An H-2 linked difference in the binding of dexamethasone to murine hepatic cytosol receptor. A possible role of endogenous modifier(s).

ABSTRACT

The binding of dexamethasone to its receptor in hepatic cytosol preparations from pregnant mice of four congenic and recombinant strains, C57BL/10, B10.A, B10.A(2R) and B10.A(5R), which have almost identical genetic backgrounds other than the H-2 complex, on day 12 of gestation was analyzed by plotting the binding of ligand against cytosol concentration. The plots of C57BL/10 and B10.A(5R) mice were straight lines, but those of the strains B10.A and B10.A(2R) were upward concave curves. The curvature probably did not result from denaturation of the receptor, as indicated by the time course of the dexamethasone binding and by the fact that at a lower concentration of the ligand, at which the receptor would be less stable, there was less curvature than at a higher concentration of the ligand. The curvature can be explained by the presence of endogenous modifier(s) using an analogy from enzymology. Mathematical analysis, partial removal of the modifier(s) by gel filtration, and mixing of the cytosols from the two types of strains indicated the presence of an unsaturated amount of a modifier(s) in the cytosol of the B10.A and B10.A(2R) strains, and the presence of a saturated amount of the cytosol of the C57BL/10 and B10.A(5R) strains. Thus, the H-2 complex contains a gene(s) which regulates the level of a modifier(s) in hepatic cytosol which affects the binding of glucocorticoid to its hepatic cytosolic receptor.