The Non-Genomic Actions of Vitamin D

Charles S Hii, Antonio Ferrante, Charles S Hii, Antonio Ferrante

Abstract

Since its discovery in 1920, a great deal of effort has gone into investigating the physiological actions of vitamin D and the impact its deficiency has on human health. Despite this intense interest, there is still disagreement on what constitutes the lower boundary of adequacy and on the Recommended Dietary Allowance. There has also been a major push to elucidate the biochemistry of vitamin D, its metabolic pathways and the mechanisms that mediate its action. Originally thought to act by altering the expression of target genes, it was realized in the mid-1980s that some of the actions of vitamin D were too rapid to be accounted for by changes at the genomic level. These rapid non-genomic actions have attracted as much interest as the genomic actions and they have spawned additional questions in an already busy field. This mini-review attempts to summarise the in vitro and in vivo work that has been conducted to characterise the rapid non-genomic actions, the mechanisms that give rise to these properties and the roles that these play in the overall action of vitamin D at the cellular level. Understanding the effects of vitamin D at the cellular level should enable the design of elegant human studies to extract the full potential of vitamin D to benefit human health.

Keywords: MAP kinases; protein kinase C; signalling molecules; vitamin D; vitamin D receptor; vitamin D response element.

Figures

Figure 1
Figure 1
The non-genomic actions of 1,25D. 1,25D acts via both genomic and non-genomic actions to regulate the expression of vitamin D responsive genes such as CY24 and those that promote anti-microbial defence. The non-genomic mechanisms, downstream of VDRn and/or VRDm complexed to caveolin1, include the activation of intracellular signalling molecules, such as PKC, PI3K, MAP kinases, CaMKII and PLA2. The range of signalling molecules being activated is related to the cell-type and status of cell maturation. Targets of these kinases include transcription factors, e.g., SP1, SP3 and RXR that bind to response elements on the promoters of vitamin D-responsive genes. Another non-genomic action of 1,25D involves the regulation of VDR binding to target proteins such as STAT1 and IKKβ that enables the cross modulation by 1,25D of gene expression mediated by non-vitamin D ligands, including IFN-α and TNF-α. This mechanism provides an avenue for 1,25D to directly regulate immune responses and anti-viral actions of immune and non-immune cells. Ligation of CD40, IFN-γ receptor and TLR2/4/8 causes an upregulation of VDR and CYP27B1 expression and this facilitates an autocrine mechanism that enables the increased availability of 1,25D and VDR to cooperate with these immune receptors for various responses, including anti-microbial activity while modulating the expression of cytokines, chemokines and type 1 interferons. The VDR, independently of 1,25D, can also exhibits a non-classical action that involves its interaction with proteins such as transcription factors or kinases to modulate cellular responses, including immune/antiviral response and stress-induced cell death. Bold arrows denote direct actions of 1,25D. Dotted arrows denote ligand binding to their receptors. Reversible arrows indicate protein-protein interaction. Arrows with double lines indicate kinase-substrate relationship. Abbreviations: 25D: 25-hydroxyvitamin D; 1,25D: 1,25 dihydroxyvitamin D; VDRm/n: membrane or nuclear vitamin D receptor; CYP27B1 and CYP24: cytochromes P450C1α and P450C24; PLA2: phospholipase A2; CaMKII: Calcium/calmodulin protein kinase II; AA: arachidonic acid; DAG: diacylglycerol; PLC: phospholipase C; IFN: interferon; TLR: Toll-like receptor; PMA: phorbol 12-myristate 13-acetate; PKC: protein kinase C; PI3K: phosphatidylinositol 3-kinase; Akt: protein kinase B; IKK: I-κB kinase; MED1; Mediator Complex Subunit 1; RXR: retinoic acid X receptor; Specificity Protein; ETS 1: Avian Erythroblastosis Virus E26 Oncogene Homolog-1; VSE: Vitamin D stimulatory element; STAT: Signal Transducer and Activator of Transcription; JAK: Janus kinase; Tyk: Tyrosine kinase; ERK: Extracellular signal Regulated protein Kinase; JNK: c-Jun N-terminal Kinase; MCP-1: Monocyte chemoattractant protein 1; CAMP: Cathelicidin Antimicrobial Peptide; IFI27L: Interferon, Alpha-Inducible Protein 27 like; IFI44L: Interferon-Induced Protein 44-Like; ISG15: Interferon-Stimulated Protein, 15 KDa; OAS: 2′-5′-Oligoadenylate Synthetase; RSAD2: Radical S-Adenosyl Methionine Domain Containing 2; “p” denotes phosphorylation; “+” denotes enhancement.

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