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.
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 63-77 , TLQP-21 exhibits a preference toward Gi/o-mediated signaling compared to β-arrestin recruitment and internalization. We also show that the purported antagonist SB290157 is a very potent C3aR1 agonist, where antagonism of ligand-stimulated C3aR1 calcium flux is caused by potent β-arrestin-mediated internalization. Finally, ligand-mediated signaling bias impacted cell function as demonstrated by the regulation of calcium influx, lipolysis in adipocytes, phagocytosis in microglia, and degranulation in mast cells. Overall, we characterize C3aR1 as a Gi/o/z-coupled receptor and demonstrate the functional relevance of ligand-mediated signaling bias in key cellular models. Due to C3aR1 and its endogenous ligands being implicated in inflammatory and metabolic diseases, these results are of relevance toward future C3aR1 drug discovery.
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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