G Alpha(I) Is Required For Carvedilol-Induced Beta(1) Adrenergic Receptor Beta-Arrestin Biased Signaling

The beta(1) adrenergic receptor (beta(1)AR) is recognized as a classical Gas-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein beta-arrestin. Some beta AR ligands, such as carvedilol, stimulate beta AR signaling preferentially through beta-arrestin, a concept known as beta-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any Gas-coupled receptor, whereby carvedilol induces the transition of the beta(1)AR from a classical Gas-coupled receptor to a G alpha(i)-coupled receptor stabilizing a distinct receptor conformation to initiate beta-arrestin- mediated signaling. Recruitment of Gai is not induced by any other beta AR ligand screened, nor is it required for beta-arrestin-bias activated by the beta(2)AR subtype of the beta AR family. Our findings demonstrate a previously unrecognized role for Gai in beta(1)AR signaling and suggest that the concept of beta-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.