Update on biological actions of 1α,25(OH) 2-vitamin D 3 (rapid effects) and 24R,25(OH) 2-vitamin D 3

Abstract

All biologic responses to vitamin D are now known to arise as a consequence of the metabolism of this seco-steroid into its two principal biologically active metabolites 1α,25(OH) 2-vitamin D 3 (1 α,25(OH) 2D 3) and 24R,25(OH) 2-vitamin D 3 (24R,25(OH) 2D 3). 1α,25(OH) 2D 3 is the dominant metabolite and produces a wide array of biological responses via interacting both with the classical vitamin D nuclear receptor (VDR nuc) that regulates gene transcription in over 30 target organs and with a putative cell membrane receptor (VDR mem1,25) that mediates rapid (within seconds to minutes) biological responses. Ligand occupancy of VDR mem1,25 is linked to signal transduction systems that can mediate the opening of Ca 2+ and chloride voltage gated channels as well as activation of MAP-kinase. MAP-kinase activation in some cells containing VDR mem1,25+VDR nuc then results in “cross-talk” from VDR mem1,25 to VDR nuc which modulates transactivation of 1α,25(OH) 2D 3 responsive gene promoters. The 24R,25(OH) 2D 3 metabolite has been shown to be an essential hormone for the process of bone fracture healing. The activity of the enzyme responsible for the production of 24R,25(OH) 2D 3, the renal 25(OH)D-24-hydroxylase, becomes elevated within 4–11 days after imposition of a tibial fracture, thereby increasing the blood concentrations of 24R,25(OH) 2D 3 by threefold. The 24R,25(OH) 2D 3 likely initiates its biological responses via binding to the ligand binding domain of a second cell membrane receptor, the VDR mem24,25, which is stereospecific for 24R,25(OH) 2D 3 in comparison with 24S,25(OH) 2D 3 and 1α,25(OH) 2D 3. This report summarizes the status of several current research frontiers in this arena of the vitamin D endocrine system.