title: β1-adrenergic receptor antagonists signal via PDE4 translocation.
abstract: It is generally assumed that antagonists of Gs-coupled receptors do not activate cAMP signalling, because they do not stimulate cAMP production via Gs-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.
authors: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California 94143, USA.
authors: Wito
authors: W
authors: Richter
authors: Delphine
authors: D
authors: Mika
authors: Elise
authors: E
authors: Blanchard
authors: Peter
authors: P
authors: Day
authors: Marco
authors: M
authors: Conti
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D018342:Receptors, Adrenergic, beta-1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
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