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Functional role of the GPCR network in hypothalamic appetite regulation

GPCR 网络在下丘脑食欲调节中的功能作用

基本信息

批准号：
130026914
负责人：
Professorin Dr. Heike Biebermann
金额：
--
依托单位：
Institut für Experimentelle Endokrinologie (CVK)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/130026914?language=en
关键词：
Functional role GPCR network hypothalamic

项目摘要

Overweight and obesity are one of the most challenging health problems worldwide. Detailed understanding of mechanisms involved in energy metabolism is the prerequisite to combat this disease. Here, especially mechanisms involved in central regulation of energy balance are of utmost importance. For pharmacological intervention G protein coupled receptors (GPCR) represent excellent targets. In hypothalamic weight regulation some GPCRs are known to play an important role like melanocortin 4 receptor (MC4R), melanocortin 3 receptor (MC3R) or ghrelin receptor (growth hormone secretagogue receptor, GHSR). For using these GPCR as drug targets extensive understanding of all features of these receptors is the prerequisite. However, so far for drug design di- or oligomerization is only rarely considered. During the current funding period we could identify a receptor region of the MC4R that is involved in dimerization. Disturbance of dimer formation resulted in modified signalling properties compared to the dimeric state. This information is potentially of interest for drug development. Besides homodimerization we could demonstrate that GPCRs involved in weight regulation are able to heteroligomerize. In this constellation functional features of either receptor could be modified as demonstrated for the MC3R/GHSR heterodimer. We speculate that beside GPCR-GPCR interaction additional interactions with other proteins might be possible. For unravelling the network of MC3R and MC4R interaction we establish a library screen based on bimolecular protein complementation assay which was suitable to identify new interaction partners for MC3R and MC4R. The most interesting candidate was the identification of glucose transporter 1 (Glut1) as interaction partner of MC3R. We could demonstrate that Glut1 is a negative modulator of MC3R function. The fact that interaction of a GPCR and a transporter was found which is of functional relevance indicates that the spectrum of possible interaction is larger than previously assumed. Therefore the overall goal of the applied funding period is the systematic and detailed examination of all so far identified interaction partners of MC3R and MC4R in vitro and in vivo. For this task methods used for determination of signalling properties and protein-protein interactions will be widen and new methods will be establish that allow the determination of the functional role of newly identified MC3R and MC4R interaction partners. Obtained data from the applied funding period will provide valuable new information on the interacting network of GPCRs involved in energy homeostasis which is much more complex than so far supposed.

超重和肥胖是全世界最具挑战性的健康问题之一。详细了解能量代谢的机制是对抗这种疾病的先决条件。在这里，能量平衡的中枢调节机制尤为重要。对于药物干预，G蛋白偶联受体（GPCR）是很好的靶点。在下丘脑体重调节中，已知一些gpcr发挥重要作用，如黑素皮质素4受体（MC4R）、黑素皮质素3受体（MC3R）或生长素受体（生长激素促分泌素受体，GHSR）。为了使用这些GPCR作为药物靶点，广泛了解这些受体的所有特征是先决条件。然而，到目前为止，在药物设计中很少考虑二聚或寡聚。在目前的资助期内，我们可以确定参与二聚化的MC4R受体区域。与二聚体状态相比，二聚体形成的干扰导致信号特性的改变。这一信息可能会对药物开发产生潜在的兴趣。除了同型二聚外，我们可以证明参与重量调节的gpcr能够异聚。MC3R/GHSR异源二聚体表明，这两个受体的功能特征都可以被修饰。我们推测除了GPCR-GPCR相互作用外，还可能与其他蛋白质相互作用。为了揭示MC3R和MC4R相互作用的网络，我们建立了一个基于双分子蛋白互补试验的文库筛选，该筛选适合于鉴定MC3R和MC4R新的相互作用伙伴。最有趣的候选是葡萄糖转运蛋白1 （Glut1）作为MC3R的相互作用伙伴的鉴定。我们可以证明Glut1是MC3R功能的负调制器。发现GPCR与转运体的相互作用具有功能相关性的事实表明，可能的相互作用范围比以前假设的要大。因此，申请资助期的总体目标是系统和详细地检查迄今为止确定的MC3R和MC4R在体外和体内的相互作用伙伴。为了完成这项任务，用于确定信号特性和蛋白质-蛋白质相互作用的方法将被扩大，并将建立新的方法，以确定新发现的MC3R和MC4R相互作用伙伴的功能作用。从申请资助期获得的数据将为参与能量稳态的gpcr相互作用网络提供有价值的新信息，该网络比迄今为止认为的要复杂得多。