1α,25-Dihydroxyvitamin D ₃ Induces Vascular Smooth Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase

Abstract

(VDRE). 2 VDR belongs to the nuclear receptor superfamily for steroid hormones, retinoic acid, and thyroid hormone (T 4 ). 3 These receptors bind to their responsive elements and alter downstream gene transcription. In addition, 1␣,25-(OH) 2 D 3 has also been shown to produce rapid, nongenomic (ie, VDRE-independent) responses. 4 Indeed, 1␣,25-(OH) 2 D 3 stimulates a wide array of rapid responses including rapid intestinal absorption of calcium (transcaltachia), 5 store-operated calcium influx, 6 activation of protein kinase C, 7 and opening of voltage-gated calcium and chloride channels. 8 Although the precise molecular mechanisms by which these rapid nongenomic responses are regulated remain unclear, a putative membrane receptor for 1␣,25-(OH) 2 D 3 or alternative pathways of the nuclear VDR have been proposed. 9 Analogs of 1␣,25-(OH) 2 D 3 have been used to differentiate the genomic (ie, VDRE-dependent) versus nongenomic responses. These analogs take advantage of the flexible conformation of 1␣,25-(OH) 2 D 3 at the 6,7 carboncarbon single bond (Figure 1). Rapid rotation about this bond allows generation of a continuum of various shapes of 1␣,25-(OH) 2 D 3 ranging from the planar extended 6-s-trans conformation to the steroid-like 6-s-cis conformation 10,11 ; these various shapes are then available to serve as ligands for appropriate receptors. Indeed, the 6-s-cis-locked analog 1␣,25-dihydroxylumisterol is a fully potent agonist of rapid, nongenomic responses of 1␣,25-(OH) 2 D 3 . 5 Thus, it has been proposed that different shapes of the conformationally flexible 1␣,25-(OH) 2 D 3 are agonists for the rapid, nongenomic (6-s-cis) and genomic (twisted 6-s-trans) responses. 12 In addition, analogs that antagonize 1␣,25-(OH) 2 D 3 responses have also been characterized. Indeed, 1␤,25-(OH) 2 D 3 (HL) is a specific antagonist of nongenomic action of 1␣,25-(OH) 2 D 3 , 8,13 whereas (23S)-25-dehydro-1␣-OH-D 3 -26,23-lactone (MK) preferentially inhibits genomic responses. 14 Original

Molecular actions of vitamin D in reproductive cell biology

“…The transform is compulsory for genomic effects, whereas the cis conformation is necessary for rapid effects (expertly reviewed by Haussler et al 2011). Unfortunately, investigations of VDR-mediated rapid responses have only been performed in vitro, showing rapid alterations in insulin secretion in β-cells (Kajikawa et al 1999), vascular smooth muscle cell migration (Rebsamen et al 2002), spermatozoa motility (Blomberg Jensen et al 2011) and calcium flux in Sertoli cells, osteoblasts, spermatozoa and intestinal cells (Norman et al 1997, Menegaz et al 2010, Blomberg Jensen et al 2011). Therefore, whether or not these alternative signalling mechanisms are physiologically relevant remain to be determined.…”

1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation–Induced Skin Carcinogenesis

“…The VDR ligand 1,25(OH) 2 D 3 is highly conformationally flexible, and it has been shown that one shape of 1,25(OH) 2 D 3 is preferred for genomic responses whereas another shape is preferred by the VDR for nongenomic responses (11)(12)(13). The 6-s-cis conformationally restricted analogue 1a,25(OH) 2 -lumisterol (JN) shows little ability to increase transcription of the osteocalcin gene in bone cells compared with 1,25(OH) 2 D 3 (14) but generates nongenomic actions in pancreatic b cells and endothelial cells (15,16).…”

Rapid nongenomic actions of thyroid hormone

“…Recently, members of the steroid hormone receptor superfamily, such as the estrogen, vitamin D, and glucocorticoid receptors, have been shown to cross-couple to the PI3-kinase͞ Akt pathway (15)(16)(17)(18). In vascular endothelial cells, the activation of the PI3-kinase͞Akt pathway by steroid hormones leads to eNOS activation and cardiovascular protection (16,18).…”