To clarify heterologous regulation of a receptor is important in considering medication. Histamine constricts the airway smooth muscle through the action to the H(1) receptor (H1R), which contributes to asthma. beta(2)-Adrenergic receptor (beta2R) agonists are widely used in asthmatic therapy for their bronchodilating effects. In this study, we investigated the effect of beta2R activation on the H1R function using Chinese hamster ovary cells stably co-expressing human histamine H1R and beta2R (CHO-H1/beta2 cell). The stimulation of beta2R 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 beta2R stimulation; however, a PKA inhibitor did not inhibit heterologous H1R phosphorylation. Our results suggest that H1R was heterologously regulated by beta2R. Not only a direct action of beta2R agonist to beta2R 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 beta2R agonists for asthmatic medication.