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 journalArticle

9 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

Fingerprint

Galanin
Receptor, Galanin, Type 2
G-Protein-Coupled Receptors
GTP-Binding Proteins
G-proteins
receptors
Gq-G11 GTP-Binding Protein alpha Subunits
Bioluminescence
Ligands
Arsenicals
Arrestin
Energy Transfer
Computer Systems
arrestins
Biosensing Techniques
arsenicals
Fluorescein
Biosensors
Energy transfer
bioluminescence

ASJC Scopus subject areas

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

Cite this

Conformational signatures in β-arrestin2 reveal natural biased agonism at a G-protein-coupled receptor. / Reyes-Alcaraz, Arfaxad; Lee, Yoo Na; Yun, Seongsik; Hwang, Jong-Ik; Seong, Jae Young.

In: Communications Biology, Vol. 1, No. 1, 128, 01.12.2018.

Research output: Contribution to journalArticle

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