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Submitted on July 14, 2006
Accepted on August 11, 2006
Department of Biochemistry & Biomedical Sciences, University of California, Riverside, CA 92521
* To whom correspondence should be addressed. E-mail: Anthony.norman{at}ucr.edu.
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 1960's 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 2 decade-long proliferation of reports which 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 1980's, a new world of 1,25(OH)2D3 mediated rapid responses (RR) was discovered. These were responses that occurred too rapidly (minutes to 1 h) 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 
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 'rapid responses? 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 Mini Review summarizes a proposed conformational ensemble model of the VDR that provides insight how different ligand shapes of 1,25(OH)2D3 acting through the VDR in different cellular locations can selectively mediate both genomic and rapid responses.
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