title: Reactivation of desensitized formyl peptide receptors by platelet activating factor: a novel receptor cross talk mechanism regulating neutrophil superoxide anion production.
abstract: Neutrophils express different chemoattractant receptors of importance for guiding the cells from the blood stream to sites of inflammation. These receptors communicate with one another, a cross talk manifested as hierarchical, heterologous receptor desensitization. We describe a new receptor cross talk mechanism, by which desensitized formyl peptide receptors (FPRdes) can be reactivated. FPR desensitization is induced through binding of specific FPR agonists and is reached after a short period of active signaling. The mechanism that transfers the receptor to a non-signaling desensitized state is not known, and a signaling pathway has so far not been described, that transfers FPRdes back to an active signaling state. The reactivation signal was generated by PAF stimulation of its receptor (PAFR) and the cross talk was uni-directional. LatrunculinA, an inhibitor of actin polymerization, induced a similar reactivation of FPRdes as PAF while the phosphatase inhibitor CalyculinA inhibited reactivation, suggesting a role for the actin cytoskeleton in receptor desensitization and reactivation. The activated PAFR could, however, reactivate FPRdes also when the cytoskeleton was disrupted prior to activation. The receptor cross talk model presented prophesies that the contact on the inner leaflet of the plasma membrane that blocks signaling between the G-protein and the FPR is not a point of no return; the receptor cross-talk from the PAFRs to the FPRdes initiates an actin-independent signaling pathway that turns desensitized receptors back to a signaling state. This represents a novel mechanism for amplification of neutrophil production of reactive oxygen species.
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Gothenburg, Göteborg, Sweden.
authors.forename: Huamei
authors.initials: H
authors.lastname: Forsman
authors.forename: Karin
authors.initials: K
authors.lastname: Önnheim
authors.forename: Emil
authors.initials: E
authors.lastname: Andréasson
authors.forename: Karin
authors.initials: K
authors.lastname: Christenson
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Claes
authors.initials: C
authors.lastname: Dahlgren
mesh_terms: D000199:Actins / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D018260:Gelsolin / Q000494:pharmacology; D006801:Humans; D008387:Marine Toxins; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009842:Oligopeptides; D010080:Oxazoles / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000199:Actins; D001381:Azepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018260:Gelsolin; D008387:Marine Toxins; D009842:Oligopeptides; D010080:Oxazoles; D010446:Peptide Fragments; D010972:Platelet Activating Factor; D044042:Receptors, Formyl Peptide; D053778:Thiazolidines; D014230:Triazoles; C527698:gelsolin (160-169); C052518:WEB 2086; D013481:Superoxides; D003571:Cytochalasin B; C059041:calyculin A; D016572:Cyclosporine; D019255:NADPH Oxidases; C050025:cyclosporin H; C037067:latrunculin A; D002118:Calcium
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