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Vitamin D Receptor: New Assignments for an Already Busy Receptor

Department of Biochemistry and Biomedical Sciences, University of California, Riverside, California 92521

Address all correspondence and requests for reprints to: Dr. Anthony W. Norman, Department of Biochemistry, University of California, Riverside, California 92506. E-mail: Anthony.norman{at}ucr.edu.

	Abstract

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With its discovery in 1920, the molecule vitamin D achieved prominence as a nutritionally essential vitamin important for calcium homeostasis, particularly in the intestine and bone. Then in 1932, the elucidation of vitamin D’s chemical structure revealed that this vitamin was in fact a steroid. But it was not until the late 1960s that it was appreciated that the steroid vitamin D was a precursor of a new steroid hormone, 1,25(OH)₂-vitamin D₃ [1,25(OH)₂D₃], that is produced by the kidney acting as an endocrine gland. The discovery in 1969 of the nuclear vitamin D receptor (VDR) for 1,25(OH)₂D₃ initiated a two-decade-long proliferation of reports that collectively described the broad sphere of influence of the vitamin D endocrine system that is defined by the presence of the VDR in over 30 tissue/organs of man. The new genomic frontiers defined by the cellular presence of the VDR include the immune system’s B and T lymphocytes, hair follicle, muscle, adipose tissue, bone marrow, and cancer cells. Unexpectedly in the mid 1980s, a new world of 1,25(OH)₂D₃-mediated rapid responses (RR) was discovered. These were responses that occurred too rapidly (minutes to an hour) to be explained as the simple consequence of the nuclear VDR regulating gene transcription. Some RR examples include the rapid intestinal absorption of calcium (transcaltachia), secretion of insulin by pancreatic ß-cells, opening of voltage-gated Ca²⁺ and Cl^– channels in osteoblasts, and the rapid migration of endothelial cells. The question then arose as to whether there was a second receptor, apart from the nuclear VDR, which responded to the presence of 1,25(OH)₂D₃ to generate RR? After some false starts, it now appears that the classic VDR, long known to reside in the cell nucleus, in some cells is also associated with caveolae present in the plasma membrane. Furthermore, the chemical properties of the conformationally flexible 1,25(OH)₂D₃ allow it to generate different shaped ligands for the VDR that are selective either for genomic or for RR. This minireview summarizes a proposed conformational ensemble model of the VDR that provides insight into how different ligand shapes of 1,25(OH)₂D₃ acting through the VDR in different cellular locations can selectively mediate both genomic and RR.

STEROID HORMONES ARE able to serve as chemical messengers in a wide number of species and target tissues to transmit signals that result in both genomic and rapid responses (RR). The ability of steroid hormones, including 1,25(OH)₂-vitamin D₃ [1,25(OH)₂D₃], to generate biological responses is defined by the presence of their cognate receptors in selected target organs and tissues. Although it is clear that steroid hormones’ genomic responses are mediated by formation of a ligand-receptor complex with the cognate receptor of the superfamily of steroid hormone nuclear receptors (1), new evidence indicates for all steroid hormones that their RR are mediated by a variety of receptor types located near or associated with the plasma membrane or its caveolae components (2). The time required for onset of the RR is system dependent and can vary from seconds (e.g. opening ion channels) to 10–60 min (e.g. activation of phosphatidylinositol-3'-kinase or endothelial nitric oxide synthase). This contrasts with genomic responses, which generally take a few hours to days to become fully manifest and which can be blocked by inhibitors of transcription and translation.

1,25(OH)₂D₃, which is a conformationally flexible molecule, is known to stimulate a wide array of RR; some examples include the rapid intestinal absorption of Ca²⁺ (transcaltachia), secretion of insulin by pancreatic ß-cells, opening of voltage-gated Ca²⁺ and Cl^– channels in osteoblasts, and the rapid migration of endothelial cells (2, 3). Intriguingly, one shape of 1,25(OH)₂D₃ is used for genomic responses, and a different shape serves as an agonist of RR (4). The question then arose as to whether there was a second receptor, apart from the nuclear vitamin D receptor (VDR), which responded to the presence of a different shaped 1,25(OH)₂D₃ to generate RR? The purpose of this minireview is to evaluate the VDR with respect to its involvement in genomic responses and then to review evidence that the same VDR is also involved in mediation of RR.

