Activation of the glucocorticoid receptor

Past and ongoing approaches to the mechanism of activation of the glucocorticoid receptor have been summarized. In vivo labelling of receptors with [ 3H] triamcinolone acetonide at various times indicates a progression in appearance and disappearance of chromatographically separable activated and unactivated forms of steroid-receptor complexes, suggesting physiological relevance of the activation process. The DNA-binding site, exclusively expressed on activated receptor complexes appears to consist minimally of lys, arg and his residues as determined by chemical probes. The DNA-binding site of the activated receptor complex may contain a divalent metal. Since addition of calf intestinal alkaline phosphatase stimulates the rate of activation of glucocorticoid-receptor complexes at 0°, the activation step, at least in part, may consist of a dephosphorylation event. Two small molecule regulators have been found. One is called “modulator” and inhibits activation. The other is pyridoxal 5′-phosphate which functions in vitro and in vivo and combines with the activated form of the steroid-receptor complex, preventing nuclear binding. The products of activation are receptors called II and IB. They have a different distribution between liver and kidney. How they arise in the cell is not yet clear but both appear to be bona fide cellular products. IB and II both have receptor functions and differ in their binding avidity for single-stranded homodeoxypolymers. The specificity of homodeoxypolymer binding by II resembles DNA polymerase-α. DNA-binding of activated binder II is inhibited by rifamycin AF 013 , a known inhibitor of DNA-binding by various nucleic acid polymerases. Based on observations on the activation mechanism of glucocorticoid receptors, a speculative model is presented.