Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism.
Autor: | Rodriguez P; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA., Laskowski LJ; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Pallais JP; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA., Bock HA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Cavalco NG; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Anderson EI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Calkins MM; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Razzoli M; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA., Sham YY; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA., McCorvy JD; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address: jmccorvy@mcw.edu., Bartolomucci A; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: abartolo@umn.edu. |
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Jazyk: | angličtina |
Zdroj: | The Journal of biological chemistry [J Biol Chem] 2024 Jan; Vol. 300 (1), pp. 105549. Date of Electronic Publication: 2023 Dec 10. |
DOI: | 10.1016/j.jbc.2023.105549 |
Abstrakt: | G protein-coupled receptors (GPCRs) are leading druggable targets for several medicines, but many GPCRs are still untapped for their therapeutic potential due to poor understanding of specific signaling properties. The complement C3a receptor 1 (C3aR1) has been extensively studied for its physiological role in C3a-mediated anaphylaxis/inflammation, and in TLQP-21-mediated lipolysis, but direct evidence for the functional relevance of the C3a and TLQP-21 ligands and signal transduction mechanisms are still limited. In addition, C3aR1 G protein coupling specificity is still unclear, and whether endogenous ligands, or drug-like compounds, show ligand-mediated biased agonism is unknown. Here, we demonstrate that C3aR1 couples preferentially to Gi/o/z proteins and can recruit β-arrestins to cause internalization. Furthermore, we showed that in comparison to C3a Competing Interests: Conflict of interest The authors declare no conflicts of interest. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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