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1,25‐Dihydroxyvitamin D 3 analog structure‐function assessment of the rapid stimulation of intestinal calcium absorption (transcaltachia)
Author(s) -
Zhou LiXin,
Nemere Ilka,
Norman Anthony W.
Publication year - 1992
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650070414
Subject(s) - stimulation , receptor , calcitriol receptor , calcium , biophysics , vitamin d and neurology , chemistry , biology , biochemistry , medicine , endocrinology
The possibility is now emerging that 1,25‐dihydroxyvitamin D 3 [1,25‐(OH) 2 D 3 ] can mediate biologic responses via both genomic and nongenomic pathways. To understand the molecular basis of the nongenomic response of transcaltachia, defined as the 1,25‐(OH) 2 D 3 ‐mediated rapid (2–10 minutes) stimulation of calcium transport from the brush border to the basal lateral membrane of the epithelial cell in vitamin D‐replete chick intestine, and to address the issue of whether the same receptor for the secosteroid serves as the signal transducer for both genomic and nongenomic pathways, we carried out structure‐function studies using seven analogs of 1,25‐(OH) 2 D 3 with different affinities for the classic nuclear 1,25‐(OH) 2 D 3 receptor as measured by determination in a steroid competition assay of the relative competitive index (RCI). The RCI of 1,25‐(OH) 2 D 3 is by definition 100. 1,25‐(OH) 2 D 3 initiates transcaltachia within 2–10 minutes of vascular perfusion and yields a biphase response curve. Dose‐dependent stimulations of Ca 2+ transport by the seven analogs indicates that different structural features are essential for initiating the transcaltachic response as contrasted with binding to the classic nuclear receptor. Vascular perfusion with analogs AT (25‐OH‐16‐ene‐23‐yne‐D 3 ) and Y (25‐OH‐23‐yne‐D 3 ), which are known to activate Ca 2+ channels but bind very poorly to the classic receptor (RCI < 0.5), are efficient in stimulating Ca 2+ transport. By comparison, compounds BT [1α,24 S ‐(OH) 2 ‐22‐en‐26,27‐dehydrovitamin D 3 ] and V (1,25‐(OH) 2 ‐16‐ene‐23‐yne‐D 3 ], which bind very well to the classic nuclear receptor (RCI 75–111) but do not activate Ca 2+ channels, are inefficient in stimulating Ca 2+ transport. These results indicate that the membrane components that respond to the analogs of 1,25‐(OH) 2 D, with activation of Ca 2+ channels have a different ligand specificity than the classic nuclear receptor.