NDLI: Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

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Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1

Content Provider	Scilit
Author	Pandey, Shubhi Li, Xaria X. Srivastava, Ashish Baidya, Mithu Kumari, Punita Dwivedi, Hemlata Chaturvedi, Madhu Ghosh, Eshan Woodruff, Trent M. Shukla, Arun K.
Copyright Year	2019
Description	Journal: Journal of Biological Chemistry The human complement component, C5a, binds two different seven-transmembrane receptors termed C5aR1 and C5aR2. C5aR1 is a prototypical G-protein–coupled receptor that couples to the $Gα_{i}$ subfamily of heterotrimeric G-proteins and β-arrestins (βarrs) following C5a stimulation. Peptide fragments derived from the C terminus of C5a can still interact with the receptor, albeit with lower affinity, and can act as agonists or antagonists. However, whether such fragments might display ligand bias at C5aR1 remains unexplored. Here, we compare C5a and a modified C-terminal fragment of C5a, $C5a^{pep}$, in terms of G-protein coupling, βarr recruitment, endocytosis, and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activation at the human C5aR1. We discover that $C5a^{pep}$ acts as a full agonist for $Gα_{i}$ coupling as measured by cAMP response and extracellular signal-regulated kinase 1/2 phosphorylation, but it displays partial agonism for βarr recruitment and receptor endocytosis. Interestingly, $C5a^{pep}$ exhibits full-agonist efficacy with respect to inhibiting lipopolysaccharide-induced interleukin-6 secretion in human macrophages, but its ability to induce human neutrophil migration is substantially lower compared with C5a, although both these responses are sensitive to pertussis toxin treatment. Taken together, our data reveal that compared with C5a, $C5a^{pep}$ exerts partial efficacy for βarr recruitment, receptor trafficking, and neutrophil migration. Our findings therefore uncover functional bias at C5aR1 and also provide a framework that can potentially be extended to chemokine receptors, which also typically interact with chemokines through a biphasic mechanism.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579481/pdf http://www.jbc.org/content/294/24/9416.full.pdf
Ending Page	9429
Page Count	14
Starting Page	9416
ISSN	00219258
e-ISSN	1083351X
DOI	10.1074/jbc.ra119.007485
Journal	Journal of Biological Chemistry
Issue Number	24
Volume Number	294
Language	English
Publisher	Elsevier BV
Publisher Date	2019-06-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology G-protein–coupled Receptor (gpcr) Cell Signaling Signal Transduction
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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