Calmodulin antagonists competitively inhibit dexamethasone binding to the glucocorticoid receptor.

Steroid hormones exert their glucocorticoid activity by binding reversibly to a receptor protein in the cytoplasm of target cells [ 1,2]. We have shown [3] that Ca2+ inhibit the rate of association of dexamethasone, a semi-synthetic glucocorticoid, with the glucocorticoid receptor. The half-maximum effect was seen at 0.3 PM free Ca2+, a concentration within the range (0. l1 PM) of fluctuations of free intracellular Ca2 + that occur in response to hormonal stimulation in several cell types [4]. Many ‘second messenger’ functions of calcium (e.g., control of protein phosphorylation) are exerted through calmodulin, a ubiquitous thermostable protein that serves as a multifunctional intracellular calcium receptor [5-81. Thus, the effect of calcium on glucocorticoid-receptor binding might be mediated by calmodulin, the more so as thermostable factor(s) and phosphorylation processes presumably control glucocorticoid receptor activity 191. Such a mechanism has been proposed for the acetylcholine receptor [lo]. Thus, we determined whether calmodulin antagonists influence dexamethasone binding to the glucocorticoid receptor. The antagonists belonged to the class of antipsychotic phenothiazines, i.e., trifluoperazine (TFP) [ 11,121, membrane-active compounds, i.e., propranolol and SKF 525A [ 131, microtubule inhibitors, i.e., vinblastine 1141, and new calmodulin inhibitors, i.e., R 24571 [151. ever, some of these and related drugs (SKF 550 and SKF 625A) competitively inhibit the binding of dexamethasone to its receptor. TFP, the most potent inhibitor, prevents induction of tyrosine aminotransferase by dexamethasone. Thus, calmodulin inhibitors may act as glucocorticoid antagonists, not via calmodulin inhibition but through a direct interaction with the glucocorticoid receptor.