Rapid Nontranscriptional Effects of Calcifediol and Calcitriol

Abstract

Classically, a secosteroid hormone, vitamin D, has been implicated in calcium and phosphate homeostasis and has been associated with the pathogenesis of rickets and osteomalacia in patients with severe nutritional vitamin D deficiency. The spectrum of known vitamin D-mediated effects has been expanded in recent years. However, the mechanisms of how exactly this hormone elicits its biological function are still not fully understood. The interaction of this metabolite with the vitamin D receptor (VDR) and, subsequently, with the vitamin D-responsive element in the region of specific target genes leading to the transcription of genes whose protein products are involved in the traditional function of calcitriol (known as genomic actions). Moreover, in addition to these transcription-dependent mechanisms, it has been recognized that the biologically active form of vitamin D3, as well as its immediate precursor metabolite, calcifediol, initiate rapid, non-genomic actions through the membrane receptors that are bound as described for other steroid hormones. So far, among the best candidates responsible for mediating rapid membrane response to vitamin D metabolites are membrane-associated VDR (VDRm) and protein disulfide isomerase family A member 3 (Pdia3). The purpose of this paper is to provide an overview of the rapid, non-genomic effects of calcifediol and calcitriol, whose elucidation could improve the understanding of the vitamin D3 endocrine system. This will contribute to a better recognition of the physiological acute functions of vitamin D3, and it could lead to the identification of novel therapeutic targets able to modulate these actions.

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections—Sepsis and COVID-19

“…Lockdowns and curfews lowered mean serum 25(OH)D concentration, thus, significantly increasing the invulnerability to the SARS-CoV-2 virus, its complications, and deaths [ 26 , 27 ]. Nutritional status is one of the critical aspects responsible for overall health and well-being, including maintaining proper immune system functioning [ 17 , 28 ]. In addition to vitamin D, other essential micronutrients, such as zinc, magnesium, omega-3 fatty acids, quercetin, etc., are also necessary to optimise the functions of the endocrine system.…”

“…These explain the non-involvement of the genomic mechanisms of the rapid action of lipid-soluble steroid hormones [ 3 ]. The cubilin-mediated endocytosis of vitamin D is another example of vitamin D membrane–receptor-associated rapid actions of vitamin D. The article by Donate et al, 2022 describes several non-genomic rapid actions of vitamin D [ 17 , 18 , 19 ].…”

Enhanced insulin activity achieved in VDRa/b ablation zebrafish

“…No significant alterations in transcriptional expression levels of pdia3 were observed in the hepatic tissue of our vdra -/-;vdrb -/fish (data not shown). However, the majority of the responses mediated by vitamin D 3 non-genomic signaling have implicated post-translational modification (24,26,27). It has been reported that pdia3 might have a significant role in calcium absorption, skeletal development, lipogenesis, and insulin regulation (24)(25)(26)(27).…”

“…However, the majority of the responses mediated by vitamin D 3 non-genomic signaling have implicated post-translational modification (24,26,27). It has been reported that pdia3 might have a significant role in calcium absorption, skeletal development, lipogenesis, and insulin regulation (24)(25)(26)(27).…”

Nongenomic Activities of Vitamin D

“…However, PDIA3 was also shown to participate in cells’ protection against the formation of thymine dimers after irradiation with UV [ 122 ]. The effect was associated with activation of PKC signaling and calcium influx [ 180 ]. In addition, 1,25(OH) 2 D 3 protected cells from UVR-induced thymine dimers via stimulation of chloride currents [ 144 ].…”