Structure-, localization-, metabolism- and ligand-dependent signaling bias of metab-olite-sensing GPCRs (C06*)

• Subject Area: Pharmacology ; Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

Our project will provide insights into the molecular mechanism and structural requirements of selected immune cell GPCRs activated by energy metabolites for their (localization- and agonist-dependent) signaling dynamics. Since metabolism is compartmentalized inside cells and locally generates agonists of metabolite-sensing GPCRs, we will analyze (i) the succinate receptor, (ii) the 5-oxo-eicosatetraenoic acid receptor and (iii) the medium-chain fatty acid receptor GPR84. We will use Förster- and bioluminescence resonance energy transfer technologies in heterologous expression systems to distinguish between signaling of a GPCR from the plasma membrane or intracellular compartments, and to gain insights into conformational receptor changes in living cells. Our approaches will then be applied to study GPCR trafficking and signaling in CRISPR/Cas9-gene edited THP1- or iPSC-derived macrophages.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Head: Privatdozentin Dr. Claudia Stäubert