title: A neutrophil inhibitory pepducin derived from FPR1 expected to target FPR1 signaling hijacks the closely related FPR2 instead.
abstract: Pepducins constitute a unique class of G-protein coupled receptor (GPCR) modulating lipopeptides. Pepducins with inhibitory effects on neutrophils could potentially be developed into anti-inflammatory pharmaceuticals. A pepducin with a peptide sequence identical to the third intracellular loop of FPR1 was found to inhibit neutrophil functions including granule mobilization and superoxide production. This FPR1-derived pepducin selectively inhibited signaling and cellular responses through FPR2, but not FPR1 as expected. Binding to the neutrophil surface of a conventional FPR2 agonist is also inhibited. The fatty acid is essential for inhibition and pepducins with shorter peptides lose in potency. In summary, a pepducin designed to target FPR1 was found to hijack FPR2 and potently inhibit neutrophil functions.
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Malene
authors.initials: M
authors.lastname: Winther
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Gabl
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Amanda
authors.initials: A
authors.lastname: Welin
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Dahlgren
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address: Huamei.forsman@rheuma.gu.se.
authors.forename: Huamei
authors.initials: H
authors.lastname: Forsman
mesh_terms: D000328:Adult; D018922:HL-60 Cells; D006801:Humans; D055666:Lipopeptides / Q000378:metabolism / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects*; D044042:Receptors, Formyl Peptide / Q000737:chemistry / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C469986:FPR1 protein, human; C105101:FPR2 protein, human; D055666:Lipopeptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin
keywords: Allosteric modulation; Formyl peptide receptor; G-protein coupled receptor; Inflammation; Inhibitor; Pepducin