Hans Braüner-Osborne

Head of the PhD school and Professor at Department of Drug Design and Pharmacology, University of Copenhagen

Title: The orphan GPR139 G protein-coupled brain receptor: identification of ligands, signaling pathways and receptor structure

Abstract: The GPR139 receptor is a G protein-coupled receptor mainly expressed in the striatum and hypothalamus. Takeda recently initiated clinical studies of the use of a GPR139 agonist as treatment of negative symptoms associated with schizophrenia showing its potential value as target for brain diseases. In the lecture I will describe how we used a combination of computational methods and cellular pharmacological assays to identify aromatic amino acids (i.e. L-Phe and L-Trp) as putative endogenous agonists and develop potent surrogate agonists. Using a range of downstream (i.e. cAMP, Ca²⁺ and inositol monophosphate) and upstream G protein-activation assays we have made a detailed map of the signaling pathways employed by GPR139 and demonstrated that it primarily signals through the Gq/11 pathway to increase intracellular Ca²⁺ and inositol monophosphate levels. GPR139 is also able to recruit Gi/o proteins but paradoxically does not appear to activate this pathway downstream. Most recently we have collaborated with structural biologist to determine CryoEM structures of GPR139 in complex with either Gq or Gi proteins providing a structural platform to understand ligand-receptor and receptor-G protein interactions.

References

Vedel L, Nøhr AC, Gloriam DE and Bräuner-Osborne H (2020) Pharmacology and function of the orphan GPR139 G protein-coupled receptor. Basic Clin Pharmacol Toxicol 126: 35-46. 

Zhou Y, Daver H, Trapkov B, Wu L, Wu M, Harpsøe K, Gentry PR, Liu K, Larionova M, Liu J, N C, Bräuner-Osborne H, Gloriam DE, T H and Liu Z (2022) Molecular insights of ligand recognition and G protein coupling of the neuromodulatory orphan receptor GPR139. Cell Res 32: 210-213.

Please join us prior to the talk for coffee and cookies.