title: Basic characteristics of the neutrophil receptors that recognize formylated peptides, a danger-associated molecular pattern generated by bacteria and mitochondria.
abstract: Proper recruitment and activation of neutrophils to/at sites of infection/inflammation relies largely on the surface expression of chemoattractant receptors of which a formyl peptide receptor (FPR1) was the first to be cloned and characterized in more detail. This receptor displays high affinity for bacterial- or mitochondrial-derived peptides that contain a formylated methionine in the N-terminus. The neutrophil chemoattractant receptors belong to the group of 7-transmembrane domain receptors that signal through activation of heterotrimeric G proteins. These receptors have been shown to be important in host defense against microbial intruders and in regulating inflammatory reactions. The two FPRs (FPR1, FPR2) expressed in neutrophils share significant sequence homology and bind many structurally diverse activating (agonistic) and inhibiting (antagonistic) ligands, ranging from peptides to lipopeptides containing peptide sequences derived from intracellular regions of the FPRs. Recent structural and functional studies of the two neutrophil FPRs have generated important information for our understanding of general pharmacological principles, governing regulation of neutrophil function and inflammation and increased knowledge of more general G-protein coupled receptor features, such as ligand recognition, biased signaling, allosteric modulation, and a unique receptor cross-talk phenomenon. This article aims to summarize recent discoveries and pharmacological characterization of neutrophil FPRs and to discuss unmet challenges, including recognition by the receptors of diverse ligands and how biased signals mediate different biological effects.
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden. Electronic address: claes.dahlgren@microbio.gu.se.
authors.forename: Claes
authors.initials: C
authors.lastname: Dahlgren
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Gabl
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden.
authors.forename: André
authors.initials: A
authors.lastname: Holdfeldt
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden.
authors.forename: Malene
authors.initials: M
authors.lastname: Winther
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden.
authors.forename: Huamei
authors.initials: H
authors.lastname: Forsman
mesh_terms: D000067531:Alarmins / Q000276:immunology / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D006801:Humans; D008024:Ligands; D055666:Lipopeptides / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D018375:Neutrophil Activation / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020239:Receptor Cross-Talk; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D000067531:Alarmins; D001426:Bacterial Proteins; C469986:FPR1 protein, human; C105101:FPR2 protein, human; D008024:Ligands; D055666:Lipopeptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D054852:Small Molecule Libraries; D002118:Calcium
keywords: Cross-talk; FPR; GPCR; Neutrophil; Signaling