Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism. J Biol Chem 2024 Jan;300(1):105549
Date
12/11/2023Pubmed ID
38072064Pubmed Central ID
PMC10796979DOI
10.1016/j.jbc.2023.105549Scopus ID
2-s2.0-85181819143 (requires institutional sign-in at Scopus site)Abstract
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 C3a63-77, 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.
Author List
Rodriguez P, Laskowski LJ, Pallais JP, Bock HA, Cavalco NG, Anderson EI, Calkins MM, Razzoli M, Sham YY, McCorvy JD, Bartolomucci AAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCalcium
Cell Line
Complement C3a
Humans
Ligands
Mice
Receptors, G-Protein-Coupled
beta-Arrestin 1
beta-Arrestins
