Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Sci. Signal., 16 June 2009
Vol. 2, Issue 75, p. re4
[DOI: 10.1126/scisignal.275re4]
REVIEWS
The Vitamin D Sterol–Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling
Mathew T. Mizwicki1* and
Anthony W. Norman1,2
1 Department of Biochemistry, University of California, Riverside, CA 92521, USA. 2 Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
Abstract:
Steroid hormones serve as chemical messengers in a wide number of species and target tissues by transmitting signals that result in both genomic and nongenomic responses. Genomic responses are mediated by the formation of a ligand-receptor complex with its cognate steroid hormone nuclear receptor (NR). Nongenomic responses can be mediated at the plasma membrane by a membrane-localized NR. The focus of this Review is on the structural attributes and molecular mechanisms underlying vitamin D sterol (VDS)–vitamin D receptor (VDR) selective and stereospecific regulation of nongenomic and genomic signaling. The VDS-VDR conformational ensemble model describes how VDSs can selectively initiate or block either nongenomic or genomic biological responses by interacting with two VDR ligand-binding pockets, one kinetically favored by 1,25(OH)2D3 (1,25D) and the other thermodynamically favored. We describe the variables that affect the three major elements of the model: the conformational flexibility of the unliganded (apo) protein, the flexibility of the VDS, and the physicochemical selectivity of the VDR genomic pocket (VDR-GP) and alternative pocket (VDR-AP). We also discuss how these three factors collectively provide a rational explanation for the complexities of VDS regulation of cell biology and highlight the current limitations of the model.
Citation: M. T. Mizwicki, A. W. Norman, The Vitamin D Sterol–Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling. Sci. Signal.2, re4 (2009).
Elizabeth M. Adler (28 September 2010) Sci. Signal.3 (141), ec295.
[DOI: 10.1126/scisignal.3141ec295] |Abstract »
EDITORS' CHOICE
Wei Wong (11 May 2010) Sci. Signal.3 (121), ec139.
[DOI: 10.1126/scisignal.3121ec139] |Abstract »
EDITORS' CHOICE
Elizabeth M. Adler (3 November 2009) Sci. Signal.2 (95), ec356.
[DOI: 10.1126/scisignal.295ec356] |Abstract »
MEETING REPORTS
Ronald N. Margolis, David D. Moore, Timothy M. Willson, and R. Kip Guy (4 August 2009) Sci. Signal.2 (82), mr5.
[DOI: 10.1126/scisignal.282mr5] |Abstract »|Full Text »|PDF »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Nuclear Receptors and Their Selective Pharmacologic Modulators.
T. P. Burris, L. A. Solt, Y. Wang, C. Crumbley, S. Banerjee, K. Griffett, T. Lundasen, T. Hughes, and D. J. Kojetin (2013)
Pharmacol. Rev.
65, 710-778
|Abstract »|Full Text »|PDF »
Relevance of vitamin D in reproduction.
J. Luk, S. Torrealday, G. Neal Perry, and L. Pal (2012)
Hum. Reprod.
27, 3015-3027
|Abstract »|Full Text »|PDF »
Intestinal Cell Phosphate Uptake and the Targeted Knockout of the 1,25D3-MARRS Receptor/PDIA3/ERp57.
I. Nemere, N. Garcia-Garbi, G. J. Hammerling, and Q. Winger (2012)
Endocrinology
153, 1609-1615
|Abstract »|Full Text »|PDF »
Optimal Serum Calcidiol Concentration for Cancer Prevention.
Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation.
S. E. Tague, G. L. Clarke, M. K. Winter, K. E. McCarson, D. E. Wright, and P. G. Smith (2011)
J. Neurosci.
31, 13728-13738
|Abstract »|Full Text »|PDF »
Vitamin D Receptor (VDR) Regulation of Voltage-Gated Chloride Channels by Ligands Preferring a VDR-Alternative Pocket (VDR-AP).
D. Menegaz, M. T. Mizwicki, A. Barrientos-Duran, N. Chen, H. L. Henry, and A. W. Norman (2011)
Mol. Endocrinol.
25, 1289-1300
|Abstract »|Full Text »|PDF »
Requirements for Vitamin D Across the Life Span.
W. B. Grant and B. J. Boucher (2011)
Biol Res Nurs
13, 120-133
|Abstract »|PDF »
Intestinal Cell Calcium Uptake and the Targeted Knockout of the 1,25D3-MARRS (Membrane-associated, Rapid Response Steroid-binding) Receptor/PDIA3/Erp57.
I. Nemere, N. Garbi, G. J. Hammerling, and R. C. Khanal (2010)
J. Biol. Chem.
285, 31859-31866
|Abstract »|Full Text »|PDF »
Plasma 25-Hydroxyvitamin D and Regulation of the Renin-Angiotensin System in Humans.
J. P. Forman, J. S. Williams, and N. D. L. Fisher (2010)
Hypertension
55, 1283-1288
|Abstract »|Full Text »|PDF »
On the Mechanism Underlying (23S)-25-Dehydro-1{alpha}(OH)-vitamin D3-26,23-lactone Antagonism of hVDRwt Gene Activation and Its Switch to a Superagonist.
M. T. Mizwicki, C. M. Bula, P. Mahinthichaichan, H. L. Henry, S. Ishizuka, and A. W. Norman (2009)
J. Biol. Chem.
284, 36292-36301
|Abstract »|Full Text »|PDF »
,25(OH)2D3 (1,25D) and the other thermodynamically favored. We describe the variables that affect the three major elements of the model: the conformational flexibility of the unliganded (apo) protein, the flexibility of the VDS, and the physicochemical selectivity of the VDR genomic pocket (VDR-GP) and alternative pocket (VDR-AP). We also discuss how these three factors collectively provide a rational explanation for the complexities of VDS regulation of cell biology and highlight the current limitations of the model.
