Gα_i is required for carvedilol-induced β₁ adrenergic receptor β-arrestin biased signaling

The β₁ adrenergic receptor (β₁AR) is recognized as a classical Gα_s-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein β-arrestin. Some βAR ligands, such as carvedilol, stimulate βAR signaling preferentially through β-arrestin, a concept known as β-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any Gα_s-coupled receptor, whereby carvedilol induces the transition of the β₁AR from a classical Gα_s-coupled receptor to a Gα_i-coupled receptor stabilizing a distinct receptor conformation to initiate β-arrestin-mediated signaling. Recruitment of Gα_i is not induced by any other βAR ligand screened, nor is it required for β-arrestin-bias activated by the β₂AR subtype of the βAR family. Our findings demonstrate a previously unrecognized role for Gα_i in β₁AR signaling and suggest that the concept of β-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.