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 beta(1)-adrenergic receptors (beta(1)ARs) increase cAMP levels locally without stimulating cAMP production directly. Binding of antagonists causes dissociation of a preformed complex between beta(1)ARs 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 beta(1)AR antagonists and might be shared by other receptor subtypes.