Rapid, Membrane-Initiated Actions of 1,25 Dihydroxyvitamin D: What Are They and What Do They Mean?

Fleet, James C.

doi:10.1093/jn/134.12.3215

Cited by 112 publications

(86 citation statements)

References 50 publications

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“…In contrast, we found that the baseline GFP-VDR distribution in ROS17/2.8 (A1G) cells was predominantly cytoplasmic (>70%), a finding that confirms what others have reported for VDR distribution in ROS 17/2.8 cells [Racz and Barsony, 1999], COS-1 (Sunn et al, 2001), and COS-7 [Racz andBarsony, 1999] kidney cells, and microwave-fixed fibroblasts [Barsony et al, 1990]. Next, [Fleet, 2004], including Caco-2 cells [Wali et al, 1992;Tien et al, 1993;Bettoun et al, 2003]. However, our inability to see membrane-associated GFP-VDR could reflect several factors including low sensitivity of the method to detect the 1-3% of VDR that is proposed to be associated with the membrane or an inability of the GFP-VDR to associate with the membrane.…”

Section: Discussionsupporting

confidence: 90%

Nucleo‐cytoplasmic cycling of the vitamin D receptor in the enterocyte‐like cell line, Caco‐2

Kłopot

Hance

Peleg

et al. 2006

J of Cellular Biochemistry

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We examined the effects of 1,25 dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) on the distribution and mobility of the vitamin D receptor (VDR) in the enterocyte-like Caco-2 cell. Confocal microscopy showed that a green fluorescent protein-vitamin D receptor (GFP-VDR) fusion protein is predominantly nuclear (58%) and it does not associate with the apical or basolateral membrane of proliferating or polarized, differentiated cells. In contrast to the previously studied cell types, neither endogenous VDR nor GFP-VDR levels accumulate in the nucleus following 1,25(OH) 2 D 3 treatment (100 nM, 30 min). However, in nuclear photobleaching experiments nuclear GFP-VDR import was significantly increased by 1,25(OH) 2 D 3 during both an early (0-5 min) and later (30-35 min) period (20% per 5 min). Compared to the natural ligand, nuclear import of GFP-VDR was 60% lower in cells treated with the 1,25(OH) 2 D 3 analog, 1-alpha-fluoro-16-ene-20-epi-23-ene-26,27-bishomo-25-hydroxyvitamin D 3 (Ro-26-9228, 5 min, 100 nM). Downstream events like ligandinduced association of VDR with chromatin at 1 h and the accumulation of CYP24 mRNA were significantly lower in Ro-26-9228 treated cells compared to 1,25(OH) 2 D 3 (60 and 95% lower, respectively). Collectively our data are consistent with a role for ligand-induced nuclear VDR import in receptor activation. In addition, ligand-dependent VDR nuclear import appears to be balanced by export, thus accounting for the lack of nuclear VDR accumulation even when VDR import is significantly elevated. Keywords intestine; nuclear trafficking; 1,25 dihydroxyvitamin D 3Intestinal calcium absorption is a critical step in the maintenance of calcium homeostasis [Fleet, 2006]. It occurs by both paracellular and transcellular pathways [Bronner, 2003;Hoenderop et al., 2005]. The transcellular calcium absorption pathway is an active process that is regulated by the active form of vitamin D, 1,25 dihydroxyvitamin D 3 (1,25(OH) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of critical proteins: calbindin D 9k (CaBPD9k), the transient receptor vanelloid family member 6 (TRPV6), and the plasma membrane calcium ATPase 1b (PMCA1b) [Fleet et al., 2002;Song et al., 2003b;Fleet, 2006].The actions of 1,25(OH) 2 D 3 are mediated by the vitamin D receptor (VDR), a transcription factor that belongs to nuclear hormone receptor superfamily [Haussler et al., 1998]. The deletion of VDR in the enterocyte results in a 70% reduction in intestinal calcium absorption efficiency that is coincident with a significant reduction in CaBPD9k, TRPV6, and PMCA1b gene expression [Van Cromphaut et al., 2001;Song et al., 2003a].Previous research shows that binding of 1,25(OH) 2 D 3 to VDR in the cytoplasm of cells stimulates heterodimerization of VDR with RXR and the redistribution of the VDR-RXR-hormone complex to the nucleus [Barsony et al., 1990;Michigami et al., 1999;Racz and Barsony, 1999;Sunn et al., 2001]. The nuclear import of the VDR-RXR-hormone complex is active [Racz and Barsony, 1999;Miyauchi ...

