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

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• The complement component C5a interacts with C5a receptor 1 (C5aR1), a G-protein-coupled receptor.
• Peptide fragments of C5a can bind C5aR1, but their potential for ligand bias is unknown.

Purpose of the Study:

• To investigate functional bias of a C5a C-terminal fragment (C5a^pep) at human C5aR1 compared to C5a.
• To assess differences in G-protein coupling, β-arrestin (βarr) recruitment, endocytosis, and signaling.

Main Methods:

• Comparison of C5a and C5a^pep effects on Gα_i coupling (cAMP), βarr recruitment, receptor endocytosis, and ERK1/2 phosphorylation.
• Assessment of C5a^pep efficacy in inhibiting IL-6 secretion and inducing neutrophil migration.

Main Results:

• C5a^pep is a full agonist for Gα_i coupling and ERK1/2 phosphorylation but a partial agonist for βarr recruitment and endocytosis.
• C5a^pep fully inhibits LPS-induced IL-6 secretion but shows reduced efficacy in neutrophil migration compared to C5a.

Conclusions:

• C5a^pep exhibits functional bias at C5aR1, demonstrating differential efficacy for βarr recruitment, receptor trafficking, and neutrophil migration.
• These findings reveal ligand bias at C5aR1 and offer a model for understanding chemokine receptor interactions.