Molecular principles of patho-physiological mechanisms of the incretin receptors with general implications for family B GPCRs

葡萄糖依赖的促胰岛素多肽(GIPR)和胰升糖素样肽-1(GLP-1)受体属于G蛋白偶联受体家族(GPCRs)。与A家族GPCRs相比，该受体家族的研究还不是很深入。到目前为止，只有细胞外激素结合域的结构信息存在，导致受体激活的所有步骤仍然不清楚。这种信息的缺乏需要填补，因为B家族GPCRs参与了几种重要的生理功能和疾病，如GIPR和患有2型糖尿病和肥胖症的GLP-1R。因此，在这项建议中，我们的目标是通过阐明分子信号机制、跨膜和细胞内结构来填补关于INTIN受体的信息不足。我们还希望利用生物信息学以及体外和体内研究，结合关于新开发的共激活变构激动剂的效果的信息，探索这两种受体与其他GPCRs的双/寡聚特性。因此，这个项目将结合现代技术来调查具体问题，这在这个星座中是独一无二的。除了加深对GIPR和GLP-1R的了解外，我们还旨在揭示B家族/B家族之间以及A家族/A家族GPCRs之间β细胞中同源和异源二聚体星座的新信息，这将为GIPR和GLP-1R相关生理调控机制的细节开辟新的视角。基于B家族GPCRs结构的高度相似性，本研究假设了一般意义上的含义。

The glucose-dependent insulinotropic polypeptide (GIPR) and the glucagon-like peptide-1 (GLP-1) receptors are members of the family B G-protein coupled receptors (GPCRs). In comparison to the family A GPCRs this receptor family is not investigated so intensively. So far, only structural information on the extracellular hormone-binding domain exists and all steps that lead to receptor activation are still unclear. This lack of information needs to be filled as family B GPCRs are involved in several important physiological functions and diseases such as the GIPR and the GLP-1R with type 2 diabetes and obesity. Therefore, in this proposal we aim to fill this lack of information for incretin receptors by elucidation of molecular signalling mechanisms, transmembrane and intracellular structures. We also want to explore di/oligomerization properties of both receptors with other GPCRs combined with information regarding effects of newly developed co-activating allosteric agonists using bioinformatics and in vitro as well as in vivo studies. This project, therefore, will combine modern techniques to investigate the specific issues, which in this constellation is unique. Beside our goal of improved understanding of the GIPR and GLP-1R, we also aim to reveal new information concerning homo- and heterodimer constellations in beta-cells between Family B/Family B, but also of Family A/Family A GPCRs, which would open new perspectives on the details of physiological regulation mechanisms related to GIPR and GLP-1R. Based on high similarity in the structure of family B GPCRs general implications are assumed from this study.