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The β 1  adrenergic receptor (β 1 AR) 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 β 1 AR 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 β 2 AR subtype of the βAR family. Our findings demonstrate a previously unrecognized role for Gα i  in β 1 AR 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.

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