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Section: Discussionsupporting

confidence: 90%

Nucleo‐cytoplasmic cycling of the vitamin D receptor in the enterocyte‐like cell line, Caco‐2

Kłopot

Hance

Peleg

et al. 2006

J of Cellular Biochemistry

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“…Two explanations have been given to these effects: (a) the existence at either the plasma membrane or the cytosol of receptors other than the NRs that mediate their genomic effects or, alternatively, (b) the presence of subpopulations of these NRs responsible for non-genomic effects at these locations. [6][7][8][9][10][11][12][13][14] On the one hand, for years literature proposing membrane or cytosolic receptors for several hormones different to NRs has been controversial. This has been many times due to the lack of definitive identification of such receptors and of their biochemical (Scatchard and saturation binding analyses) and functional characterization.…”

Section: Do Nuclear Receptors Mediate Extranuclear Effects?mentioning

confidence: 99%

“…8,9,12,18,30 In principle, extranuclear-initiated NR actions may regulate gene expression: (a) by the modulation of the transcriptional activity of NRs themselves or, (b) independently of NR transcription factor activity.…”

Section: Nuclear and Extranuclear Nr Effects Integratementioning

confidence: 99%

Nuclear receptors: Genomic and non-genomic effects converge

Ordóñez‐Morán¹,

Muñoz²

2009

Cell Cycle

100

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“…These include interaction of calcitriol with a membrane receptor, either a novel receptor or the known vitamin D receptor, thereby activating cell signalling pathways (Nemere and Campbell, 2000;Holick, 2003;Evans et al, 2004;Fleet, 2004;Mizwicki et al, 2004;Dusso et al, 2005;Hendy et al, 2006). There is growing direct evidence that the traditional vitamin D receptor may also have a unique, nontranscriptional role in plasma membrane initiated signalling (Fleet, 2004 (Berger et al, 1988;Sandgren et al, 1991;Rougui et al, 1998;Sheinin et al, 2000;Chatterjee, 2001;Holick, 2003;Lee et al, 2003).…”

mentioning

confidence: 99%

Vitamin D receptor distribution in intestines of domesticated sheep Ovis ammon f. aries

Riner

Boos

Hässig

et al. 2007

Journal of Morphology

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The biologically active form of vitamin D, i.e., 1,25‐dihydroxycholecalciferol or calcitriol, plays an important role in bone metabolism and calcium homeostasis, which is often disturbed at the onset of lactation in high milk‐yielding domestic ruminants. Gene transcription is modulated via vitamin D receptors, but nongenomic effects of vitamin D via membrane receptors have also been described. In the intestines, vitamin D promotes calcium absorption via vitamin D receptors. Vitamin D receptors are of clinical relevance, but have not been systematically assessed within all segments of the intestine in any species. Thus, we present for the first time an immunohistochemical study of the distribution patterns of the vitamin D receptor protein in sheep, which may be the basis for present and future investigations on mineral homeostasis in domestic ruminants. Tissue probes of the intestines were collected from five lambs and five nonlactating and nonpregnant dams, fixed in formalin, embedded in paraffin, and used for the assessment of vitamin D receptor protein. Nuclear vitamin D receptor immunoreaction was scored semiquantitatively and exhibited a segment‐specific distribution pattern. Goblet cells always were devoid of any vitamin D receptor immunoreaction. Surface epithelial cells and enterocytes of the crypt openings generally demonstrated only a weak immunoreaction. Basally and/or intermediately located crypt epithelial cells exhibited stronger immunoreactions in duodenum, jejunum, and colon descendens. This basal/intermediate to superficial gradient was most pronounced in the duodenum and less evident in jejunum and colon descendens and not observed in ileum and cecum. There were no age‐dependent variations in vitamin D receptor protein expression. Results demonstrate that intestinal vitamin D receptor distribution patterns are segment‐specific and strongest immunoreactions correlate with highest intestinal calcium absorptive activities, as reported in literature. Strong expression of vitamin D receptors within the lower half of crypts also suggests a role for calcitriol in epithelial differentiation and cellular homeostasis. J. Morphol., 2008. © 2007 Wiley‐Liss, Inc.

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Rapid, Membrane-Initiated Actions of 1,25 Dihydroxyvitamin D: What Are They and What Do They Mean?

Cited by 112 publications

References 50 publications

Nucleo‐cytoplasmic cycling of the vitamin D receptor in the enterocyte‐like cell line, Caco‐2

Nucleo‐cytoplasmic cycling of the vitamin D receptor in the enterocyte‐like cell line, Caco‐2

Nuclear receptors: Genomic and non-genomic effects converge

Vitamin D receptor distribution in intestines of domesticated sheep Ovis ammon f. aries

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