GLUCOCORTICOIDS DOWN-REGULATE BETA(1)-ADRENERGIC-RECEPTOR EXPRESSION BY SUPPRESSING TRANSCRIPTION OF THE RECEPTOR GENE

The expression of beta(2)-adrenergic receptors is up-regulated by glucocorticoids. In contrast, beta(1)-adrenergic receptors display glucocorticoid-induced down-regulation. In rat C6 glioma cells, which express both of these subtypes of beta-adrenergic receptors, the synthetic glucocorticoid dexamethasone stimulates no change in the total beta-adrenergic receptor content, but rather shifts the beta(1):beta(2) ratio from 80:20 to 50:50. Radioligand binding and immunoblotting demonstrate a sharp decline in beta(1)-adrenergic receptor expression. Metabolic labelling of cells with [S-35]-methionine in tandem with immunoprecipitation by beta(1)-adrenergic-receptor-specific antibodies reveals a sharp decline in the synthesis of the receptor within 48 h for cells challenged with glucocorticoid. Steady-state levels of beta(1)-adrenergic-receptor mRNA declined from 0.47 to 0.26 amol/mu g of total cellular RNA within 2h of dexamethasone challenge, as measured by DNA-excess solution hybridization. The stability of receptor mRNA was not influenced by glucocorticoid; the half-lives of the beta(1)- and beta(2)-subtype mRNAs were 1.7 and 1.5 h respectively. Nuclear run-on assays revealed the basis for the down-regulation of receptor expression, i.e. a sharp decline in the relative rate of transcription for the beta(1)-adrenergic-receptor gene in nuclei from dexamethasone-treated as compared with vehicle-treated cells. These data demonstrate transcriptional suppression as a molecular explanation for glucocorticoid-induced down-regulation of beta(1)-adrenergic receptors.