Agonist-induced destabilization of β-adrenergic receptor mRNA. Attenuation of glucocorticoid-induced up-regulation of β-adrenergic receptors

β-Adrenergic receptor expression and receptor mRNA levels are down-regulated by β-adrenergic agonists and upregulated by glucocorticoids. The interaction between these two opposing regulatory pathways was investigated at the levels of receptor and receptor mRNA in DDT₁ MF-2 hamster vas deferens cells. Dexamethasone blunted a marked decrease in receptor expression induced by isoproterenol alone, as made visible by indirect immunofluorescence using antireceptor antibodies. Receptor mRNA levels were quantified by DNA-excess solution hybridization. Dexamethasone stimulated a sharp increase in receptor mRNA at 4 h following the addition of steroid in either the absence or the presence of isoproterenol. By 12 h, dexamethasone treatment resulted in a new steady-state level of receptor mRNA double that observed in untreated cells. Isoproterenol blunted the dexamethasone effect observed at 12 h. Cells treated with isoproterenol and dexamethasone in combination displayed a new steady-state level only 30% greater than untreated cells. Measured by nuclear run-on assays, transcription rates of the receptor gene were unaffected in cells challenged with isoproterenol alone. Dexamethasone, in contrast, stimulated a 4-fold increase in β₂-adrenergic receptor gene transcription. Isoproterenol and dexamethasone in combination promoted a transcription rate comparable to dexamethasone alone. The half-life of receptor mRNA in untreated and dexamethasone-treated cells was 12 h. In contrast, β-adrenergic receptor mRNA half-life declined to 5 h in cells that were treated with isoproterenol in the presence or absence of dexamethasone. Agonist-promoted destabilization and steroid-induced transcription provide mechanisms for the interplay of two opposing pathways controlling receptor mRNA levels.