Genetic behavioral screen identifies an orphan anti-opioid system

Abstract

Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide–binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein–coupled receptor signaling principles.

Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective

“…In situ hybridization experiments showed that GPR139 and MOR are expressed in the same brain regions, including the medial habenula (MHb) and locus coeruleus (LC). Wang et al (2019) further provided electrophysiological evidence to support the functional interaction of MOR and GPR139. In cultured brain slices, GPR139 deficiency reduced the basal firing rate of MHb neurons and increased opioid sensitivity of LC neurons.…”

“…By whole genome sequencing of these mutants, they identified an orphan receptor FRPR-13 (its homologous protein GPR139 in mammals) as a negative regulator of MOR function in vivo. Wang et al (2019) further investigated the functional interaction of MOR and GPR139 in transfected HEK cells. In transfected HEK293T cells, MOR activation causes hyperpolarization of membrane potential due to opening of the G protein-coupled inwardly-rectifying potassium channels (GIRKs) and expression of GPR139 inhibited these abovementioned effects.…”

“…Thus, it was concluded that GPR139 regulates the function of MOR in a cell-autonomous manner. Wang et al (2019) finally investigated the role of GPR139 in morphine-induced behavioral changes in mice. They observed that GPR139 knockout (KO) mice had normal baseline learning, nociception, locomotor activities, and motor coordination.…”

Novel approaches leading towards peptide GPCR de‐orphanisation

“…GPR55 preferentially couples to G 12/13 and is a challenging receptor target, so further studies are required in G protein assays and relevant physiological contexts. Equally, the potential interaction of GPR55 with PAC 1 is worthy of investigation, particularly given the recent description of crosstalk between the μ‐opioid receptor and the orphan receptor GPR139 (Wang et al, ).…”

“…Interestingly, new large-scale transcriptome and proteome studies now have improved coverage of human peptides and proteins, which may also lead to the discovery of previously unappreciated protein products (Jiang et al, 2019). Orphan receptors may also require additional signalling partners that were absent from our experimental setups, such as other GPCRs or receptor activity-modifying proteins (Lorenzen et al, 2019;Wang et al, 2019). Alternatively, these receptors may not have peptide ligands or be constitutively active (Martin, Steurer, & Aronstam, 2015), or their activating molecules may be produced exogenously, as suggested for microbiome-derived ligands for GPR119 (Cohen et al, 2017).…”