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Sci. Signal., 16 June 2009
Vol. 2, Issue 75, p. re4
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.
Gloss: Vitamin D3 was discovered 90 years ago as a dietary agent that prevented the bone disease rickets. Subsequently, it was learned that vitamin D3 itself is biologically inert and only generates biological effects through participation in a two-step metabolic process that generates the steroid hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 or 1,25D]. Binding of 1,25D to its vitamin D receptor (VDR) results in various biological responses. The VDR is present in 37 tissues of the body, where it has been shown to function in five physiological systems in addition to the intestine and bone (where it plays a critical role in calcium homeostasis). In these target tissues, the VDR functions both in the cell nucleus (as a transcriptional factor to regulate genes containing a vitamin D response element) and at or near the plasma membrane (as a mediator of rapid signal transduction pathways). Here, we discuss the evidence supporting a vitamin D sterol–VDR conformational ensemble model, whereby different shapes of the 1,25D hormone bind to two different ligand-binding pockets of a flexible VDR to selectively modulate either genomic or rapid responses.