| First Author | Cheshmehkani A | Year | 2017 |
| Journal | Biochem Pharmacol | Volume | 146 |
| Pages | 139-150 | PubMed ID | 28943238 |
| Mgi Jnum | J:252560 | Mgi Id | MGI:6107339 |
| Doi | 10.1016/j.bcp.2017.09.008 | Citation | Cheshmehkani A, et al. (2017) Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal beta-arrestin phosphosensor in Raw 264.7 macrophages. Biochem Pharmacol 146:139-150 |
| abstractText | 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 beta-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Galphaq/11 and beta-arrestin, while FFA4-L is intrinsically biased solely towards beta-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for beta-arrestin interactability and signaling. Given the significance of beta-arrestin in the anti-inflammatory function of FFA4, the goal of this study was to examine the role of the C-terminal beta-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 beta-arrestin mediated. On the contrary, FFA4-S, as well as the truncated C-terminal congener lacking the beta-arrestin phosphosensor were both able to reduce LPS-induced NF-kappaB 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. |
