title: 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.
authors.affiliation: Pulmonary Division, Department of Pediatrics, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Bamberg
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
authors.forename: Hyun
authors.initials: H
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Zahra
authors.forename: Jenny
authors.initials: J
authors.lastname: Jackson
authors.forename: Yun Si
authors.initials: YS
authors.lastname: Lim
authors.forename: Peter L
authors.initials: PL
authors.lastname: Whitfeld
authors.forename: Stewart
authors.initials: S
authors.lastname: Craig
authors.forename: Erin
authors.initials: E
authors.lastname: Corsini
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Norma P
authors.initials: NP
authors.lastname: Gerard
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D044087:Receptor, Anaphylatoxin C5a / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014018:Tissue Distribution; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C417003:C5aR2 protein, human; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases