STIMULATION BY 1-ALPHA,25(OH)(2)-VITAMIN-D-3 OF WHOLE-CELL CHLORIDE CURRENTS IN OSTEOBLASTIC ROS-17 2.8 CELLS - A STRUCTURE-FUNCTION STUDY/

1 alpha,25-Dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) can generate bi ological responses via genomic and nongenomic mechanisms, This article reports for the first time the effects of 1 alpha,25(OH)(2)D-3 and st ructurally related analogs on whole cell chloride currents in osteobla stic cells. 1 alpha,25(OH)(2)D-3 promoted the rapid enhancement of out wardly rectifying Cl- currents in 93% of the osteoblasts in a concentr ation-dependent manner, with a maximal increase of about 4-fold betwee n 0.5 and 5 nM. This effect of 1 alpha,25(OH)(2)D-3 was blocked by 1 n M stereoisomer 1 beta,25(OH)(2)D-3. when added to the bath before 1 al pha,25(OH)(2)D-3. On the other hand, 1 nM of the 6-s-cis locked analog 1 alpha,25(OH)(2)-lumisterol(3) significantly increased by about 2.2- fold outward Cl- currents in the ROS 17/2.8 cells, whereas the increas e promoted by same concentration of the 6-s-trans locked analog 1 alph a,25(OH)(2)-tachysterol (0.8-fold) was significantly lower, suggesting that the 6-s-cis locked or steroid-like form was preferred over the e xtended 6-s-trans conformer to promote these rapid effects of the horm one, We conclude that the agonist effects of 1 alpha,25(OH)(2)D-3 in o steoblasts at the cellular membrane level seem to be determined by som e structural, features of the molecule which may be crucial for its in teraction with a putative membrane receptor in the cell surface.