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The orphan receptor GPR139 signals via Gq/11 to oppose opioid effects

https://doi.org/10.1074/jbc.AC120.014770Get rights and content
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The interplay between G protein–coupled receptors (GPCRs) is critical for controlling neuronal activity that shapes neuromodulatory outcomes. Recent evidence indicates that the orphan receptor GPR139 influences opioid modulation of key brain circuits by opposing the actions of the µ-opioid receptor (MOR). However, the function of GPR139 and its signaling mechanisms are poorly understood. In this study, we report that GPR139 activates multiple heterotrimeric G proteins, including members of the Gq/11 and Gi/o families. Using a panel of reporter assays in reconstituted HEK293T/17 cells, we found that GPR139 functions via the Gq/11 pathway and thereby distinctly regulates cellular effector systems, including stimulation of cAMP production and inhibition of G protein inward rectifying potassium (GIRK) channels. Electrophysiological recordings from medial habenular neurons revealed that GPR139 signaling via Gq/11 is necessary and sufficient for counteracting MOR-mediated inhibition of neuronal firing. These results uncover a mechanistic interplay between GPCRs involved in controlling opioidergic neuromodulation in the brain.

G protein-coupled receptor 139 (GPR139)
brain
neuron
GPCR signaling
opioids
orphan receptor
medial habenula
G protein-coupled receptor (GPCR)
heterotrimeric G protein
opiate opioid
cell signaling
cellular regulation
adenylate cyclase (adenylyl cyclase)
GIRK channel

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Author contributions—H. M. S. and K. A. M. conceptualization; H. M. S. data curation; H. M. S., S. Z., and I. M. formal analysis; H. M. S., S. Z., and I. M. investigation; H. M. S. and K. A. M. writing-original draft; H. M. S., S. Z., I. M., B. G., and K. A. M. writing-review and editing; B. G. resources; B. G. and K. A. M. funding acquisition; K. A. M. supervision; K. A. M. project administration.

Funding and additional information—This work was supported by National Institutes of Health Grants DA036596 (to K. A. M.), DA048036 (to B. G. and K. A. M.), DA047771 (to H. M. S.), and DA048579 (to S. Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest—B. G. and K. A. M. have filed a patent on the utility of GPR139 as a drug target.

Abbreviations—The abbreviations used are:

    GPCR

    G protein–coupled receptor

    AC

    adenylyl cyclase

    MOR

    µ-opioid receptor

    GIRK

    G protein inward rectifying potassium

    BRET

    bioluminescence resonance energy transfer

    FSK

    forskolin

    PIP2

    phosphatidylinositol 4,5-bisphosphate

    mHb

    medial habenula

    HA

    hemagglutinin

    HASP

    HA signal peptide.