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 principal mediator of a wide array of biological responses through the far reaching network of the vitamin D endocrine system (VDE). The steroid hormone 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 binding protein (DBP). Also 1 alpha,25(OH)(2)D-3 is known to initiate biological responses through a nuclear receptor, the nVDR (50 kDa) which regulates selected gene transcription and, in addition in some target tissues, through a second receptor located in the cell membrane, the mVDR (approximate to 60 kDa), which is linked to protein kinase C and/or voltage-gated Ca2+ channels so as to generate biological responses very rapidly. 1 alpha,25(OH)(2)D-3 as a ligand is unusually conformationally 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 which undergoes chair-chair conformational interconversion characteristic of cyclohexane rings. This paper reviews the evidence that different shapes 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 effectively 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 alpha,25(OH)(2)D-3 in regulating gene transcription.