Few studies have addressed the effects of classical anti-inflammatory glucocorticoids on platelet function. Here, we report for the first time that human platelets contain the glucocorticoid receptor (GR) as identified by a combination of biochemical and functional techniques. Ligand-binding studies revealed the presence of a high- and low-affinity binding site for [H-3]-dexamethasone in platelets. The 2 GR ligands prednisolone and dexamethasone competed for [H-3]-dexamethasone binding, as did the mineralocorticoid aldosterone. However, while prednisolone (1-10 mu M) reduced adenosine diphosphate (ADP, 4 mu M) and thromboxane A(2) receptor agonist U46619 induced platelet aggregation (up to 75%), dexamethasone had no effect. The inhibition produced by prednisolone was reversed by preincubation with the GR antagonist mifepristone (10 mu M; RU486), suggesting the functional importance of the ligand-receptor complex. In addition, prednisolone caused a marked (similar to 50%) reduction in thromboxane B-2 levels, whereas dexamethasone was without effect. The apparently anomalous binding data were clarified by the fact that washed platelets (1) contained mineralocorticoid receptor and that (2) it was associated with GR. Taken together, our data suggest that platelet GR forms a heterodimeric complex with the mineralocorticoid receptor that is susceptible to differential activation by specific receptor ligands.
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