DOI: 10.1101/515700Jan 9, 2019Paper

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

BioRxiv : the Preprint Server for Biology
Shubhi PandeyArun K Shukla

Abstract

The human complement component, C5a, binds two different seven transmembrane receptors termed as C5aR1 and C5aR2. C5aR1 is a prototypical G protein-coupled receptor that couples to Gαi sub-family of heterotrimeric G proteins and β-arrestins (βarr) following C5a stimulation. Peptide fragments derived from the carboxyl-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, C5apep, in terms of G protein coupling, βarr recruitment, endocytosis and ERK1/2 MAP kinase activation at the human C5aR1. We discover that C5apep acts as a full-agonist for G protein coupling, while only displaying partial agonism for βarr recruitment. We also observe that whilst C5apep is significantly less efficient in inducing C5aR1 endocytosis compared to C5a, it exhibits robust activation of ERK1/2 phosphorylation at levels similar to C5a. Interestingly, C5apep displays full-agonist efficacy with respect to inhibiting LPS induced IL-6 secretion in human macrophages, but its ability to induce human neutrophil migration is substantially lower ...Continue Reading

Related Concepts

Complement C5a
Endocytosis
Guanosine
Interleukin-6
Ligands
Lipopolysaccharides
Macrophage
Neutrophil
Peptide Fragments
Peptides

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