title: Rapid and genomic biological responses are mediated by different shapes of the agonist steroid hormone, 1alpha,25(OH)2vitamin D3.
abstract: The hormone 1alpha,25(OH)2vitamin D3 (1,25-D) produces biological responses via both genomic and rapid mechanisms. The genomic responses are linked to a nuclear receptor, while the rapid responses are believed to utilize other signal transduction pathways that are likely linked to a putative cell membrane receptor for 1,25-D. The natural seco-steroid, 1,25-D, is capable of facile rotation about its 6,7 single carbon bond to permit generation of a continuum of potential ligand shapes extending from the 6-s-cis (6C) to the 6-s-trans (6T). To identify the shape of the conformer(s) that can serve as agonists for the genomic and rapid responses, we synthesized two families of analogs that were locked in either the 6T or 6C conformation. We found that 6T-locked analogs were inactive or significantly less active than 1,25-D in both rapid responses (transcaltachia or the rapid stimulation of intestinal Ca2+ absorption in perfused chick intestine, stimulation of whole cell chloride currents in osteoblastic ROS 17/2.8 cells, and stimulation of phosphorylation of mitogen-activated protein kinase in promyelocytic NB4 leukemic cells) and in genomic responses (induction of osteocalcin in human MG-63 osteoblastic cells). For genomic responses, the 6C-locked analogs bound poorly to the nuclear receptor and were much less potent than 1,25-D. In contrast, the 6C-locked analogs were potent agonists of the three rapid responses studied and had activities equivalent to 1,25-D. These results demonstrate that the signal transduction pathways that support rapid and genomic responses can discriminate between different shapes of the conformationally flexible 1,25-D.
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology