Chapter 35 - 1α,25(OH)2 Vitamin D3Vitamin D Nuclear Receptor (VDR) and Plasma Vitamin D-Binding Protein (DBP) Structures and Ligand Shape Preferences for Genomic and Rapid Biological Responses

Abstract

Studies have shown that vitamin D is metabolized to a biologically active form, 1α,25(OH)2 vitamin D3 [1α,25(OH)2 D3] that functions as a steroid hormone. 1α,25(OH)2 D3 can generate at least three functionally different shapes that effectively accommodate the ligand-binding domain requirements of the vitamin D nuclear receptor (VDR) nuc, the caveolae-associated VDR mem, and DBP proteins. The key organ in the vitamin D endocrine system is the kidney where the renal proximal tubule is responsible for producing the hormonal 1α,25(OH)2 D3 that circulates in the blood in accordance with strict physiological signals. This chapter illustrates a figure that integrates the signal transduction pathways that are used by the nuclear VDR and the membrane-associated VDR with 1α,25(OH)2 D3 functioning as a conformationally flexible agonist. This model emphasizes the complexity of overlapping and interconnecting signal transduction pathways. Furthermore, it determines whether the membrane VDR can communicate with the nucleus of the cell to modulate gene transcription. It also summarizes that at least five different systems (pancreas β-cell, adipocytes, vascular smooth muscle, intestine, and osteoblasts) where molecular biological evidence has been obtained for the process of crosstalk from 1α,25(OH)2D3 rapid responses to changes in gene expression in the cell nucleus. One important challenge is to identify and fully biochemically characterize the membrane-associated VDR.