DIFFERING SHAPES OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 FUNCTION AS LIGANDS FOR THE D-BINDING PROTEIN, NUCLEAR RECEPTOR AND MEMBRANE-RECEPTOR -A STATUS-REPORT

1 alpha,25-Dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3] is the principa l mediator of a wide array of biological responses through the far rea ching network of the vitamin D endocrine system (VDE). The steroid hor mone 1 alpha,25(OH)(2)D-3 is delivered to the various target organs of the VDE via a specific plasma transport protein, the vitamin D bindin g protein (DBP). Also 1 alpha,25(OH)(2)D-3 is known to initiate biolog ical responses through a nuclear receptor, the nVDR (50 kDa) which reg ulates selected gene transcription and, in addition in some target tis sues, through a second receptor located in the cell membrane, the mVDR (approximate to 60 kDa), which is linked to protein kinase C and/or v oltage-gated Ca2+ channels so as to generate biological responses very rapidly. 1 alpha,25(OH)(2)D-3 as a ligand is unusually conformational ly flexible due to the eight carbon side chain, the seco B-ring which permits rotation about the 6-7 single carbon bond, and the A-ring whic h undergoes chair-chair conformational interconversion characteristic of cyclohexane rings. This paper reviews the evidence that different s hapes of the 1 alpha,25(OH)(2)D-3 satisfy the optimal requirements of the ligand binding domains of the DBP, nVDR and mVDR. The presence of a relatively rigid side chain (imposed by the presence of an aromatic ring) enhances Ligand interaction 23 fold with the DBP, but diminishes ligand affinity for the nVDR by 100 fold. The mVDR responds effective ly to analogs of 1 alpha,25(OH)(2)D-3 which are 6-s-cis locked [e.g. 1 alpha,25(OH)(2)-previtamin D-3 or 1 alpha,25(OH)(2)-provitamin D-3], but these same analogs have only 1-2% of the activity of 1 alpha,25(OH )(2)D-3 in regulating gene transcription. Finally the 6-s-trans analog , 1 alpha,25(OH)(2)-tachysterol(3), had <0.1% of the activity of 1 alp ha,25(OH)(2)D-3 in regulating gene transcription.