Topic summary
GPR139
G-protein coupled receptor 139 (GPR139) is a G protein-coupled receptor that in humans is encoded by the GPR139gene. It is coupled to the Gq/11 pathway, which is functionally opposite to the Gi/o inhibitory signaling of classical opioid receptors. It is evolutionarily ancient and highly conserved across vertebratephylogenetic taxa, suggesting a fundamental role in neurophysiology. In humans, the receptor is exclusively expressed in the brain tissue, particularly in the medial habenula, septum, striatum, and hypothalamus.
Historically classified as an orphan receptor, activated only by L-tryptophan and L-phenylalanine in very high concentrations, GPR139 was deorphanized in 2025 as a novel, non-canonical opioid receptor specific to dynorphins, which selectively promote G protein activation of the receptor. It is proposed to function as a molecular homeostatic brake for excessive canonical opioid and D2 receptor signaling. Tryptamine is also a potent agonist of the GPR139 and has been reported to regulate sleep.
Research has shown that mice with loss of GPR139 experience schizophrenia-like symptomatology that is rescued with the dopamine receptor antagonisthaloperidol and the μ-opioid receptorantagonistnaltrexone.