Cross-regulation between G-protein-coupled receptors: Activation of β₂-adrenergic receptors increases α₁-adrenergic receptor mRNA levels

Stimulation of DDT₁ MF-2 vas deferens cells with epinephrine resulted in a time- and dose-dependent loss of α₁-adrenergic receptor-specific ligand binding. Regulation of α₁-adrenergic receptor mRNA was characterized. In monolayer culture, cells displayed 0.7 ± 0.05 amol of α₁-adrenergic receptor mRNA/μg of total cellular RNA. Epinephrine, which acts at both α₁- and β₂-adrenergic receptors of DDT₁ MF-2 cells, induced a short term (2-8 h) increase (50-70%) in the abundance of α₁-adrenergic receptor mRNA. Propranolol, a β₂-adrenergic receptor antagonist, attenuated the epinephrine-mediated increase in α₁-adrenergic receptor mRNA but did not affect the decrease in α₁-adrenergic receptor-specific ligand binding. Phentolamine, an α₁-adrenergic receptor antagonist, did not attenuate the epinephrine-mediated increase in α₁-adrenergic receptor mRNA at 4 h but did block the decrease in α₁-adrenergic receptor-specific ligand binding. The half-life of the α₁-adrenergic receptor mRNA was ∼7 h in untreated cells as well as in cells challenged with epinephrine. The epinephrine-promoted increase in α₁-adrenergic receptor mRNA was found to result from cross-regulation via β₂-adrenergic receptors. Cholera toxin, forskolin, as well as the cyclic AMP analog CPT cAMP (8-(4-chlorophenylthio)adenosine 3′:5′-cyclic monophosphate) increased the α₁-adrenergic receptor mRNA at 4 h, as did epinephrine in the presence of α₁-antagonists but not in the presence of a β-adrenergic antagonist. This is the first report of heterologous upregulation of mRNA levels of adrenergic receptors. Cross-regulation between α₁- and β₂-adrenergic receptor-mediated pathways at 4 h occurs at the level of mRNA whereas later down-regulation of α₁-receptor mRNA and binding proceed via agonist activation of α₁-adrenergic receptors.