It has been generally assumed for receptor-ligand interactions that the ligand is frozen in a single conformation dictated by both the structural constraints of the ligand and the three-dimensional architecture of the peptide chains that create the ligand binding domain (LBD) of the receptor(s). The ligands for the thyroid receptor (T₃), the retinoic acid receptor (retinoic acid), and the VDR are all conformationally flexible, and the x-ray crystallographic structure for each receptor indicates that only one definitive conformer was present in each LBD (2). This clearly demonstrates that steroid receptors can capture one ligand conformation from a very large population of flexible conformers.

Figure 1, A–C, summarizes the three structural features of 1,25(OH)₂D₃ that empower its exceptional flexibility and as a consequence define its ability to generate a multitude of different agonist shapes for the VDR and other putative receptors. Figure 1, E and F, illustrates the shape of the optimal ligand for VDR-mediated nuclear responses and for RR as well for a second protein of the vitamin D endocrine system, the plasma transport protein, or vitamin D binding protein (DBP), the x-ray structure of which has also been elucidated. It is clear that the VDR, DBP, and the receptor for 1,25(OH)₂D₃-mediated RR each have a characteristic ligand shape. As a consequence, it may be possible to chemically synthesize analogs of 1,25(OH)₂D₃ that are selective for genomic responses or RR.

View larger version (32K): [in this window] [in a new window]   FIG. 1. The complex world of structural aspects of 1,25(OH)2D3. A, Structure of 1,25(OH)2D3 and identification of the three structural aspects of vitamin D seco-steroids that contribute to the conformational flexibility of this class of molecules. The side chain, because of the five single carbon-carbon bonds (indicated by the five arrows), is very conformationally flexible. B, The cyclohexane-like A-ring is free to interchange rapidly, millions of times per second, between a pair of chair-chair conformers effectively equilibrating the key 1- and 3ß-hydroxyls between equatorial and axial orientations. Thus, when the 1-hydroxyl is axial, the 3ß-hydroxyl is equatorial, and vice versa. C, Rotational freedom about the 6–7 carbon-carbon single bond of the seco B-ring allows conformations ranging from the open and extended 6-s-trans conformation, used by the VDR for genomic responses, to the more steroid-like 6-s-cis form of the hormone believed to be used by the VDR for RR. The inset box provides the structure of the 6-s-cis locked JN, which is of equivalent potency to 1,25(OH)2D3 in mediating RR. D, Structure of JN, which is chemically locked in a permanent 6-s-cis shape and has potency equivalent to 1,25(OH)2D3 in mediating RR (see Table 2 and text). E and F, Space-filling (E) and stick (F) representations illustrating the clear differences in the shapes of the three optimal ligands for the nuclear localized VDR (left), the membrane-caveolae localized VDR (middle), and the plasma DBP (right). The nuclear VDR ligand [1,25(OH)2D3] is in a bowl-shaped twisted 6-s-trans conformation with the A-ring and side chain both 30° above the plane of the C/D-ring. The relatively planar 6-s-cis locked JN is a ligand for the membrane VDR. The DBP ligand [25(OH)D3] is in a twisted 6-s-trans orientation with the A-ring C10–C19 exocyclic alkene 30° below the plane of the C/D-ring and the side chain almost 90° below the C/D-ring plane. Each of the illustrated molecules has its 25-OH pointed to the right and the A-ring to the left. The shapes of the nuclear VDR (29 ) and DBP (34 ) ligands were learned from the separate determination of the x-ray structure of each protein, whereas the shape of the membrane VDR ligand was determined by computer modeling.

View this table: [in this window] [in a new window]   TABLE 1. 1,25(OH)2D3 structure-function analysis of rapid responses

The current view of this laboratory is that transcaltachia and many other 1,25(OH)₂D₃-mediated RR are initiated by a membrane-localized receptor that binds 1,25(OH)₂D₃ (7). Recent work in our laboratory has focused on isolation of the intestinal, kidney, or lung membrane fractions that contains caveolae. Caveolae are flask-shaped membrane invaginations that are enriched in the sphingolipids and cholesterol commonly found in both caveolae and/or lipid rafts (8). The caveolae-enriched membrane fraction is isolated from chick or rat intestine, kidney, or lung tissue by Percoll buoyant density centrifugation. We find under both in vivo and in vitro conditions that there is a saturable binding of high-specific-activity tritiated 1,25(OH)₂D₃ in the caveolae-enriched membrane fraction. This binding activity is steroid specific for 1-hydroxylated analogs and for 1,25(OH)₂D₃ has a distribution constant (K_d) equal to 1.4 nM, which is identical to the nuclear VDR K_d for 1,25(OH)₂D₃ (7). Furthermore, by confocal microscopy, we showed that green fluorescent labeled antibodies to the classical nuclear VDR colocalized with red fluorescent labeled antibodies to caveolin-1 in caveolae present in the plasma membrane of ROS-17.2,8 osteoblast cells (7).

