β1‐adrenergic receptor antagonists signal via PDE4 translocation

It is generally assumed that antagonists of G_s‐coupled receptors do not activate cAMP signalling, because they do not stimulate cAMP production via G_s‐protein/adenylyl cyclase activation. Here, we report a new signalling pathway whereby antagonists of β₁‐adrenergic receptors (β₁ARs) increase cAMP levels locally without stimulating cAMP production directly. Binding of antagonists causes dissociation of a preformed complex between β₁ARs and Type‐4 cyclic nucleotide phosphodiesterases (PDE4s). This reduces the local concentration of cAMP‐hydrolytic activity, thereby increasing submembrane cAMP and PKA activity. Our study identifies receptor/PDE4 complex dissociation as a novel mechanism of antagonist action that contributes to the pharmacological properties of β₁AR antagonists and might be shared by other receptor subtypes.