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Mechanisms of homologous and heterologous phosphorylation of FFA receptor 4 (GPR120): GRK6 and PKC mediate phosphorylation of Thr³⁴⁷, Ser³⁵⁰, and Ser³⁵⁷ in the C-terminal tail.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2014 Feb 15; Vol. 87 (4), pp. 650-9. Date of Electronic Publication: 2014 Jan 08. - Publication Year :
- 2014
-
Abstract
- Free fatty acid receptor 4 (FFA4), previously known as GPR120, is a G protein-coupled receptor that promotes numerous anti-inflammatory and antidiabetic effects upon its agonism by long chained unsaturated fatty acids. We have previously demonstrated that agonism of FFA4 with docosahexaenoic acid (DHA) and alpha-linoleic acid (ALA) facilitates rapid and transient phosphorylation of FFA4 expressed ectopically on the surface of HEK293 cells. However, the precise mechanisms that promote FFA4 phosphorylation remain elusive. In the current study, we examined the mechanisms behind both heterologous and homologous phosphorylation of FFA4 and set out to identify the foci of FFA4 phosphorylation. Our results demonstrate that basal and heterologous phosphorylation of FFA4 are mediated by protein kinase C (PKC), while G protein-coupled receptor kinase 6 (GRK6) plays the predominant role in DHA-mediated phosphorylation of FFA4. Furthermore, we identify Thr(347), Ser(350), and Ser(357) in the C-terminal tail as major sites of FFA4 phosphorylation. Concurrent mutation of these three sites leads to a FFA4 receptor that seemingly affects Gαq/11 signaling in a positive manner as demonstrated by heightened intracellular Ca(2+) responses following agonism with DHA. Importantly, this phosphodefective FFA4 mutant lacked the ability to promote β-arrestin-2 recruitment to the cell membrane. Since many of the functionally beneficial physiological effects of FFA4 are noted to be β-arrestin mediated, these findings could provide insight into the structural requirements for FFA4 function.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence
G-Protein-Coupled Receptor Kinases genetics
HEK293 Cells
Humans
Molecular Sequence Data
Mutation
Peptide Fragments genetics
Phosphorylation physiology
Protein Kinase C genetics
Receptors, G-Protein-Coupled genetics
Sequence Homology, Amino Acid
Serine genetics
Threonine genetics
G-Protein-Coupled Receptor Kinases metabolism
Peptide Fragments metabolism
Protein Kinase C metabolism
Receptors, G-Protein-Coupled metabolism
Serine metabolism
Threonine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 87
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24412271
- Full Text :
- https://doi.org/10.1016/j.bcp.2013.12.016