Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01855-z
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Funding
- National Institutes of Health [HL056687, HL075443]
- AHA Predoctoral Fellowship [14PRE20480352]
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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.
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