Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4

beta(1)- and beta(2)-adrenergic receptors (beta ARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta(1)AR but not beta(2)AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that beta(1)AR forms a signaling complex with a cAMP-specific phosphodiesterase ( PDE) in a manner inherently different from a beta(2)AR/beta-arrestin/ PDE complex reported previously. The beta(1)AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the beta(2)AR is a prerequisite for the recruitment of a complex consisting of beta-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of beta(1)- and beta(2)-adrenoceptor signaling.