Both the author’s laboratory (7) and that of Lieberherr and Garabedian (9) have separately concluded that the RR effects of 1,25(OH)₂D₃ require a functional VDR. We found that in VDR-knockout mice (VDR-KO), 1,25(OH)₂D₃ was unable to stimulate the opening of voltage-gated Ca²⁺ and Cl^– channels (7, 10) and that there was a loss of 70–90% in the ability of [³H]1,25(OH)₂D₃ to bind to isolated caveolae membrane fractions obtained from VDR-KO intestine, lung, and kidney tissues (7). The residual binding of [³H]1,25(OH)₂D₃ present in VDR-KO tissues was found to be attributable to the presence of a truncated form of the VDR present in the strain of VDR-KO mice employed in our studies (10). Lieberherr and Garabedian found that in fibroblasts obtained from a patient with the genetic disease of vitamin D-resistant rickets, a single point mutation in the VDR (Lys45Glu) resulted in the loss of 1,25(OH)₂D₃ RR (9).

Thus, this laboratory’s view is that the classical VDR normally associated with the cell nucleus and gene transcription can also be resident near to or associated with caveolae present in the plasma membrane. It has also been reported that the estrogen receptor and androgen receptor are associated with caveolae of (2).

It is apparent that for the VDR there is a perceived problem, because a 6-s-trans shape of 1,25(OH)₂D₃ is obligatory for genomic responses, whereas a 6-s-cis shape is required for RR. This then poses the conundrum as to how a receptor with one LBD can bind ligands of quite different shapes to generate two quite different biological outcomes? Yet, the x-ray structure of the VDR revealed only one LBD, that which bound the 6-s-trans shape (see Fig. 1E).

One possible solution to the conundrum was obtained from molecular modeling of the VDR (11). Using the atomic coordinates of the x-ray structures of the VDR and computer modeling (see Fig. 2A), we have been able to identify the presence of a putative alternative LBD in the VDR that can accommodate via computer docking either the appropriate natural hormone or analogs that are known to be agonists only for RR (see Fig. 2A) (11). Figure 2A illustrates for the VDR the classical nuclear ligand pocket (red) and the proposed alternative ligand pocket (blue). Each ligand pocket is envisioned to have separate portals. The entrance to the nuclear pocket is dependent upon helix 12 being in an open configuration so that the hormone/ligand can enter into the LBD pocket and gain access to integral H-bonding residues thereby fully occupying the genomic pocket. Next, helix 12 moves to reclose the portal. The surprising discovery is that the alternative pocket and the genomic pocket overlap. Each of these pockets uses the same hydrogen-bonding partners of the VDR to stabilize the A-rings of the bound ligands; however, the remaining interactions of the C/D-ring and side chain of the ligand in the genomic or alternative pockets are entirely unique. Although the K_d of the genomic pocket is known from equilibrium binding experiments with [³H]1,25(OH)₂D₃ to be approximately 1.4 nM (7), it is possible that the alternative pocket may have a different K_d. In general, the effective doses of 1,25(OH)₂D₃ required to initiate RR have been found to be in the range of 1–10 nM.

