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

J Biol Chem. 2020 Jul 31;295(31):10822-10830. doi: 10.1074/jbc.AC120.014770. Epub 2020 Jun 23.

Abstract

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.

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / metabolism*
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*
  • Second Messenger Systems*

Substances

  • GNA11 protein, mouse
  • GTP-Binding Protein alpha Subunits
  • Gpr139 protein, mouse
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid, mu
  • Cyclic AMP
  • GTP-Binding Protein alpha Subunits, Gq-G11