De-orphanization and characterization of transcellular and intracellular signaling mechanisms of the orphan G-protein coupled receptor GP158

Dr. Uwe Schulte (Institute of Physiology II, University of Freiburg)

The class III G-protein coupled receptor GPR158 is one of the most abundant GPCRs in brain, but neither its natural ligand(s) nor its physiological function(s) are presently known. By using an unbiased functional proteomic approach, we found that this receptor is associated with non-classical G protein subunits and signaling modulators forming large complexes (around 1 MDa). These complexes are localized in presynaptic compartments where they may interact with CaV2 channel-associated protein networks. We are using our proteomic approach, metabolomics, immunocytochemistry and functional assays as well as a knockout mouse model to identify natural ligands of GPR158, to determine the quaternary structure of the native receptor and to investigate its associated signaling pathways and presynaptic functions.