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PMID:12470609

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Citation

Lavigne, MC, Murphy, PM, Leto, TL and Gao, JL The N-formylpeptide receptor (FPR) and a second G(i)-coupled receptor mediate fMet-Leu-Phe-stimulated activation of NADPH oxidase in murine neutrophils. Cell. Immunol. 218:7-12

Abstract

N-Formylypeptides such as fMet-Leu-Phe (fMLF) potently induce superoxide production through NADPH oxidase activation. The receptors that mediate this response have not been defined. Here, we provide definitive proof using a mouse model that formyl peptide receptor (FPR) is a receptor, but not the only receptor, that mediates fMLF-induced oxidase activation. In wild-type (FPR(+/+)) mouse neutrophils, superoxide production is dependent on the concentration of fMLF with an EC(50) of approximately 5 microM and a peak at approximately 50 microM. In contrast, FPR-deficient (FPR(-/-)) mouse neutrophils produced markedly less superoxide with an EC(50) of approximately 50 microM and a peak at approximately 200 microM. Yet, FPR(+/+) and FPR(-/-) neutrophils showed similar oxidase activation kinetics and G(i) protein-dependent pharmacological sensitivities. These results suggested that a second receptor, likely FPR2, mediates superoxide production at high concentrations of fMLF. This less sensitive second pathway may permit continued oxidant generation in response to formyl peptides when FPR is desensitized in high concentrations of the chemotactic gradient.

Links

PubMed

Keywords

Androstadienes/pharmacology; Animals; Chemotaxis/drug effects; Chemotaxis/physiology; Complement C5a/pharmacology; Cytochalasin B/analogs & derivatives; Cytochalasin B/pharmacology; Enzyme Activation/drug effects; Enzyme Inhibitors/pharmacology; GTP-Binding Protein alpha Subunits, Gi-Go/physiology; Genistein/pharmacology; Indoles/pharmacology; Kinetics; Maleimides/pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Formylmethionine Leucyl-Phenylalanine/pharmacology; NADPH Oxidase/metabolism; Neutrophils/drug effects; Neutrophils/enzymology; Pertussis Toxin/pharmacology; Receptors, Formyl Peptide; Receptors, Immunologic/deficiency; Receptors, Immunologic/drug effects; Receptors, Immunologic/genetics; Receptors, Immunologic/physiology; Receptors, Peptide/deficiency; Receptors, Peptide/drug effects; Receptors, Peptide/genetics; Receptors, Peptide/physiology; Signal Transduction/drug effects; Signal Transduction/physiology; Superoxides/metabolism; Thapsigargin/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FPRS1

acts_upstream_of_or_within

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FPRS1

acts_upstream_of_or_within

GO:0006935: chemotaxis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FPR1

acts_upstream_of_or_within

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FPR1

acts_upstream_of_or_within

GO:0006935: chemotaxis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CXCR2

acts_upstream_of_or_within

GO:0006935: chemotaxis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CXCR2

enables

GO:0004950: chemokine receptor activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete


See also

References

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