Cluster of Excellence, University of Freiburg

Spatiotemporal specificity and dynamics of metabotropic neurotransmitter signaling

Dr. Uwe Schulte (CIBSS-AI), Institute of Physiology II (Faculty of Medicine), University of Freiburg

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G-protein coupled receptors (GPCRs) are 7 transmembrane-domain containing proteins that convert local ligand binding into a diversity of cellular reactions. We recently resolved the interactomes of three distinct types of native neurotransmitter GPCRs, GABAB, dopamine receptors (DRs) and glutamate receptors (mGluRs) using comprehensive functional proteomics (AP-MS, csBN-MS). These analyses revealed novel determinants of G protein signaling kinetics (KCTDs 8,12,16, RGS9) and specific coupling to effectors (Cav2 channels, adenylate cyclase 5, HCN channels and linkers AJAP, amyloid-beta A4, homer proteins 1,2,3) that assemble into distinct macromolecular complexes, thus opening a route to molecular understanding of GPCR signaling entities and their extensive spatiotemporal dynamics. In this project, we will investigate the molecular diversity of these three model GPCRs in different spatio-temporal domains: Their tissue and cell-type specificity, their cellular biogenesis and remodeling during development as well as interaction dynamics in response to receptor (in)activation or changes in cellular conditions. Finally, we will investigate the functional significance of the identified GPCR constituents for receptor-signaling, subcellular localization and spatiotemporal dynamics.

 

(GABAB receptor assemblies, modified from Schwenk et al., 2016)