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

Jialu Wang, Kenji Hanada, Dean P. Staus, Michael A. Makara, Giri Raj Dahal, Qiang Chen, Andrea Ahles, Stefan Engelhardt and Howard A. Rockman ()
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Jialu Wang: Duke University Medical Center
Kenji Hanada: Duke University Medical Center
Dean P. Staus: Duke University Medical Center
Michael A. Makara: Duke University Medical Center
Giri Raj Dahal: Duke University Medical Center
Qiang Chen: Duke University Medical Center
Andrea Ahles: Technical University of Munich
Stefan Engelhardt: Technical University of Munich
Howard A. Rockman: Duke University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01855-z

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