Signaling from β(1)- and β(2)-adrenergic receptors is defined by differential interactions with PDE4

β(1)- and β(2)-adrenergic receptors (βARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by β(1)AR but not β(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 β(1)AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a β(2)AR/β-arrestin/PDE complex reported previously. The β(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 β(2)AR is a prerequisite for the recruitment of a complex consisting of β-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 β(1)- and β(2)-adrenoceptor signaling.