Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Allosteric receptor modulation of FFA2R turns natural agonists into potent activators of the superoxide generating neutrophil NADPH-oxidase

Jonas Mårtensson, André Holdfeldt, Martina Sundqvist, Michael Gabl, Lena Björkman, Huamei Forsman, Claes Dahlgren
doi: https://doi.org/10.1101/284935
Jonas Mårtensson
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
2Unit of Rheumatology, Sahlgrenska University hospital, Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
André Holdfeldt
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martina Sundqvist
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Gabl
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lena Björkman
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
2Unit of Rheumatology, Sahlgrenska University hospital, Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Huamei Forsman
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claes Dahlgren
1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: Claes.Dahlgren@microbio.gu.se
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Acetate, agonist for the free fatty acid receptor 2 (FFA2R/GPR43), triggers an increase in the cytosolic concentration of free Ca2+ in neutrophils without any assembly of the superoxide generating NADPH-oxidase. We show that the phenylacetamide compound 58 (Cmp58; (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide, lacking a direct activating effect on neutrophils, acts as a positive allosteric FFA2R modulator that turns acetate into a potent activating agonist that triggers an assembly of the NADPH-oxidase. The NADPH-oxidase activity could be further increased in neutrophils treated with the pro-inflammatory cytokine TNF. Many neutrophil chemoattractant receptors are stored in secretory organelles but no FFA2R mobilization was induced in neutrophils treated with TNF. The receptor selectivity was demonstrated through the inhibition of the neutrophil response induced by the combined action of acetate and Cmp58 by the FFA2R antagonist CATPB. Allosteric modulators that positively co-operate with natural FFA2R agonists and prime neutrophils in their response to such agonists, may serve as good tools for further unraveling the physiological functions of the FFA2R and its involvement in various diseases. In this study, allosteric modulation of FFA2R is introduced as a novel receptor selective mechanism to prime neutrophils to produce increased amounts of reactive oxygen species.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted March 19, 2018.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Allosteric receptor modulation of FFA2R turns natural agonists into potent activators of the superoxide generating neutrophil NADPH-oxidase
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Allosteric receptor modulation of FFA2R turns natural agonists into potent activators of the superoxide generating neutrophil NADPH-oxidase
Jonas Mårtensson, André Holdfeldt, Martina Sundqvist, Michael Gabl, Lena Björkman, Huamei Forsman, Claes Dahlgren
bioRxiv 284935; doi: https://doi.org/10.1101/284935
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Allosteric receptor modulation of FFA2R turns natural agonists into potent activators of the superoxide generating neutrophil NADPH-oxidase
Jonas Mårtensson, André Holdfeldt, Martina Sundqvist, Michael Gabl, Lena Björkman, Huamei Forsman, Claes Dahlgren
bioRxiv 284935; doi: https://doi.org/10.1101/284935

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cell Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3512)
  • Biochemistry (7352)
  • Bioengineering (5329)
  • Bioinformatics (20277)
  • Biophysics (10026)
  • Cancer Biology (7749)
  • Cell Biology (11319)
  • Clinical Trials (138)
  • Developmental Biology (6440)
  • Ecology (9958)
  • Epidemiology (2065)
  • Evolutionary Biology (13336)
  • Genetics (9362)
  • Genomics (12592)
  • Immunology (7714)
  • Microbiology (19046)
  • Molecular Biology (7447)
  • Neuroscience (41063)
  • Paleontology (300)
  • Pathology (1231)
  • Pharmacology and Toxicology (2139)
  • Physiology (3164)
  • Plant Biology (6866)
  • Scientific Communication and Education (1274)
  • Synthetic Biology (1898)
  • Systems Biology (5318)
  • Zoology (1089)