Molecular Control of GPCR Signaling

G protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins with a huge variety of ligands. They have essential functions in health and disease, and are the molecular target for about one third of all current pharmaceuticals. Peptide- and protein-activated GPCRs are still underrepresented in the clinical intervention, but the number of peptide therapeutics is constantly increasing. Understanding how peptide ligands interact to their receptors, and which pathways are triggered downstream of receptor activation is an essential step toward the development of more potent and selective drugs. To address these questions, we use rational mutagenesis of receptor and ligands guided by structural models and measure multiple downstream pathways in cellulo. Moreover, protein-protein interactions are analyzed in cellular contexts to obtain spatio-temporal insights into receptor signaling. 

Evolution of neuropeptide GPCR specificity and signaling

Peptide-binding GPCRs are involved in the regulation of energy homeostasis and neuroendocrine regulation. Reflecting their essential physiologic functions, many GPCR systems are conserved down to basal animals. This deep evolutional conservation also opens avenues to study common and individual principles of receptor function. Moreover, relatively simple model organism might be used to study aspects of receptor signaling or test compounds in an in vivo context. The round worm C. elegans is a valuable model organism in this regard, as all main G protein pathways and an arrestin homolog are present. Moreover, it offers a vast genetic toolbox and its translucence enables fluorescent techniques. 

PEPTIDE Ligands for Orphan GPCRs

The endogenous ligands of many GPCRs are currently unknown. Recent bioinformatics analyses, however, show that several of these orphan receptors share sequence signatures of well-characterized peptide-activated GPCRs. In a collaborative project, we have identified regulated expression of some of these putative peptide-GPCRs in pathophysiologic states, suggesting untapped pharmacological potential. We aim to develop peptides to specifically target the receptors. Activity of the ligands will be mapped in several downstream signaling pathways to provide a palette of lead structures with diverse biological activities to modulate the physiological state of cells and tissues. For example, we are looking for peptides to improve cell survival in ischemic cells.


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