GPR139


G-protein coupled receptor 139 is a G protein-coupled receptor that in humans is encoded by the GPR139 gene. 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 vertebrate phylogenetic 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.
Research has shown that mice with loss of GPR139 experience schizophrenia-like symptomatology that is rescued with the dopamine receptor antagonist haloperidol and the μ-opioid receptor antagonist naltrexone.

Interactions with μ-opioid receptor

GPR139 appears to counter μ-opioid receptors through multiple mechanisms.
GPR139 constitutively promotes MOR desensitization. Expression of GPR139 at stoichiometric levels promoted β-arrestin recruitment to activated MORs. Appropriately, expression inhibited MOR — induced G protein activation. Overexpression of GPR139, but not stoichiometric expression, also decreased MOR at the cell surface.
GPR139 counteracts MOR signaling at secondary effectors. GPR139 expression inhibited GIRK channel activity through a Gq/11-dependent pathway. GPR139 activation increased cAMP production, also through a Gq/11-dependent pathway.

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Agonists