The N-formylpeptide receptor (FPR) and a second G(i)-coupled receptor mediate fMet-Leu-Phe-stimulated activation of NADPH oxidase in murine neutrophils.
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.
Lavigne
Mark C
MC
Laboratory of Host Defenses, NIAID, NIH, Bethesda, MD 20892, USA.
Murphy
Philip M
PM
Leto
Thomas L
TL
Gao
Ji-Liang
JL
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D015936:Complement C5a / Q000494:pharmacology; D003571:Cytochalasin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D037342:Pertussis Toxin / Q000494:pharmacology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018000:Receptors, Peptide / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D013481:Superoxides; C024794:dihydrocytochalasin B; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019284:Thapsigargin; D015936:Complement C5a; D019833:Genistein; D019255:NADPH Oxidases; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C088060:bisindolylmaleimide; D000077191:Wortmannin