Conformational signatures in β-arrestin2 reveal natural biased agonism at a G-protein-coupled receptor

Arfaxad Reyes-Alcaraz, Yoo Na Lee, Seongsik Yun, Jong Ik Hwang, Jae Young Seong

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Discovery of biased ligands and receptor mutants allows characterization of G-protein- and β-arrestin-mediated signaling mechanisms of G-protein-coupled receptors (GPCRs). However, the structural mechanisms underlying biased agonism remain unclear for many GPCRs. We show that while Galanin induces the activation of the galanin receptor 2 (Galr2) that leads to a robust stimulation toward Gαq-protein and β-arrestin1/2, an alternative ligand Spexin and its analog have biased agonism toward G-protein signaling relative to Galanin. We used intramolecular fluorescein arsenical hairpin bioluminescence resonance energy transfer-based biosensors of β-arrestin2 combined with NanoBit technology to measure β-arrestin2–Galr2 interactions in real-time living systems. We found that Spexin and Galanin induce specific active conformations of Galr2, which may lead to different internalization rates of the receptor as well as different signaling outputs. This work represents an additional pharmacological evidence of endogenous G-protein-biased agonism at a GPCR.

Original languageEnglish
Article number128
JournalCommunications Biology
Volume1
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Bibliographical note

Funding Information:
This work was supported by grants from the Research Program (NRF-2015M3A9E7029172) of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning. We want to thank especially to Professor Asuka Inoue from Tohoku University in Japan for the kind gift of HEK293 knockout cell lines used in this work.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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