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

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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.