Systematic profiling reveals broad G protein coupling and context-dependent modulation of cyclic AMP by the orphan receptor GPR139

20/08/2026

AI Summary

GPR139 couples broadly to Gi/o, Gq/11 and G12/13 and paradoxically increases cAMP via previously undetected Gs coupling.
Context determines outcome: Gs-driven cAMP signalling dominates normally, while Gi/o-mediated cAMP inhibition emerges when Gs signalling is absent.
Structurally diverse agonists show ligand-specific signalling and functional selectivity, informing pathway-selective drug development for CNS disorders; physiological translation remains to be established.

Br J Pharmacol. 2026 Aug 20. doi: 10.1111/bph.70606. Online ahead of print.

ABSTRACT

BACKGROUND 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.

PMID:42619573 | DOI:10.1111/bph.70606

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