Abstract
The β1 adrenergic receptor (β1AR) is recognized as a classical Gαs-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 Gαs-coupled receptor, whereby carvedilol induces the transition of the β1AR from a classical Gαs-coupled receptor to a Gαi-coupled receptor stabilizing a distinct receptor conformation to initiate β-arrestin-mediated signaling. Recruitment of Gαi 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 Gαi 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.
Highlights
The β1 adrenergic receptor (β1AR) is recognized as a classical Gαs-coupled receptor
To determine whether Gαi is required for carvedilol-stimulated β adrenergic receptors (βARs) signaling, we tested the effect of the Gαi inhibitor pertussis toxin (PTX) on carvedilol-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in HEK293 cells stably expressing FLAG-tagged β1AR or β2AR
Carvedilol, a ligand classically known as a βAR antagonist, activates β-arrestin signaling by switching the uniquely Gαs-coupled β1AR to a Gαicoupled receptor
Summary
The β1 adrenergic receptor (β1AR) is recognized as a classical Gαs-coupled receptor. Agonist binding initiates G protein-mediated signaling and signaling through the multifunctional adapter protein β-arrestin. Current data suggest a much greater complexity of GPCR signaling than the two-state (active or inactive) model whereby multiple receptor conformations can exist, each with a different affinity for its transducer, resulting in the activation of distinct cellular signaling pathways[15,16,17] Whereas balanced ligands, such as isoproterenol, stabilize βAR conformations signal with equal efficacy through G proteins and β-arrestins, some ligands stabilize conformations that selectively recruit only one of the transducers to stimulate a specific subset of cellular signals, a process termed “biased agonism”[18, 19]. The prevailing mechanistic concept of β-arrestin-bias for the Gαscoupled β1AR is ligand-stimulated activation of β-arrestin in the absence of G protein coupling Recently it has been demonstrated for the angiotensin II type 1 receptor that the weak β-arrestin-biased agonist, [1Sar4Ile8Ile]-angiotensin II, is capable of activating both Gαq and Gαi[22], indicating a possible role of G proteins in β-arrestin-mediated signaling. These data underscore the complexity of β-arrestin-biased agonism and have important implications for identifying new therapeutic agents to selectively target β-arrestin-biased signaling
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