The ? adrenergic receptor (?AR) is recognized as a classical G?-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein ?-arrestin. Some ?AR ligands, such as carvedilol, stimulate ?AR signaling preferentially through ?-arrestin, a concept known as ?-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any G?-coupled receptor, whereby carvedilol induces the transition of the ?AR from a classical G?-coupled receptor to a G?-coupled receptor stabilizing a distinct receptor conformation to initiate ?-arrestin-mediated signaling. Recruitment of G? is not induced by any other ?AR ligand screened, nor is it required for ?-arrestin-bias activated by the ?AR subtype of the ?AR family. Our findings demonstrate a previously unrecognized role for G? in ?AR signaling and suggest that the concept of ?-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.     «

The ? adrenergic receptor (?AR) is recognized as a classical G?-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein ?-arrestin. Some ?AR ligands, such as carvedilol, stimulate ?AR signaling preferentially through ?-arrestin, a concept known as ?-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any G?-coupled receptor, whereby carvedilol induces the transi...     »