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Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.

Authors
  • Cheshmehkani, Ameneh1
  • Senatorov, Ilya S1
  • Dhuguru, Jyothi2
  • Ghoneim, Ola2
  • Moniri, Nader H3
  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA 30341, USA.
  • 2 Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, CT 06103, USA.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA 30341, USA. Electronic address: [email protected]
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Dec 15, 2017
Volume
146
Pages
139–150
Identifiers
DOI: 10.1016/j.bcp.2017.09.008
PMID: 28943238
Source
Medline
Keywords
License
Unknown

Abstract

Agonism of the G protein-coupled free-fatty acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with β-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and β-arrestin, while FFA4-L is intrinsically biased solely towards β-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for β-arrestin interactability and signaling. Given the significance of β-arrestin in the anti-inflammatory function of FFA4, the goal of this study was to examine the role of the C-terminal β-arrestin phosphosensor in FFA4 signaling induced by PMA and LPS in murine Raw 264.7 macrophages. Our data reveal for the first time that both FFA4 isoforms modulate PMA-induced ROS generation, and that abolishment of the FFA4-S, but not FFA4-L C-terminal phosphosensor, is detrimental to this effect. Furthermore, we show that while both isoforms reduce PMA-induced expression of COX-2, removal of the FFA4-S phosphosensor significantly decreases this response, suggesting that these effects of FFA4-S are β-arrestin mediated. On the contrary, FFA4-S, as well as the truncated C-terminal congener lacking the β-arrestin phosphosensor were both able to reduce LPS-induced NF-κB activity and ERK1/2 phosphorylation. However, FFA4-L and its corresponding mutant were incapable of modulating either, suggesting that these responses are mediated by G protein coupling. Taken together, our data reveal important structure-function and signaling differences between the two FFA4 isoforms, and for the first time link FFA4 to modulation of ROS in macrophages.

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