Minireview: vitamin D receptor: new assignments for an already busy receptor

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, 1alpha,25(OH)2-vitamin D3 [1alpha,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 1alpha,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 1alpha,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 beta-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 1alpha,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 1alpha,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 1alpha,25(OH)2D3 acting through the VDR in different cellular locations can selectively mediate both genomic and RR.