Functional role of the GPCR network in hypothalamic appetite regulation

点击翻译按钮获取中文摘要

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.