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Reactivation of Desensitized Formyl Peptide Receptors by Platelet Activating Factor: A Novel Receptor Cross Talk Mechanism Regulating Neutrophil Superoxide Anion Production

Journal article
Authors Huamei Forsman
Karin Önnheim
Emil Andréasson
Karin Christenson
Anna Karlsson
Johan Bylund
Claes Dahlgren
Published in Plos One
Volume 8
Issue 3
Pages Article Number: e60169
ISSN 1932-6203
Publication year 2013
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages Article Number: e60169
Language en
Links dx.doi.org/10.1371/journal.pone.006...
Keywords protein-coupled receptors, c5a chemoattractant receptors, nadph-oxidase, response, intracellular calcium, ligand recognition, n-formylpeptide, beta-arrestins, phosphorylation, cytoskeleton, leukocytes
Subject categories Medical Biotechnology

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.

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