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

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 beta-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.

Type Journal
ISBN 1083-351X (Electronic) 0021-9258 (Linking)
Authors Bamberg, C. E.; Mackay, C. R.; Lee, H.; Zahra, D.; Jackson, J.; Lim, Y. S.; Whitfeld, P. L.; Craig, S. Corsini, E.; Lu, B.; Gerard, C.; Gerard, N. P.:
Publisher Name J BIOL CHEM
Published Date 2010-03-05 00:00:00
Published Volume 285
Published Issue 10
Published Pages 7633-44
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20044484
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?10749_11017/10 Bamberg JBC_.pdf