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 language | English |
|---|---|
| Article number | 128 |
| Journal | Communications Biology |
| Volume | 1 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Dec 1 |
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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 journal › Article
}
TY - JOUR
T1 - Conformational signatures in β-arrestin2 reveal natural biased agonism at a G-protein-coupled receptor
AU - Reyes-Alcaraz, Arfaxad
AU - Lee, Yoo Na
AU - Yun, Seongsik
AU - Hwang, Jong-Ik
AU - Seong, Jae Young
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-018-0134-3
DO - 10.1038/s42003-018-0134-3
M3 - Article
AN - SCOPUS:85070417554
VL - 1
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 128
ER -