transcellular transport (8). At the endoplasmic reticulum PDIA3 together with CRT and CANX is involved in protein folding (9). In mitochondria, PDIA3 is believed to regulate apoptosis (10), but the involvement of 1,25(OH)2D3 in this function of PDIA is unclear (11). In alternative ligand pathway (orange arrows) hundreds of natural or synthetic secosteroids were shown to be biologically active and metabolized by classic (CYP27A1, CYP2R1, CYP27B1 or CYP24A1) or non-classic (CYP11A1, CYP3A4) cytochromes (10). Some of these compounds were shown to bind VDR and may activate genomic vitamin D signalling
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