β2-Adrenergic Receptor-Mediated Histamine H1Receptor Down-Regulation: Another Possible Advantage of β2Agonists in Asthmatic Therapy

To clarify heterologous regulation of a receptor is important in considering medication. Histamine constricts the airway smooth muscle through the action to the H1receptor (H1R), which contributes to asthma. β2-Adrenergic receptor (β2R) agonists are widely used in asthmatic therapy for their bronchodilating effects. In this study, we investigated the effect of β2R activation on the H1R function using Chinese hamster ovary cells stably co-expressing human histamine H1R and β2R (CHO-H1/β2 cell). The stimulation of β2R resulted in the decrease of H1R in the membrane. Heterologous H1R down-regulation was significantly reversed in the presence of the cyclic AMP-dependent protein kinase (PKA) inhibitor KT5720. Since phosphorylation of G protein-coupled receptor (GPCR) by second messenger-dependent kinases, is proposed to be a key step initiating heterologous receptor desensitization, we examined whether heterologous H1R down-regulation was accompanied by H1R phosphorylation. H1R was phosphorylated by β2R stimulation; however, a PKA inhibitor did not inhibit heterologous H1R phosphorylation. Our results suggest that H1R was heterologously regulated by β2R. Not only a direct action of β2R agonist to β2R causing bronchodilation but also indirect action that reduces the number of H1R responsible for bronchoconstriction might contribute to a decrease in the bronchial resistance, which proposes another possible advantage of β2R agonists for asthmatic medication.