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Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Artikel i vetenskaplig tidskrift
Författare Simon Lind
Martina Sundqvist
R. Holmdahl
Claes Dahlgren
Huamei Forsman
P. Olofsson
Publicerad i Biochemical Pharmacology
Volym 166
Sidor 163-173
ISSN 0006-2952
Publiceringsår 2019
Publicerad vid Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Sidor 163-173
Språk en
Länkar dx.doi.org/10.1016/j.bcp.2019.04.03...
Ämnesord Neutrophils, Formyl peptide receptors, Receptor agonists, NADPH-oxidase, beta-Arrestin, Balanced agonism, chronic granulomatous-disease, formyl peptide receptors, reduced, oxidative burst, met-leu-phe, nadph-oxidase, inflammatory responses, respiratory burst, cyclosporine-h, activation, arthritis, Pharmacology & Pharmacy
Ämneskategorier Reumatologi och inflammation


Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and downstream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by MPO-H2O2 halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gaq-independent transient rise in intracellular Ca2+ and recruitment of beta-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.

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