Melanocortin-4 Receptor Traffic and Signaling

Melanocortin-4 受体交通和信号传导

基本信息

批准号：
8274821
负责人：
GIULIA BALDINI
金额：
$ 30.12万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274821
关键词：
ART protein Abbreviations Accounting Agonist Area Arrestins Back Binding Biochemical Biological Assay Brain Brain Diseases Cell membrane Cell surface Cellular biology Coupled Data Defect Desire for food Disease Dissociation Eating Embryo Endocytosis Endoplasmic Reticulum Energy Metabolism Epitopes Fluorescence Fluorescence Microscopy Food Energy G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors GRK GTP-Binding Proteins Green Fluorescent Proteins Hemagglutinin Hormones Human Hypothalamic structure Immunoelectron Microscopy Individual Kidney Knowledge Ligands Link Location Melanocortin 4 Receptor Melanocortin 4 receptor mutation Melanocyte stimulating hormone Membrane Molecular Mood Disorders Neuroblastoma Neurons Obesity Parkinson Disease Pathogenesis Pathway interactions Peroxidases Phosphorylation Play Population Positioning Attribute Post-Translational Protein Processing Protein Dephosphorylation Protein Family Proteins Rattus Receptor Cell Receptor Signaling Recycling Residencies Role Route Schizophrenia Signal Transduction Sorting - Cell Movement Testing Ubiquitination Variant alpha-Melanocyte stimulating hormone base desensitization endoplasmic reticulum stress energy balance feeding hepatocyte growth factor-regulated tyrosine kinase substrate human MC4R protein loss of function member neuroblastoma cell new therapeutic target nexin novel obesity prevention palmitoylation paraventricular nucleus prevent protein activation protein folding protein misfolding receptor receptor binding receptor function receptor recycling response tetramethylrhodamine trafficking trans-Golgi Network

项目摘要

Project Summary Melanocortin-4 receptor (MC4R) is a G-protein-Coupled Receptor (GPCR) expressed in many areas of the brain including the paraventricular nucleus of the hypothalamus. At this location, MC4R expressing neurons receive signals generated by other neurons that release the orexigenic hormone alpha-MSH, which binds and activates MC4R. MC4R mutations account for most of the monogenetic defects that cause obesity, indicating a role in appetite control. Preliminary data from the PI show that MC4R functions as an atypical GPCR because, rather than being endocytosed in response to agonist stimulation, the receptor is constitutively internalized and recycled back to the plasma membrane. In addition it is found that alpha-MSH sequesters MC4R from the plasma membrane by blocking the receptor in an intracellular localization, rather than by increasing its rate of endocytosis. Preliminary results from the PI also indicate that several variants linked to human obesity have defective traffic along the biosynthetic pathway and are retained in the endoplasmic reticulum (ER). The central hypothesis of this proposal is that MC4R cell traffic is essential to modulate receptor activity. In Aim 1, by using a combination of fluorescence-based and biochemical assays, it is determined whether agonist-dependent post-translational modifications of MC4R and binding to specific factors control recycling of the receptor back to the plasma membrane and receptor re-sensitization. Immunoelectron microscopy will be used to determine the intracellular distribution of endogenous MC4R in neurons of the paraventricular nucleus of rat hypothalamus. In Aim 2 the hypothesis is tested that obesity-linked variants that are inefficiently expressed at the plasma membrane are retained in the ER as misfolded proteins, self-associate, and are inefficiently degraded. Possible routes to rescue cell surface expression of such variants will be investigated. It is anticipated that these studies will broaden our understanding of traffic and signaling of MC4R and of obesity- linked variants and will help find new targets for therapies against obesity.

项目概要 Melanocortin-4 受体 (MC4R) 是一种 G 蛋白偶联受体 (GPCR)，表达于大脑的许多区域，包括下丘脑的室旁核。在在此位置，表达 MC4R 的神经元接收其他神经元产生的信号，这些信号释放促食欲激素 α-MSH，该激素结合并激活 MC4R。 MC4R 突变是导致肥胖的大部分单基因缺陷的原因，这表明控制食欲的作用。来自 PI 的初步数据表明 MC4R 的功能是非典型 GPCR，因为，而不是响应激动剂而被内吞刺激后，受体被组成性内化并循环回血浆膜。此外，还发现 α-MSH 从血浆中隔离 MC4R 通过阻断细胞内定位的受体，而不是通过增加其内吞作用的速率。 PI 的初步结果还表明与人类肥胖相关的几种变体在生物合成过程中存在缺陷途径并保留在内质网（ER）中。中心假设为该提议认为 MC4R 细胞交通对于调节受体活性至关重要。在目标 1 中，通过结合使用基于荧光和生化的检测，可以确定 MC4R 是否存在激动剂依赖性翻译后修饰并与特定因素控制受体再循环回质膜，并且受体再敏化。免疫电子显微镜将用于确定室旁核神经元内源性 MC4R 的细胞内分布大鼠下丘脑。在目标 2 中，测试了与肥胖相关的变异的假设在质膜上低效表达并以错误折叠的形式保留在 ER 中蛋白质自缔合，且降解效率低下。拯救细胞的可能途径将研究此类变体的表面表达。预计这些研究将拓宽我们对 MC4R 和肥胖的交通和信号传导的理解相关变体将有助于找到治疗肥胖的新靶标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Constitutive cholesterol-dependent endocytosis of melanocortin-4 receptor (MC4R) is essential to maintain receptor responsiveness to α-melanocyte-stimulating hormone (α-MSH).

黑皮质素 4 受体 (MC4R) 的组成型胆固醇依赖性内吞作用对于维持受体对 α-黑素细胞刺激激素 (α-MSH) 的反应性至关重要。

DOI：
发表时间：
2012-06-22
期刊：
影响因子：
0
作者：
McDaniel, Faith K;Molden, Brent M;Mohammad, Sameer;Baldini, Giovanna;McPike, Lakisha;Narducci, Paola;Granell, Susana;Baldini, Giulia
通讯作者：
Baldini, Giulia

Exposure of MC4R to agonist in the endoplasmic reticulum stabilizes an active conformation of the receptor that does not desensitize.

MC4R 在内质网中暴露于激动剂可稳定受体的活性构象，不会脱敏。