The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction

Claire E Bamberg, Charles Mackay, Hyun Lee, David Zahra, Jenny Jackson, Yun Si Lim, Peter L Whitfeld, Stewart Craig, Erin Corsini, Bao Lu, Craig Gerard, Norman P Gerard

Research output: Contribution to journalArticleResearchpeer-review

164 Citations (Scopus)

Abstract

The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and I?-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the beta -arrestin pathway. Association of C5L2 with beta -arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the beta -arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.
Original languageEnglish
Pages (from-to)7633 - 7644
Number of pages12
JournalThe Journal of Biological Chemistry
Volume285
Issue number10
DOIs
Publication statusPublished - 2010
Externally publishedYes

Cite this