The role of phosphorylation in regulating the antidiabetic effects of O3FAR-1


Principal Investigator: Nader H Moniri
Abstract: DESCRIPTION (provided by applicant): The omega-3 fatty acid receptor (O3FAR1), also commonly referred to as GPR120, is a G protein-coupled receptor (GPCR) that has been shown to be agonized by long chained unsaturated fatty acids, specifically, those belonging to the omega-3 fatty acid (O3FA) family. This receptor has generated considerable interest due to its ability to stimulate intestinal secretion of the incretin hormone glucagon-like-peptide-1 (GLP-1), which stimulates pancreatic b-cells leading to insulin secretion and subsequently, decreases in blood glucose. In addition to this effect, it has recently been demonstrated that agonism of O3FAR1 leads to profound anti- inflammatory effects via inhibition of the NF-KB and JNK proinflammatory pathways, which when otherwise activated in macrophages, lead to insulin resistance, weight gain, and type 2 diabetes. Our laboratory has revealed that two human O3FAR1 isoforms, O3FAR1-long and short, exist as a consequence of alternative mRNA splicing and our results suggest that these isoforms are differentially regulated by receptor phosphorylation. Our preliminary data also show that G protein-coupled receptor kinase-6 (GRK6) is responsible for homologous (agonist-induced) phosphorylation of O3FAR1 isoforms. Importantly, the antidiabetic effects of O3FAR1 have been shown to be dependent on b-arrestin-2 partner proteins, which are recruited only to GRK-phosphorylated receptors, suggesting that receptor phosphorylation drives O3FAR1 antidiabetic activity. Additionally, our results demonstrate that basal phosphorylation of O3FAR1, which regulates receptor expression and agonist sensitivity, is mediated by protein kinase C (PKC), and that there are differential affects of PKC on the two O3FAR1 isoforms. We propose two specific aims that will provide structural guidance on mechanisms of O3FAR1 activation and signal regulation, and will also provide a better understanding of signaling differences between the two O3FAR1 isoforms. In specific aim one, we will localize the specific sites of GRK and PKC mediated phosphorylation of O3FAR1 isoforms using a proteomic- driven approach. In specific aim two, we will assess the functional significance of these phosphorylation mechanisms with respect to their ability to regulate receptor interactions with b-arrestin-2, activate the Gaq/11- phospholipase C/Ca+2 signaling pathway, secrete GLP-1, and produce anti-inflammatory effects via inhibition of JNK and NF-KB pathways. Collectively, these results will provide structural insight into mechanisms of phospho-regulation of all known O3FAR1 functions. Since research activities at Mercer University's College of Pharmacy and Health Sciences are fully dependent on student integration, this project will allow for incorporation of graduate (PhD), professional (PharmD), and undergraduate students within an established and significant research project, and will greatly strengthen the research environment, consistent with the goals of the AREA funding mechanism.
Funding Period: 2013-03-01 - 2016-02-29
more information: NIH RePORT

Top Publications

  1. pmc 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
    Rebecca N Burns
    Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA
    Biochem Pharmacol 87:650-9. 2014

Research Grants

Detail Information


  1. pmc 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
    Rebecca N Burns
    Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA
    Biochem Pharmacol 87:650-9. 2014
    ..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. ..

Research Grants30

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    ..In addition, the proposed studies will provide training opportunities for under-represented minority students at NCCU and prepare them for future careers in biomedical research. ..
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    Eugene B Chang; Fiscal Year: 2013
    ..Through its cost-effective, enabling technologies and services, the DDRCC has been a major factor in the advancement of scholarship and discovery in IBD and digestive diseases at the University of Chicago. ..
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    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
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    ..These studies of in vivo mechanisms of [unreadable]-cell proliferation may provide therapeutic approaches for diabetes mellitus in humans. ..
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    ..Understanding the effect of these interventions on glucose metabolism and GLP-1 secretion (amongst other gut hormones) will immeasurably increase our ability to develop new treatment strategies in individuals affected with diabetes. ..
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    Mitchell A Lazar; Fiscal Year: 2013
    ..abstract_text> ..
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    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
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    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..