权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

磷酸化在调节 O3FAR-1 抗糖尿病作用中的作用

基本信息

批准号：
8495521
负责人：
Nader H Moniri
金额：
$ 40.98万
依托单位：
MERCER UNIVERSITY MACON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495521
关键词：
Affect Affinity Agonist Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antidiabetic Drugs Arrestins Binding Biomedical Research Blood Glucose Body Weight decreased Cell surface Coupling Cyclic AMP-Dependent Protein Kinases Cytoplasmic Tail Data Dietary Fats Doctor of Pharmacy Doctor of Philosophy Environment Equilibrium Family Funding Mechanisms G Protein-Coupled Receptor Kinase Family G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Goals Grant Health Sciences Hormones Human Inflammatory Insulin Insulin Resistance Intestinal Secretions Intestines Knowledge L Cells Laboratories Lead Light MAPK8 gene Mediating Messenger RNA Molecular Nature Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Omega-3 Fatty Acids Pain Pathway interactions Pharmacy facility Phospholipase C Phosphorylation Phosphotransferases Physiological Play Process Protein Isoforms Protein Kinase C Proteins Proteomics RNA Splicing Receptor Activation Recruitment Activity Regulation Reporting Research Research Activity Research Project Grants Role Scaffolding Protein Second Messenger Systems Signal Pathway Signal Transduction Signaling Protein Site Smell Perception Structure of beta Cell of islet Students Taste Perception Universities Unsaturated Fatty Acids Weight Gain arrestin 2 citrate carrier college glucagon-like peptide glucagon-like peptide 1 guanine nucleotide binding protein human GRK6 protein incretin hormone insight insulin secretion interest macrophage protein activation public health relevance receptor receptor expression response scaffold second messenger undergraduate student

项目摘要

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.

描述（由申请人提供）：omega-3脂肪酸受体（O3FAR1），通常也被称为GPR120，是一种G蛋白偶联受体（GPCR），已被证明可被长链不饱和脂肪酸，特别是那些属于omega-3脂肪酸（O3FA）家族的脂肪酸所痛苦。这种受体引起了相当大的兴趣，因为它能够刺激肠促胰岛素激素胰高血糖素样肽-1 （GLP-1）的肠道分泌，这种激素刺激胰腺b细胞导致胰岛素分泌，随后降低血糖。除了这种作用外，最近有研究表明，O3FAR1的激动作用通过抑制NF-KB和JNK促炎通路而产生深远的抗炎作用，当这些促炎通路在巨噬细胞中被激活时，会导致胰岛素抵抗、体重增加和2型糖尿病。我们的实验室已经揭示了两种人类O3FAR1亚型，O3FAR1长和短，作为替代mRNA剪接的结果而存在，我们的结果表明这些亚型受受体磷酸化的差异调节。我们的初步数据还表明，G蛋白偶联受体激酶-6 （GRK6）负责同源（激动剂诱导）O3FAR1亚型的磷酸化。重要的是，O3FAR1的抗糖尿病作用已被证明依赖于b-arrestin-2伴侣蛋白，而b-arrestin-2伴侣蛋白仅被grk磷酸化的受体募集，这表明受体磷酸化驱动O3FAR1的抗糖尿病活性。此外，我们的研究结果表明，调节受体表达和激动剂敏感性的O3FAR1的基础磷酸化是由蛋白激酶C （PKC）介导的，PKC对两种O3FAR1亚型的影响是不同的。我们提出了两个具体目标，这将为O3FAR1激活和信号调节机制提供结构指导，并将更好地理解两种O3FAR1亚型之间的信号传导差异。在特定目标一中，我们将使用蛋白质组学驱动的方法定位GRK和PKC介导的O3FAR1亚型磷酸化的特定位点。在具体目标二中，我们将评估这些磷酸化机制的功能意义，包括它们调节受体与b-arrestin-2的相互作用、激活Gaq/11-磷脂酶C/Ca+2信号通路、分泌GLP-1以及通过抑制JNK和NF-KB通路产生抗炎作用的能力。总的来说，这些结果将为所有已知的O3FAR1功能的磷酸化调控机制提供结构性的见解。由于美世大学药学与健康科学学院的研究活动完全依赖于学生的整合，因此该项目将允许研究生（博士）、专业学生（药学博士）和本科生在一个已建立的重要研究项目中合并，并将大大加强研究环境，与AREA资助机制的目标一致。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Carboxy-Terminal Phosphoregulation of the Long Splice Isoform of Free-Fatty Acid Receptor-4 Mediates β-Arrestin Recruitment and Signaling to ERK1/2.

游离脂肪酸受体 4 长剪接亚型的羧基末端磷酸调节介导 β-抑制蛋白招募和 ERK1/2 信号传导。

DOI：
10.1124/mol.119.117697
发表时间：
2020
期刊：
Molecular pharmacology
影响因子：
3.6
作者：
Senatorov,IlyaS;Cheshmehkani,Ameneh;Burns,RebeccaN;Singh,Kirti;Moniri,NaderH
通讯作者：
Moniri,NaderH

The role of free-fatty acid receptor-4 (FFA4) in human cancers and cancer cell lines.