Down-regulation of histamine H1 receptors by β2-adrenoceptor-mediated inhibition of H1 receptor gene transcription

Histamine H1 receptor (H1R) levels vary under various pathological conditions, and these changes may be responsible for some pathogenesis such as in allergic rhinitis. Several stimulants, including histamine, muscarinic agonists and platelet‐activating factor, have now been shown to regulate H1R levels and may have roles in regulating the H1R level in physiological and pathological conditions. Results for β2‐adrenoceptor (β2AR) stimulation are conflicting, however. β2AR up‐regulated H1R in bovine tracheal smooth muscle, but down‐regulated human H1R expressed in Chinese hamster ovary (CHO) cells. It is possible that this discrepancy comes from the differences in the preparations used for each study: the former cell expressed bovine H1R and the latter cell expressed human H1R. Moreover, CHO cells have been shown to be inadequate for studying the effects on H1R gene expression, because the cells express non‐endogenous stably transfected H1R under the control of the SV40 promoter. Therefore, in this study, we have investigated the role of β2AR stimulation in H1R gene regulation using human U373 astrocytoma cells that express endogenous H1R and transfected β2AR. Stimulation of β2AR significantly reduced H1R promoter activity and H1R mRNA levels. H1R mRNA stability was slightly reduced by β2AR stimulation, although this was not significant. The decrease of H1R mRNA by β2AR stimulation was blocked by the protein kinase A (PKA) inhibitor KT5720, suggesting the involvement of PKA. These results indicate that the β2AR is involved in the down‐regulation of human H1R by inhibiting H1R gene transcription through a PKA‐dependent process.