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beta1AR and beta2AR are co-expressed and play a central role in the responses of various organs to sympathetic stimulation. Both receptors were confirmed to form heterodimers in HEK 293 cells co-expressing the both receptors by using co-immunoprecipitation and BRET. The heterodimerization is not considered to affect this signaling pathway because beta-adrenergic stimulated adenylyl cyclase activity is observed to be identical in cells expressing beta1AR, beta2AR, or both receptors at similar levels. A significant agonist-promoted internalization of the beta2AR activates ERK1/2 MAPK in beta2AR-expressing cells, while no beta-adrenergic stimulated ERK1/2 phosphorylation was observed in cells co-expressing beta1AR and both receptors. Agonist-promoted internalization of the beta2AR was inhibited upon co-expression of the beta1AR, which by itself internalized to a lesser extent. Therefore, heterodimerization between beta1AR and beta2AR inhibits the agonist-promoted internalization of the beta2AR and the activation of the ERK1/2 MAPK signaling pathway. |