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Functional and sign...
Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949
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- Lind, Simon, 1993 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research,Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE)
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- Sundqvist, Martina (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research,Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE)
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- Holmdahl, R. (författare)
- Karolinska Institutet
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- Dahlgren, Claes, 1949 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research,Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE)
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- Forsman, Huamei (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research,Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE)
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- Olofsson-Sahl, Peter (författare)
- Högskolan Väst,Grants and Innovation Office (GIO),Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177 (SWE
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- Engelska.
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 166, s. 163-173
- Relaterad länk:
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https://www.biorxiv....
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https://doi.org/10.1...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Nyckelord
- 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
- Neutrophils
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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