Systematic profiling reveals broad G protein coupling and context‐dependent modulation of cyclic AMP by the orphan receptor GPR139
Boris Trapkov, Hans Bräuner, Alexander Sebastian HauserBackground and Purpose
G protein‐coupled receptors (GPCRs) are major drug targets, yet many orphan receptors remain poorly characterized. GPR139 has been implicated in CNS disorders, including schizophrenia and depression, but its signalling mechanisms remain unclear. This study aimed to systematically define the G protein coupling profile and downstream signalling behaviour of GPR139.
Experimental Approach
GPR139 signalling was profiled using BRET‐based G protein coupling assays, a panel of genetic G protein knockout cell lines, and complementary second messenger and arrestin recruitment assays to assess pathway engagement and functional outcomes.
Key Results
GPR139 exhibited broad coupling to multiple G protein families, including G i/o , G q/11 and G 12/13 , but not detectably to G s/olf in standard G protein coupling assays. Despite this, receptor activation increased intracellular cAMP through previously undetected G s coupling. This G s ‐driven response dominated under normal conditions, whereas G i/o ‐mediated cAMP inhibition became apparent when G s signalling was absent. Furthermore, structurally diverse agonists displayed ligand‐specific signalling profiles, indicating functional selectivity.
Conclusion and Implications
These findings reveal that GPR139 signalling is highly context‐ and ligand‐dependent, characterized by hidden coupling and dynamic integration of opposing pathways. This work advances understanding of GPCR signalling complexity and highlights the importance of cellular context in determining functional outcomes. The results provide a framework for studying orphan receptors and support the development of pathway‐selective therapeutic agents targeting GPR139 in CNS disorders, although translation to physiological systems remains to be established.