The N-formylpeptide receptor (FPR) and a second Gi-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 EC50 of ∼5 μM and a peak at ∼50 μM. In contrast, FPR-deficient (FPR−/−) mouse neutrophils produced markedly less superoxide with an EC50 of ∼50 μM and a peak at ∼200 μM. Yet, FPR+/+ and FPR−/− neutrophils showed similar oxidase activation kinetics and Gi 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.