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Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes

View ORCID ProfileKevin Zheng, View ORCID ProfileJeffrey S. Smith, View ORCID ProfileAnmol Warman, Issac Choi, Jaimee N. Gundry, View ORCID ProfileThomas F. Pack, Asuka Inoue, Marc G. Caron, View ORCID ProfileSudarshan Rajagopal
doi: https://doi.org/10.1101/2020.06.11.146605
Kevin Zheng
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
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Jeffrey S. Smith
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
2Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
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Anmol Warman
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
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Issac Choi
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
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Jaimee N. Gundry
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
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Thomas F. Pack
3Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
4Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
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Asuka Inoue
5Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
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Marc G. Caron
3Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
6Department of Pharmaceutical Sciences, Tohoku University, Japan
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Sudarshan Rajagopal
1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
2Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
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  • For correspondence: sudarshan.rajagopal@duke.edu
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Abstract

G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, signal through the proximal effectors G proteins and β-arrestins to influence nearly every biological process. Classically, the G protein and β-arrestin signaling pathways have largely been considered separable. Recently, direct interactions between Gα protein and β-arrestin have been described and suggest a distinct GPCR signaling pathway. Within these newly described Gα:β-arrestin complexes, Gαi/o, but not other Gα protein subtypes, have been appreciated to directly interact with β-arrestin, regardless of canonical GPCR Gα protein subtype coupling. However it is unclear how biased agonists differentially regulate this newly described Gαi:β-arrestin interaction, if at all. Here we report that endogenous ligands (chemokines) of the GPCR CXCR3, CXCL9, CXCL10, and CXCL11, along with two small molecule biased CXCR3 agonists, differentially promote the formation of Gαi:β-arrestin complexes. The ability of CXCR3 agonists to form Gαi:β-arrestin complexes does not correlate well with either G protein signaling or β-arrestin recruitment. Conformational biosensors demonstrate that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We find these Gαi:β-arrestin complexes can associate with CXCR3, but not with ERK. These findings further support that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of biased agonism.

Competing Interest Statement

The authors have declared no competing interest.

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Posted June 12, 2020.
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Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes
Kevin Zheng, Jeffrey S. Smith, Anmol Warman, Issac Choi, Jaimee N. Gundry, Thomas F. Pack, Asuka Inoue, Marc G. Caron, Sudarshan Rajagopal
bioRxiv 2020.06.11.146605; doi: https://doi.org/10.1101/2020.06.11.146605
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Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes
Kevin Zheng, Jeffrey S. Smith, Anmol Warman, Issac Choi, Jaimee N. Gundry, Thomas F. Pack, Asuka Inoue, Marc G. Caron, Sudarshan Rajagopal
bioRxiv 2020.06.11.146605; doi: https://doi.org/10.1101/2020.06.11.146605

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