Intestinal Cell Calcium Uptake and the Targeted Knockout of the 1,25D3-MARRS (Membrane-associated, Rapid Response Steroid-binding) Receptor/PDIA3/Erp57

Abstract

Enterocytes from female or male KO mice failed to exhibit steroid hormone-stimulated PKA activity, but did respond to forskolin with enhanced calcium uptake. We conclude that the 1,25D 3 -MARRS receptor is of central importance to steroid hormone-stimulated calcium uptake in mammalian intestinal cells.Rapid, pre-genomic responses have been documented for estradiol in uterine (1) and immune cells (2), endothelium (3, 4), for progesterone in oocytes (5), 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) 3 in intestinal cells (6), and osteoblasts (7). Pregenomic responses have also been documented for other steroid hormones (8, 9). It is now well accepted that steroid hormones are capable of acting through membrane-localized receptors to initiate pre-genomic effects as well as through regulation of gene expression (9). The identity of these cell surface receptors, however, has been the subject of debate. For the steroid hormone 1,25(OH) 2 D 3 , two possible candidates exist: the classical vitamin D receptor (VDR) (10) and the more recently discovered and unrelated 1,25D 3 -MARRS (membrane-associated, rapid response, steroid binding) receptor/PDIA3/ERp57 (11). Wali et al. (7) have reported that the VDR is not required for the rapid actions of 1,25(OH) 2 D 3 in mouse osteoblasts, whereas Mizwicki et al. (10) have argued that only the VDR is necessary to mediate the rapid actions of 1,25(OH) 2 D 3 , despite our reports that RNAi against the 1,25D 3 -MARRS receptor, as well as preincubation of intestinal cells with our neutralizing antibody to the 1,25D 3 -MARRS receptor, eliminates the rapid actions of 1,25(OH) 2 D 3 on phosphate uptake (11).In the studies described in this report, genetically engineered mice are used to produce a targeted knock-out of the 1,25D 3 -MARRS receptor in intestinal epithelial cells and are tested, along with littermates, for their response to the steroid hormone 1,25(OH) 2 D 3 .

ERp57/GRP58: A protein with multiple functions

“…PKCα and PKCβ are both activated by 1α,25-(OH) 2 D 3 binding to ERp57 in isolated intestinal epithelial cells from chicks, with subsequent stimulation of phosphate uptake [43,46]. ERp57 is also important for the steroid hormone-stimulated calcium uptake in mammalian intestinal cells [47]. ERp57 modulates the vitamin D-mediated anti-cancer activity, specifically in breast cancer; ERp57 knockdown selectively increases the sensitivity of MCF-7 cells to agents related to vitamin D [48].…”

Calcium and vitamin D in obesity

“…1,25(OH) 2 D 3 produces its biological effects via both receptor-mediated regulation of nuclear events and rapid actions independent of genomic pathways (21,55,57) . The genomic responses utilise signal-transduction pathways linked to the nuclear/cytosolic VDR, while the rapid responses utilise signal-transduction pathways linked to the membrane VDR localised in the plasma and, possibly, endoplasmic reticulum membranes (58) as well as to the plasma membrane-associated rapid response steroid hormone-binding protein (59,60) . Nuclear and membrane VDR have been demonstrated in many (over forty) tissues, including adipose tissue (21,53,61) .…”

Membrane depolarization regulates intracellular RANKL transport in non-excitable osteoblasts

“…To investigate the non-genomic action of VD 3 signaling on RANKLiT, we focused on the 1,25D 3 -MARRS receptor (1,25D 3 -MARRSR; also known as ERp57/ PDIA3). The 1,25D 3 -MARRSR is a recently discovered membrane-bound vitamin D 3 receptor [32,33] that is mainly localized on the cell membrane. The VDR localizes not only in the nucleus but also on the cell membrane [32].…”