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FPR2 signaling without beta-arrestin recruitment alters the functional repertoire of neutrophils
Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2017 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 145, p. 114-122Article in journal (Refereed) Published
Abstract [en]

G-protein coupled receptor (GPCR) biased agonism or functional selectivity has become an essential concept in GPCR research over the last years. Receptor-specific biased agonists selectively trigger one signaling pathway over another and induce a restricted/directed functional response. In this study, we aimed to characterize the concept of biased agonism for FPR2, a member of the formyl peptide receptor (FPR) subfamily of GPCRs. We show that the earlier described FPR2-activating pepducin F2Pal(10) is a biased FPR2 agonist. The effects of F2Pal(10) on neutrophil function differed in several aspects compared to those mediated by WKYMVM, a conventional FPR2-specific peptide agonist. Upon interaction with FPR2 expressed by neutrophils both F2Pal(10) and WKYMVM activated the PLC-PIP2-Ca2+ signaling pathway and the superoxide-generating NADPH-oxidase, but only WKYMVM activated the receptor to recruit B-arrestin. The functional consequences linked to a lack of B-arrestin recruitment were further explored, and we demonstrate that FPR2 desensitization occurred independent of B-arrestin. Despite this, reactivation of desensitized receptors achieved through a disruption of the cytoskeleton and through a novel FPR2 cross-talk mechanism with P2Y(2)R (the ATP receptor) and PAFR (the receptor for PAF) differed between F2Pal(10)-desensitized and WKYMVM-desensitized neutrophils. Further, the inability to recruit beta-arrestin was found to be associated with a reduced rate of receptor internalization and impaired chemotaxis in neutrophils. In summary, we provide experimental evidence of biased agonism for FPR2 and our data disclose critical roles of beta-arrestin in neutrophil chemotaxis and reactivation of desensitized receptors. (C) 2017 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD , 2017. Vol. 145, p. 114-122
Keywords [en]
Formyl peptide receptor, Pepducin, beta-Arrestin, Chemotaxis, Biased agonism, Desensitization, Reactivation
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-342657DOI: 10.1016/j.bcp.2017.08.018ISI: 000415784600012PubMedID: 28855087OAI: oai:DiVA.org:uu-342657DiVA, id: diva2:1186290
Funder
Swedish Research Council, 2015-005601Swedish Research Council, 2015-02448Åke Wiberg Foundation, M15-0051Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved

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Lomei, Jalal

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