Glucocorticoids down-regulate β₁-adrenergic-receptor expression by suppressing transcription of the receptor gene

The expression of β₂-adrenergic receptors is up-regulated by glucocorticoids. In contrast β₁-adrenergic receptors display glucocorticoid-induced down-regulation. In rat C6 glioma cells, which express both of these subtypes of β-adrenergic receptors, the synthetic glucocorticoid dexamethasone stimulates no change in the total β-adrenergic receptor content, but rather shifts the β₁:β₂ ratio from 80:20 to 50:50. Radioligand binding and immunoblotting demonstrate a sharp decline in β₁-adrenergic receptor expression. Metabolic labelling of cells with [³⁵S]-methionine in tandem with immunoprecipitation by β₁-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 β₁-adrenergic-receptor mRNA declined from 0.47 to 0.26 amol/μg of total cellular RNA within β₁:β₂ h 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 β₁- and β₂-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 β₁-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 β₁-adrenergic receptors.