Cation-dependent vitamin D activation of human renal cortical guanylate cyclase

The objective of this investigation was to determine whether physiological levels of vitamin D and its metabolites have part of their mechanisms of action through stimulation of guanylate cyclase (EC 4.6.1.2). These sterols enhanced both soluble and particulate guanylate cyclase activities as well as cGMP levels two- to threefold in human and rat tissues. At a concentration of 1 nM, 1,25(OH)2D3 greater than 25(OH)D3 greater than vitamin D3 greater than 24,25(OH)2D3 = 25,26(OH)2D3 = vitamin D2. Dose-response curves revealed that maximal stimulation of guanylate cyclase by these sterols was at 1 nM and that there was no augmented guanylate cyclase activity at 0.01 nM. The precursors of vitamin D, cholesterol and 7-dehydrocholesterol, had no effect on guanylate cyclase activity. The activation of guanylate cyclase activity by the vitamin D sterols required the presence of manganese ion. Calcium was not as efficient as manganese in optimizing basal or hormone-stimulated guanylate cyclase activity. Vitamin D and its metabolites failed to stimulate adenylate cyclase (EC 4.6.1.1) activity. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of vitamin D at the cellular level.