View larger version (31K): [in this window] [in a new window]   FIG. 2. Structural details of the VDR that support a conformational ensemble model. A, Details of the LBD in the ribbon structures of the nuclear VDR: X, differences in the volume and shape of the interior of the VDR LBD (light blue) with the structure of the 1,25(OH)2D3 shown in wire-frame as revealed by x-ray crystallography of the protein plus ligand; Y, illustration for the VDR of the location of the classic genomic pocket (red: 1,25(OH)2-vitamin D3, a genomic agonist) and a putative alternative pocket (blue: 1,25(OH)2-lumisterol, a nongenomic 6-s-cis locked agonist) as studied by molecular modeling. Helix 12 (H12) is colored brown and shown in the closed conformation. The proposed alternative pocket portal lies between the C terminus of H1 and N terminus of H3. An intriguing aspect of the two ligand binding pocket model is that the A-ring of ligands bound to either the genomic pocket or alternative pocket use the same hydrogen-bonding partners (R274, S237, and S278) to stabilize their 1- and 3ß-hydroxyls. The conserved helix 5 R274 is shown in Corey Pauling (CPK) space filling model; thus, the VDR cannot bind two ligands simultaneously. Details of the modeling are provided in Refs. 2 and 11 . B, Schematic model of a receptor ensemble model to describe how a classic steroid receptor could accommodate differently shaped ligands that result in the initiation of either RR or genomic responses. The ensemble model proposes that there is a population of three different unoccupied receptor species (a, b, and c) illustrated by different positions of helix 12 (H12; colored brown) that are in rapid equilibrium with one another; each receptor conformer species may preferentially bind differently shaped ligands (35 ). In this example, transient occupancy of the alternative pocket by a ligand could/would lead to initiation of RR, whereas occupancy of the classical pocket by a ligand would lead to activation of genomic responses; both of these pockets are illustrated for the VDR in A. The alternative pocket is accessible in all three H12 conformers (a, b, and c). Occupancy of this alternative pocket is favored before achieving the steady-state equilibrium only for the receptor’s natural ligands given the increased accessibility coupled with weaker van der Waals interactions compared with genomic pocket occupancy. Receptor conformer (c) is the only conformer able to accept ligands that can bind to the classical ligand binding site leading to genomic responses because in conformers a and b, H12 blocks ligand accessibility to the conserved H5 Arg residue located at the innermost part of the classic ligand binding pocket. An interesting consequence of the receptor ensemble concept may be that association of the nuclear receptor with caveolae or cell membranes may change the ligand binding preferences to favor the alternative pocket. Ligand occupancy of this genomic pocket is favored under steady-state conditions because of the increase in thermodynamic stability derived from hydrophobic interactions. It is possible that drug analogs, especially those related to the natural hormone(s), may have differential fractional occupancies of the two pockets, thus affecting the efficiency of the cellular signaling pathways mediated by either pocket.

Figure 3 is a summary figure that integrates the signal transduction pathways that are used by the nuclear VDR and the membrane-associated VDR using 1,25(OH)₂D₃ as a conformationally flexible agonist. This model emphasizes the complexity of overlapping and interconnecting signal transduction pathways. Although there is a solid and secure foundation describing 1,25(OH)₂D₃-mediated genomic actions, 1,25(OH)₂D₃-mediated RR are still in their developmental phase. One extraordinary challenge will be to identify and fully biochemically characterize the membrane-associated VDR. An equally daunting task will be to define in the various cell systems that display RR the identification of the specific signal transduction pathways that contribute to mediation of a specific rapid biological response. An additional important question is whether the membrane VDR can communicate with the nucleus of the cell to modulate gene transcription. In data not shown, but summarized in Fig. 3, there are at least five different systems where molecular biological evidence has been obtained for the process of cross-talk from 1,25(OH)₂D₃ RR to changes in gene expression in the cell nucleus. In these studies, 6-s-cis locked analogs have been shown to modulate genomic responses at relatively early time intervals (2–4 h). Without a doubt, it is clear that the already busy genomic oriented VDR has new assignments in the realm of 1,25(OH)₂D₃-mediated RR.

View larger version (39K): [in this window] [in a new window]   FIG. 3. Schematic model describing how the conformationally flexible 1,25(OH)2D3 can interact with the VDR localized in the cell nucleus to generate genomic responses or in caveolae of the plasma membrane to generate RR. Binding of 1,25(OH)2D3 to the caveolae-associated VDR may result in the activation of one or more second messenger systems, including phospholipase C (PKC), protein kinase C, G protein-coupled receptors, or phosphatidylinositol-3'-kinase (PI3K). There are a number of possible outcomes including opening of the voltage-gated calcium or chloride channels or generation of the indicated second messengers. Some of these second messengers, particularly RAF/MAPK, may engage in cross-talk with the nucleus to modulate gene expression. PtdIns-3,4,5-P3, Phosphatidylinositol-3,4,5-trisphosphate.

	Acknowledgments

 
I thank Dr. Matt Mizwicki for his extensive computer modeling of the VDR ligand-binding domain and also Professor Helen Henry for a critical reading of this manuscript.

Received July 8, 2006. Accepted August 7, 2006.

	Footnotes

 
Work from the author’s laboratory has been supported by National Institutes of Health Grant DK-009012 for the past 39 yr.

Disclosure summary: The author has nothing to declare.

First Published Online August 31, 2006

Abbreviations: 1,25(OH)₂D₃, 1,25(OH)₂-vitamin D₃; DBP, vitamin D binding protein; JN, 1,25(OH)₂-lumisterol; KO, knockout; LBD, ligand binding domain; RR, rapid response(s); VDR, vitamin D receptor.

Received July 14, 2006.

Accepted for publication August 11, 2006.

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