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

葡萄糖依赖性促胰岛素多肽（GIPR）和胰高血糖素样肽-1（GLP-1）受体是B G蛋白偶联受体（GPCR）家族的成员。与家族A GPCR相比，该受体家族没有被如此深入地研究。到目前为止，只存在胞外酶结合结构域的结构信息，导致受体活化的所有步骤仍然不清楚。由于家族B GPCR涉及几种重要的生理功能和疾病，如GIPR和GLP-1 R与2型糖尿病和肥胖症，因此需要填补这种信息的缺乏。因此，在本提案中，我们的目标是通过阐明分子信号传导机制、跨膜和细胞内结构来填补肠促胰岛素受体信息的缺乏。我们还希望探索这两种受体与其他GPCR的二聚/寡聚化特性，并结合使用生物信息学和体外以及体内研究的新开发的共激活变构激动剂的作用的信息。因此，本项目将结合联合收割机来调查这一星座中独特的具体问题。除了提高对GIPR和GLP-1 R的理解之外，我们还旨在揭示关于家族B/家族B以及家族A/家族A GPCR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-1 R相关生理调节机制的细节开辟新的视角。基于家族B GPCR结构的高度相似性，本研究假设了一般意义。

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.